Using Lasers to Treat Vitreous Floaters: Laser Vitreolysis in the UK and Europe

In July, I decided to write about the use of lasers to treat eye floaters. I found three doctors in the United States specializing in this technique. After obtaining information about their practices, I wrote about their experiences in treating floaters. That article has drawn worldwide response, with over 1000 page views and still counting. In doing the research for that writeup, I learned that there were other doctors, in other parts of the World, also treating floaters and decided to contact some of these and see if they would be interested in sharing their stories as well.

I was able to identify at least six doctors in the UK and in Europe who perform laser vitreolysis. I  asked them to fill out the same questionnaire that I had used for the American doctors, and five of them agreed, with one declining. These are the stories of the five who agreed to participate.

Laser Vitreolysis in the UK and Europe

I won’t get into the details of what floaters are, what causes them and how are they treated. The answers to those questions and more are contained in the first report. (Using Lasers to Treat Vitreous Floaters: Laser Vitreolysis)

In that report I also discuss what laser vitreolysis is all about – what kind of floaters can be treated, and how the procedure is done.

What I would like to introduce in this report, is a short synopsis of the discovery of the ophthalmic YAG laser and its first use in treating anomalies in the vitreous.

The Ophthalmic YAG Laser and its Use in the Vitreous

As I have previously reported, the first laser, a ruby laser, was invented in 1960 by Ted Maiman at Hughes Research Laboratories in California. The first YAG laser was built in 1964 by Guesic, Marcos and Van Uteit at Bell Labs, and was a continuous wave (CW) laser. CW YAG lasers are still  used in surgery for cutting and coagulation of tissue. The first pulsed lasers for ophthalmology (Q-switched and mode-locked) were independently developed by Danielle Aron-Rosa in France (mode-locked) and Franz Fankhauser in Switzerland (Q-switched) in the mid-1970s and commercialized several years later by several companies.

Mode-locked lasers were difficult to maintain and eventually were replaced by Q-switched devices, which are smaller and more easily maintained.

In 1983, the first ophthalmic YAG lasers won FDA marketing approval in the U.S. and by 1984 or 1985, there were at least thirty different companies marketing Q-switched YAG lasers to the ophthalmic community. Today, there are probably five or six  major suppliers of ophthalmic YAGs, and these lasers are found in just about every general or refractive ophthalmologist’s office, primarily for performing posterior capsulotomies (the removal of opacified posterior capsular tissue following intraocular lens insertion during cataract removal procedures).

It was probably Dr. Fankhauser, using his Lasag Q-switched laser in the late 1970s or early 1980s that first performed work in the vitreous to cut vitreous strands, using special optics that he had designed. According to Dr. Scott Geller, the first doctor to specialize in this technique in the U.S., he heard about the work that Dr. Fankhauser was doing and visited him in Switzerland in the early 1980s. He was impressed with what he saw and decided to begin using his ophthalmic YAG laser in the vitreous upon his return to the United States.

Dr. Geller probably performed his first laser vitreolysis in 1985 or 1986 and began to specialize in treating floaters by about 1989.

Dr. John Karickhoff believes he did his first floater, an opacified string stretched across the visual axis in early 1990, with no knowledge that the procedure had been done elsewhere. Thinking that the procedure was only suitable for strands he did not do it again until 1999. He himself had developed a bothersome floater, learned about Dr. Geller and had Dr. Geller treat his floater. He then observed Dr. Geller perform the procedure on isolated floaters, learned about the technique used and brought this technique back into his office and began performing the procedure in earnest at that time.

The third U.S. doctor to specialize in treating floaters, Dr. James Johnson, had opened a LASIK practice in 2007. He had seen Dr. Karickhoff’s web site and bought his book Laser Treatment of Floaters. He found the technique intriguing, enjoyed some early success in treating floaters and, within a year, had closed his LASIK practice and began specializing in performing laser virtreolysis.

That brings us to the doctors specializing in this technique in the UK and Europe.

European Doctors Specializing in Treating Eye Floaters

In my research, I identified six doctors who use lasers to treat eye floaters. Five agreed to participate in this survey. I will begin with the three doctors doing the procedure on the European Continent.

Bern, Switzerland – Dr. Franz Fankhauser

First, you must understand, this is the son of the inventor of the pulsed YAG laser. When I first made contact with Dr. Fankhauser, I thought I had reached the father, but quickly learned that the father, who is in his mid-80s, is retired, but taught his son how to treat floaters and still comes into the office once a week to check up on his son.

Dr. Franz Fankhauser (the younger) follows in his father’s footsteps in practicing ophthalmology.

He obtained his MD degree from the University of Bern Medical School, Bern, Switzerland. He did  further studies at the following medical schools: Stanford University Medical School, Dept. of Ophthalmology; Community Hospital Neumünster, Dept. of Surgery, Zurich, Switzerland;  Tuft’s University Medical School, Dept. of Ophthalmology, Boston, USA; Bascom Palmer Eye Institute, University of Miami, Miami, USA; Residency at University of Zurich, Dept. of Ophthalmology, Zurich, Switzerland; UMDS at the University of London; an MBA degree from the Leipzig Graduate School of Management, and his PhD from the Dept. of Ophthalmology of the University of Dresden, Dresden, Germany. He has also worked  for two ophthalmic laser producers, Schwind Eye-Tech-Solutions and Wavelight GmbH.

In May 2008, he joined his father’s eye practice, Augenzentrum Fankhauser AG as CEO, and continues in his father’s tradition of providing excellent ophthalmic care to his patients.

Treating Eye Floaters

Dr. Fankhauser began treating eye floaters in 1993. He got involved because of his father as a logical continuance of his father’s family business. He uses, as did his father, a LASAG Microrupter II YAG laser for his work on floaters, using a prototype delivery system. Dr. Fankhauser told me that he has treated hundreds of patients, with about an 80% success rate, defined as a significant improvement of the disturbance. It usually takes betweeen two to five treatment sessions, depending on the type of floater being treated. The practice charges approximately 2900 CHF (Swiss francs), including both pre- and post-operative examinations.

His practice can be reached at the following address:

Franz Fankhauser MD PhD MBA

Augenzentrum Fankhauser AG

Gutenbergstrasse 18

CH-3011 Bern

Switzerland

Tel. +41 31 301 9880

Fax. +41 31 301 9881

www.augenzentrum-fankhauser.ch

info@augenzentrum-fankhauser.ch

Antwerp, Belgium – Professor. Marie-Jose Tassignon

Professor Marie-José Tassignon completed her undergraduate study and her degree in ophthalmology at the University Hospital Brussels (AZ VUB) and her doctoral degree at Rijksuniversiteit Leiden. She began her professional career at the University Hospital Brussels in the early 1980s, working her way up to become Associate Professor in ophthalmology. In 1991 she joined the Ophthalmology Department at the University Hospital Antwerp, and in 2008 was named its Medical Director. It was the first Department of Ophthalmology in Belgium to offer refractive surgery to  its patients.

Since 1991, she has lead the department and it has experienced a steady growth. Professor Tassignon has established an international reputation in the field of ophthalmology, mainly in the subspecialities of cataract, corneal and vitreo-retinal surgery. She has proven to be an outstanding clinician and successful director of the Centre for Ophthalmology over the past 15 years. Not only has she managed to advance medical care, but the Centre's research activities have also expanded and earned international recognition.

Professor Tassignon has developed and patented an intraocular lens that has zero posterior capsule opacification – eliminating the need for post-catarct laser surgery to remove the usual opacification. This particular lens is called "bag-in-the-lens" which is in contrast to the classical "lens-in-the-bag" concept of fixation. This new lens in not implanted in the capsular bag but supported by the capsular bag.

In addition to being Medical Director of Antwerp University Hospital, she has previously chaired both the European Society of Cataract and Refractive Surgery (ESCRS) and the European Board of Ophthalmology (EBO).

Treating Eye Floaters

Although Professor Tassignon does not take eye floater patients directly, she does treat those patients that have been referred by other ophthalmologists and who fit her treatment criteria(1). She began treating eye floaters with the YAG laser in 1999. She started these treatments because of her familiarity with YAG laser surgery in ophthalmology (secondary cataracts). She recognized the challenge to treat vitreo-retinal stands for vaso-proliferative retinal pathologies. She uses the Lasag Microrupter II laser, as did Prof. Fankhauser, its inventor.

To date, because her practice is not a primary floater clinic, but only by referrals, as noted above, she has treated about 150 patients. Her success rate depends upon the type of floater encountered, and since only “well suspended” floaters respond well, her success rate is only about 25% to all type of floaters. Most floaters take either one or two laser sessions, rarely three. Since there is a dedicated social security number for treating floaters in Belgium, the charge is about 250 euros.

Professor Tassignon can be reached at her office at the University Hospital Antwerp as shown below:

Marie-José Tassignon, MD, PhD, Febo

Head of the Department of Ophthalmology

University Hospital Antwerp, Belgium

UZA - Ophthalmology Centre

Wilrijkstraat 10

B-2650 Edegem

Belgium

tel. 00 32 3 821 33 77

fax. 00 32 3 825 19 26

http://www.healthcarebelgium.com/index.php?id=193

marie-jose.tassignon@uza.be

1. T.Van Dorselaer, F.Van de Velde, M.J.Tassignon: Eligibility criteria for Nd-YAG  laser treatment of high symptomatic vitreous floaters. Bull.Soc.belge.Ophtalmol., 280, 15-22, 2001

Nantes, France – Dr. Eric Mehel

After eight years of medical school at the University René Descartes PARIS,  Dr. Eric Mehel moved to Nantes to specialize in ophthalmology. This, after his eight years in residence at CHU Hotel Dieu, in Paris under the direction of Professors QUERE and PECHEREAU. At the Hotel Dieu Hospital he held various posts, including as Head of Clinic and Hospital Doctor. He also taught in the Ophthalmology Department at the Hospital.

He now specializes in all areas of ophthalmology, including cataract removal and refractive surgery. Dr. Mehel is the head ophthalmologist in Nantes at a private practice, in association with several other specialized ophthalmologists. They are grouped around a technology platform that allows efficient treatment of all ophthalmic areas and diseases.

The treatment of floaters with a YAG laser is done only in Dr. Mehel’s office.

Dr Mehel operates exclusively at the Sourdille Clinic, located in Nantes, acclaimed as a  reference center dedicated exclusively to ophthalmology.

Treating Eye Floaters

Dr. Mehel began treating eye floaters about two years ago. He did this because he saw the need to help people suffering from this problem. He knew about the use of YAG lasers to do this because of his knowledge of the work of Dr. Geller in the U.S. He uses the same Microrupter II laser from Lasag as does Dr. Geller. To date, he has treated about 300 patients. He describes “success” as allowing his patients to resume a normal life. It usually takes between 3-6 sessions to remove floaters and he charges approximately 250 euros for the service.

His practice can be reached at the following address:

Docteur Eric Mehel

88 rue des Hauts pavées,

44000 Nantes Clinique Sourdille,

Place Anatole France 44 000

Nantes, France

Tél :06  42 30 41 16

Tél : 02 51 77 10 50

http://www.corps-flottants.org/

http://operation-myopie.org/

dr.emehel@ophtalmologiste.com

And, two of the doctors performing the procedure in the UK:

Altrincham Cheshire, England – Mr. Brendan Moriarty

Mr Brendan J. Moriarty MA (Cantab), MB, B.Chir, FRCS FRC Ophth, MD  qualified in medicine from Cambridge University. He trained in ophthalmology at the Bristol Eye Hospital, the Western Ophthalmic Hospital (London), the Prince Charles Eye Unit (Windsor) and St Paul's Eye Hospital (Liverpool). In 1987 he was appointed as fellow to the Dept. of Glaucoma at the Moorfields Eye Hospital in London.

He also has extensive experience in third world eye care and was Medical Director to Project ORBIS, the internationally renowned 'flying eye hospital'. He remains a visiting expert in glaucoma and cataract surgery to Project ORBIS and is a regular volunteer and advisor. In addition, he spent two years as fellow to the Medical Research Council, devising laser treatment to prevent blindness from sickle cell disease. During his time in Jamaica, he established free cataract facilities and introduced the rubella prevention programme to tackle childhood blindness. He was recognised for this work by the International Man of Achievement award in 1989.

Brendan Moriarty now holds a consultant post at Leighton Hospital in Crewe, Cheshire. He consults privately in Altrincham at the Prospect Eye Clinic, and in Macclesfield at the Regency Hospital.

His special interests are cataract surgery, glaucoma and laser treatment of floaters and visual rehabilitation in macular degeneration. He is a member of the UK, European and American Societies of Cataract and Refractive Surgeons and he is regularly invited to lecture internationally on glaucoma and macular degeneration. NICE, the National Institute for Clinical Excellence, have recently recognised Mr. Moriarty's expertise in surgery for Macular Degeneration by appointing him Special Advisor.

Treating Eye Floaters

Mr. Moriarty first started using the YAG laser in the vitreous in 1986 when he was working in Jamaica. He did a study with Professor Jampol from Chicago on the use of the YAG laser to treat tractitional retinal detachments in patients with sickle cell retinopathy. He then started using the YAG laser to treat floaters about 10 years’ ago after reading some articles, particularly Larry Benjamin’s article in the British Journal of Ophthalmology. He got involved because he had become very aware of how disturbing it was to have floaters when he had one temporarily in his left eye and questioned the received wisdom of many Health Care Professionals, namely that ‘nothing could be done’.

As he puts it, “I started treating floaters because I have had a significant number of patients who are severely disabled by it.” The laser he presently uses is the Lumenis Aura. He has had this for over 2 years’ and is delighted with its performance, particularly in light of the fact that often one needs to use about 1,000 to 1,500 mjs per eye in a treatment session. The only modification he has used for his delivery system is the Karickhoff contact lens for treating the mid-vitreous.

He claims he treats about 100 patients per year, so that he has treated approximately 1000 patients over the ten years he has been treating floaters.

Success very much depends on the type of floaters and their position. He presented a paper at MEACO in Dubai in 2007 where he indicated that he was able to get between 60% and 70% of patients cured and about a further 20% significantly improved. There remains about 10% of patients who do not feel that the treatment has made any difference. This is largely caused by floaters being within 2 mm of the retina and therefore not accessible by the laser.

It usually takes about 2 – 4 sessions to treat patients which are separated by a period of 4 – 6 weeks. For private patients without insurance he charges £950 per eye. This includes all treatments required to treat one eye.

His practice can be reached at:

Brendan J Moriarty

Consultant Ophthalmic Surgeon

The Prospect Eye Clinic

Suite 1.2, 20 Market Street

Altrincham, Cheshire

WA14 1PF

To make appointments or refer a patient to the Prospect Eye Clinic, please book online or contact Deryn Fawcett:

Phone: :  00 44 (0) 161 927 3177

Fax: 00 44 (0) 161 927 3178

Email: deryn@brendanmoriarty.com

www.prospecteyeclinic.com

www.brendanmoriarty.com

London, England – Mr. Steven Bailey

Mr. Steven Bailey completed his specialist training at Moorfields Eye Hospital, and was included on the Specialist Register in 1992. He has been part of the corneal and external eye disease and contact lens services at Moorfields since the late 1980s. He has been in private medical practice as an ophthalmologist since 1989.

He has a special interest in keratoconus and is experienced in corneal collagen cross-linking (C3-R).

Mr. Bailey has been performing laser assisted refractive and therapeutic procedures since 1992. He trained in LASIK surgery in November 1995 and became one of the pioneers of this surgery in the UK. He was amongst the first eye surgeons in the UK accredited in the application of WavePrint wave-front guided laser treatments. He is one of only a few surgeons in the UK who have gained the Royal College of Ophthalmologists Certificate of Competence in laser refractive surgery and is an examiner for this qualification..

He was one of the early users of botulinum toxin ( BOTOX Cosmetic) at Moorfields and he is very experienced in its application for medical and cosmetic uses.

He lectures internationally and teaches on medical and optometric post-graduate training programmes. He has had papers on human physiology and ocular medicine and surgery published in peer-reviewed journals.

Treating Eye Floaters

Mr. Bailey became involved in treating eye floaters in 1999, because of patient demand for this service. He uses both Zeiss and Litetechnica YAG lasers in treating floaters, and has treated about 200 patients.

In terms of success, he said that all but one patient had improvement of their symptoms, and that those with discrete, axial, floaters do best. He defines success as a subjectively satisfactory improvement in symptoms without complications. It usually takes either one of two sessions to remove floaters. In his office, the charge for treatment is the cost of a one-hour consultation and necessary tests at  395, with the laser treatment costing  500 plus  175 for the use of the laser facility.

His practice can be reached at the following address:

Mr C Steven Bailey, BSc FRCS FRCOphth DO

99 Harley Street

London

W1G 6AQ

England

T: +44 (0)7973 691727

F: +44 (0)20 7431 2008

www.csbailey.com

http://www.eyecarelondon.com/html/contact.html

(This is the contact form from his website to make an appointment.)

The Netherlands

Since this article was written, I have heard from another European ophthalmologist that wrote to tell me that he, too, has a practice to treat floaters, in the Netherlands. Dr. Feike Gerbrandy said that he has treated a little over 100 eyes since he began using his YAG laser to treat floaters in September 2009. He is still treating about 30 of those eyes that require further laser treatment, but that his success rate to date is about 92%.

In addition, he is working with a vitreoretinal surgeon, Dr. Marco Mura, who has performed vitrectomies on four patients with floaters that were so extensive that the laser treatment failed.

Dr. Gerbrandy can be contacted at the following address:

Feike Gerbrandy, MD

Oogziekenhuis Zonnestraal
's-Gravelandseweg 76
1217 ET Hilversum
Netherlands
0031-8 88 77 77 77

www.oogfloaters.nl
info@floaterlaser.nl

Apeliotus Vision Science’s AdaptDx Device for Early Detection of Dry AMD – A First Report

I follow The Massachusetts Eye and Ear Infirmary (MEEI) on Twitter, and late last month I noticed a message looking for candidates to participate in a trial using the Apeliotus AdaptDx to detect the early stages of  AMD. This was the first I had heard about either this company or the device, and my natural curiosity compelled me to look further into both.

All I could find online was a document from 2008, describing the startup of this company out of Atlanta. I did not know the president, John Edwards, but I was quite familiar with one of the company’s advisors, Steve Martin (former CEO of CibaVision). So, I reached out to both and John agreed that I was one of the good guys, and that he could work with me to bring this writeup, about what he and his company were doing, to you.

History of the Company

This is the story of how an entrepreneur started a company, Apeliotus Technologies, with the express goal to seek out medical technologies residing within universities in the South East, for evaluation towards the possibility of licensing them for possible commercialization.

John Edwards, previously on the management teams of three successful university spin-off companies, started Apeliotus in 2003, to address the “development gap” that exists between academic innovations from research universities in the South East. His idea is to spend between three to five years and up to $3 million validating both the technology and its potential market value, and if he finds a technology meeting his criteria, launch a dedicated spin-off venture for commercialization or licensing to an established industry company or partner.

That is how he came across the technology under development by Dr. Gregory Jackson, then at the University of Alabama at Birmingham (UAB). Dr. Jackson is a psychophysicist  specializing in vision and the effects of aging on vision. He stumbled upon the concept that some seniors had good dark adaptation – the quick response from, for example being blinded by a camera’s flash (photobleaching) and then re-adapting to seeing normally again, while some seniors took a much longer time to re-adapt. In fact, he found an anomaly in those seniors who had the early and later stages of age-related macular degeneration and those who did not.

Seniors with AMD had much slower re-adaption times than seniors who did not show signs of AMD.

Edwards & Jackson licensed the ideas and intellectual property from  UAB in March 2004, and started the spin-off company Apeliotus Vision Science. (With Dr. Jackson moving to Pennsylvania State University in 2008, the company is now headquartered in Hershey, PA.)

The company has applied for and won three Small Business Innovation Research (SBIR) grants and three Foundation Grants amounting to about $1.5 million, in order to fund the building of prototypes of its AdaptDx diagnostic devices, and to run the clinical trials necessary to gain FDA approval of the device. An additional $1 million in venture capital funds has been obtained from Life Sciences Greenhouse and Ben Franklin Technology Partners.

The company has applied for a 510(k) as a Class I device, based on its initial clinical trials on a small number of patients, and expects to receive that approval by the end of this year or early in 2011.

An additional clinical trial of up to 200 people, for final validation, is currently underway at three independent sites including Mass Eye & Ear Institute in Boston; the Wilmer Eye Institute at Johns Hopkins University in Baltimore; and at the Hershey Eye Center at Penn State University in Hershey. Results are expected to be available by the second half of next year. If the results follow those obtained to date – with 90% sensitivity and 100% specificity, the company hopes to begin marketing its AdaptDx diagnostic device during next year's fourth quarter.

The Problem

Blindness due to the onset of age-related macular degeneration (AMD) is the leading visual problem among those over the age of 65 in the United States and the world. It affects over 30 million people worldwide, including one in six over age 65 and one in three over age 75. In the U.S., there are currently over 18 million people with the disease. Fortunately, only about 10% are afflicted with the “wet” form, which causes blindness, while about 90% have the “dry” form, which is generally a precursor to the wet form. However, as shown in the accompanying table, about 8 million people in the U.S. have intermediate dry AMD, and 15%-20% of them will progress into wet AMD within about 5 years. In 2007, it was estimated by Market Scope, based on NEI/NIH data, that 1.4 million Americans had advanced wet AMD (CNV or choroidal neovascularization) and, without intervention and treatment, could lose significant vision or become blind. With the aging of the population and people living longer, these numbers will only increase.

Table 1.  AMD Cases in the U.S. by Type and Stage in 2007 (based on estimates by Market Scope, made from NEI and NIH data developed in 2000. Ophthalmic Market Perspectives, Market Scope, June 2008.)


Unfortunately, there is no effective diagnostic for the early detection of the dry form of AMD to allow intervention before the conversion to the wet form of the disease and the onset of significant vision loss.

A Possible Solution

Apeliotus Vision Science has developed a simple diagnostic device for the detection of the early to advanced stages of dry age-related macular degeneration. It is called the AdaptDx.

A commercial prototype of the AdaptDx is shown in Figure 1. It is based on a functional test of dark adaptation (the transition from being light-adapted to being dark-adapted). Specifically, the AdaptDx measures the rate of recovery of scotopic sensitivity, or dark vision, after photobleaching. Patients are exposed to a standard camera flash and then asked to indicate when they can detect a progressively dimmer spot of light presented as a randomly timed flash at the edge of the macula. Testing is completely non-invasive, and can be performed by an unskilled operator in ≤ 10 minutes with a minimum of patient burden.

Figure 1. The AdaptDx.

Physiological Basis of AMD

AMD is related to a breakdown of the retinal pigment epithelium (RPE)/Bruch’s membrane complex in the retina, and measurement of dark adaptation is essentially a bioassay of the health of this membrane complex. During the AMD disease course, the RPE/Bruch’s function deteriorates, hampering nutrient and oxygen transport to the photoreceptors. As a side effect, the photoreceptors exhibit impaired dark adaptation because they require these nutrients for replenishment of photopigments and clearance of opsin, a group of light sensitive proteins found in the photoreceptors --  to regain dark vision sensitivity after light exposure. Consequently, impaired dark adaptation is a hallmark of early AMD.

Figure 2 compares recovery of dark vision following photobleaching for a normal older adult, an early-stage AMD patient and a late-stage AMD patient. The time for recovery to a benchmark sensitivity (the “rod intercept”) is used as a diagnostic parameter. There is a marked deterioration of dark adaptation speed as the disease progresses. Indeed, studies at UAB have shown that dark adaptation is impaired up to four years before AMD is clinically evident.

Figure 2. Dark adaptation curves showing marked impairment for early and late AMD patients.

Demonstration Studies

Proof-of-concept for the AdaptDx has been validated in replicate studies at University of Alabama at Birmingham (UAB) and Penn State University (PSU). The UAB study (N=26) compared two cohorts of old adults: 17 having early-to-late AMD and 9 having normal retinas (as determined by fundus photography grading). Diagnostic sensitivity and specificity were 88% (two false negatives) and 100% (no false positives). The effect size was extremely large, with mean recovery time for AMD patients twice that of normal older adults. Furthermore, the degree of impairment tracked disease severity. The PSU study (N=47) compared 33 AMD patients with 14 normal older adults.  Diagnostic sensitivity and specificity were 91% (three false negatives) and 100% (no false positives), and mean recovery time for AMD patients was again twice that of normal old adults. In a separate study of 40 normal adults and AMD patients, test-retest reliability was shown to be very high (intraclass correlation of 0.95). As previously noted, a final validation study is ongoing at MEEI, Johns Hopkins, and PSU. It is comparing 140 patients having early-to-advanced AMD with 60 normal older adults. The study is scheduled to be completed by the end of 2010.

Figure 3. Dark adaptation times for normal adults and AMD patients in UAB Study. Data are mean rod intercept ±1 SD. Dotted line is cut point between normal and abnormal.

Business Aspects

Clinical Practice

The AdaptDx has tremendous potential as a tool for AMD screening by optometrists and ophthalmologists. Glaucoma screening, which is routine practice, provides a direct precedent. Visual field testing using instruments such as the Humphrey perimeter is the standard for glaucoma screening. Although dark adaptometers and visual field perimeters measure completely different disease states, they are very similar in size, operation and cost. Both are psychophysical tests. Both take between 5 and 20 minutes depending on whether an initial screening test (for baseline evaluation) or a full diagnostic analysis is being performed. Both have reimbursements between $60 and $80 per test. The only difference is that, unlike glaucoma, everyone over age 50 years of age is at risk for AMD. Consequently, there is a larger need for AMD screening.

Treatment Options

Early identification of dry AMD enables a growing array of options to delay or limit vision loss. First, the Age-Related Eye Disease Study (AREDS) demonstrated that anti-oxidant supplements such as Ocuvite PerserVision (Bausch & Lomb) and I-CAPS (Alcon Labs) can delay or even halt the progression from dry AMD, where vision loss is minimal, to wet AMD, where vision loss is severe.

Second, Lucentis and Avastin (Genentech) are FDA-approved drugs that can halt – and in some cases reverse -- the vision loss associated with wet AMD, if caught in its very early stages. However, there is a direct correlation between the effectiveness of these drugs and beginning treatment as soon as possible after conversion from dry to wet AMD. Identification of AMD while it is still in the mid to late dry stage will allow physicians to monitor progression toward wet AMD and begin treatment with Lucentis or Avastin at the earliest possible time.

Editors Note: I have done an extensive writeup on another device that can be used by patients in the advanced stages of dry AMD to monitor their progression to the very earliest stages of the wet form of the disease. This device, produced by Notal Vision, can be prescribed by a retinal physician to be used at home by the patient in the advanced stage of dry AMD. If used as directed (three times a week), it will detect the changeover and send a warning to a call center that then informs the patient’s doctor to call him/her into his office for treatment with one of the anti-VEGF drugs (Lucentis or Avastin) to ward off significant vision loss before it can occur. This device would be a perfect compliment to the AdaptDx.)

Finally, there are at least a dozen therapeutics in development for direct treatment of dry AMD, including fenretinide (Sirion Therapeutics), OT-551 (Othera Pharmaceuticals), compstatin/POT-4 (Potentia Pharmaceuticals), ACU-4429 (Acucela) and anti-CFH (Optherion). Apeliotus Vision Science is collaborating with several of these companies on the use of dark adaption to identify likely responders and track treatment progress.

(Editors Note: I have also posted a complete look at all of the new drugs under development for treating the dry form of AMD. Please see AMD Update 6.)

Reimbursement

The Centers for Medicare and Medicaid Services (CMS) and private insurers such as BlueCross/BlueShield already offer generous reimbursements for dark adaptation testing (CPT Code 92284). For example, the 2008 CMS reimbursement for dark adaptation (w/interpretation and report) was $69 in Atlanta, GA. This compares with $79 for fundus photography (w/interpretation and report) and $67 for an intermediate visual field examination. Based on the similar operating and cost characteristics for glaucoma screening via visual field examination (which is a profit center in optometry and general ophthalmology practices), AMD screening via dark adaptation should also be commercially attractive.

However, even without reimbursement there are compelling patient care and economic incentives for dark adaptation testing.

1. Elevated Examination – Patients with a documented eye condition merit greater scrutiny during an office visit and more frequent office visits. Routine screening of all patients over age 50 would identify a significant number of individuals with otherwise undetected dry AMD. These patients would then be eligible for comprehensive examinations vs. the basic examinations that would otherwise be given (and eligible for the commensurately higher reimbursement). Furthermore, they could be encouraged to schedule semi-annual visits to monitor their condition rather than the annual or even less frequent visits that might be appropriate in the absence of an AMD diagnosis.


2. Patient Recruitment – Unfortunately, most people only visit an optometrist or ophthalmologist when they are in need of a new eye glass prescription or they have a dramatic change in vision. In regions with a large number of senior citizens, almost all of whom either know or have heard about someone with AMD, offering free AMD screening would be a strong inducement for individuals to schedule an office visit and result in physicians building larger practices.

In Conclusion

With the aging of the population, as the average person lives to an older age, the need for screening and detecting AMD, a normal aging occurrence, before it can cause significant vision loss becomes an ever important function for the medical community.

The development and marketing of a device such as the AdaptDx by Apeliotus Vision Science appears to be on track for accomplishing such a function. It, along with the device from Notal Vision, can become important diagnostic tools in the armamentarium of ophthalmic practitioners.


For further information about Apeliotus (and some of the other innovations they are pursuing) or about Apeliotus Vision Science and its AdaptDx, John Edwards can be contacted in Atlanta at jedwards@apeliotus.com or by phone at (404) 875 9561. Dr. Gregory Jackson can be reached at Apeliotus Vision Science in Hersehy, PA at eyeresearcher@yahoo.com, or (717) 531-6774.

Selective Laser Trabeculoplasty (SLT) Technology for Treating Open-Angle Glaucoma to be Featured on the Discovery Channel

I received the following press release from Lumenis, that it’s SLT technology was going to be featured on the Discovery Channel’s Health Heroes program during the September 24-27, 2010 period. It got me thinking about how I have always been a believer that SLT is a superior first option for treating open-angle glaucoma, and that this announcement would give me the opportunity to reiterate this again in my online Journal.

The announcement also gives me the opportunity to provide you with links to my previous writings on the subject of treating glaucoma, which you can find following the news release.

Lumenis Selective Laser Trabeculoplasty (SLT) Technology to be featured on the Discovery Channel, highlighting its significant clinical benefits to glaucoma patients worldwide

Lumenis Ltd. one of the world's largest medical laser companies and a global developer, manufacturer and seller of laser, light-based and radiofrequency devices for ophthalmic, aesthetic, and surgical applications, announced today that its patented SLT technology for managing open-angle glaucoma will be featured on the Discovery Channel program, Health Heroes, during September 24-27, 2010.

“We are very excited that Selective Laser Trabeculoplasty (SLT), a breakthrough technology for managing open-angle glaucoma that our company developed and brought to market, is being recognized by the Discovery Channel”, said Dov Ofer, President and CEO of Lumenis. “This validates yet again how this remarkable technology has positively impacted and improved the lives of hundreds of thousands of glaucoma patients worldwide.”

SLT technology was pioneered and introduced to the medical market by Lumenis in 2001, based on the scientific and clinical work of Mark Latina MD and colleagues. It is a safe and non-invasive in-office procedure that effectively reduces eye pressure in patients with open-angle glaucoma -- the most common form of glaucoma. The SLT mechanism of action does not rely on costly medications. Instead, it utilizes an advanced non-thermal energy beam that selectively targets specific melanin-containing cells within the eye. This produces a natural biological response that leads to pressure drop very shortly after the treatment is performed.

“Glaucoma patients worldwide struggle with a debilitating condition that, if not carefully and properly managed, can result in significant vision loss and even blindness,” said Kfir Azoulay who heads Lumenis Vision’s Global Marketing Organization. “SLT offers these patients the benefit of a clinically proven treatment that can halt the progression of the disease and maintain their vision.” Mr. Azoulay also added: “We take immense pride in the fact that our technology has helped preserve the eyesight of hundreds of thousands of glaucoma patients worldwide, and has also reduced their dependency on daily intake of costly medications which also produce detrimental side effects.”

Health Heroes is an exciting program that identifies and explores today's latest medical advances in all areas of health and wellness. Developed through the real life experiences of industry experts, physicians and their patients, this series combines scientific and clinical data with touching story telling, to deliver the best and most accurate information to viewers.

The program boasts interviews with renowned glaucoma specialists and technology experts, among them Jason Bacharach MD, Jorge Alvarado MD, Alan Robin MD, Tom Brunner (President of the Glaucoma Research Foundation), and others.

Editor’s Note: If you missed the program while it was on the air, you can catch it on the Lumenis website.


About Lumenis

Lumenis, one of the world's largest medical laser companies, is a global developer, manufacturer and distributor of laser and light-based devices for surgical, ophthalmic and aesthetic applications, with more than 800 employees worldwide.Lumenis has nearly 250 patents, over 75 FDA clearances, an installed base of over 80,000 systems and presence in over 100 countries. Lumenis endeavors to bring the finest state of the art technology products to the market, fulfilling the highest standards of excellence, quality and reliability, delivering premium value and service to its customers. The name Lumenis is derived from the Latin words meaning "Light of Life" highlighting the light which is the basis of our technologies used to enhance life. For more information about Lumenis and its products, please visit: www.lumenis.com


Articles About the Use of SLT in Treating Primary Open-Angle Glaucoma:

Following are the articles I have written and  posted online on treatments for glaucoma and on the use of SLT, in particular, for treating this disease.

SLT: New Treatment for Glaucoma Becomes Available; Ocular Surgery News, May 15, 2001.

In this column, written for Ocular Surgery News, I interviewed the inventor Mark Latina, of the new laser treatment for glaucoma, selective laser trabecloplasty, and wrote about its application compared to argon laser trabeculoplasty, the then standard of care.

Advances in the Treatment of Glaucoma; Optistock Industry Overview, Fall 2001.

This article was published by Optistock.com as part of an Industry Overview. My piece, on glaucoma, was a comprehensive overview of the then current thoughts on treatment of this significant disease.

An Update on the Use of SLT for Treating Glaucoma, Fall 2006

In this piece, following the 2006 AAO Meeting, I picked up Michael Lachman’s article about SLT becoming a first-line therapy for open-angle glaucoma, which follows closely my thoughts, first published in 2001..

A Primer on the Use of Stem Cells in Ophthalmology

I recently came across an interesting news release from International Stem Cell Corporation (ISCO) announcing that it had formed a new business unit, Cytovis, to focus on stem cell programs in ophthalmology, including CytoCor for the cornea and CytoRet for the retina.

That got me thinking about how little I knew about what was going on in stem cell research in ophthalmology, despite having written about two developments in the field, the London Project to Cure Blindness and the University of California Irvine (UCI) program to develop an artificial retina based on stem cell research.

I decided to become better informed by taking a closer look at what was happening in this field, and presenting that story.

Introduction

Commenting on a EuroRetina Meeting held earlier in 2008, John Morrow of Newport Biotech Consultants noted, as reported by Ophthalmology Times Europe in September 2008, “Stem Cells are looked upon as either an ethical train wreck or the gateway to the alleviation of human illness, depending on which side of the political spectrum one resides. This unfortunate notoriety has resulted in unprecedented coverage in the media, but this has not done much to advance the cause of this technology. Yet recent ophthalmologic research suggests that the medical applications of stem cells hold notable promise for the treatment of ocular degenerative conditions and that realization of this potential may come about in the near future.”

I think Dr. Morrow’s thoughts eloquently sum up the subject. Stem cell research is politically charged but holds tremendous promise for the future, especially in ophthalmology.

What are Stem Cells?

Every organ and tissue in our bodies is made up of specialized cells that originally come from a pool of stem cells in the very early embryo (“embryonic stem cells”). Throughout our lives we rely to a much more limited degree on rare deposits of stem cells in certain areas of the body (“adult stem cells”) to regenerate organs and tissues that are injured or lost, such as our skin, our hair, our blood and the lining of our gut.

Stem cells are like a blank microchip that can be programmed to perform particular tasks. Under proper conditions, stem cells develop or “differentiate” into specialized cells that carry out a specific function, such as in the skin, muscle, liver, or in the eye. Additionally, stem cells can grow extensively without differentiating and give rise to more stem cells. These two characteristics, “pluripotency” and “self-renewal”, distinguish stem cells from other cells in the body and give stem cells their tremendous therapeutic promise for a wide range of degenerative diseases.

The Four Types of Stem Cells

The four most commonly used and described classes of stem cells are "embryonic stem cells" (embryonic SCs, or human embryonic stem cells hESCs), "induced pluripotent stem cells" (ipSCs), "adult stem cells" (adult SCs) and "parthenogenetic stem cells" (hpSCs).

Besides the embryonic and adult stem cells already used by the body, two other classes of stem cells are increasingly used in medical research, the induced pluripotent stem cells and human parthenogenetic stem cells.

Embryonic stem cells are derived from fertilized human eggs ("oocytes") in the very early stages of development. They are truly pluripotent, in principle enabling them to become any body tissue and thus providing their tremendous clinical potential. However, embryonic stem cells are associated with significant ethical, political and religious controversy since a fertilized egg, under the right circumstances, has the potential to develop into a human. Another major (albeit much less published) issue with embryonic stem cells is that, since they essentially are a transplant from one person (the fertilized egg) to another person (the recipient patient) (“allogeneic treatment”), therapeutic cells and tissues derived from embryonic stem cells can be expected to provoke an immune response from the recipient and be rejected.

In contrast, induced pluripotent stem cells are adult and fully differentiated cells (e.g. skin cells) that are chemically, physically, genetically or otherwise driven back to earlier developmental stages. While creation of such cells does not involve the use or destruction of a fertilized egg, it does require dramatic changes in gene expression that may have unknown biological impact and likely will be subject to substantial scrutiny by regulatory authorities before any approval for therapeutic use. Also, due to immune rejection, induced pluripotent stem cells have to be derived from the patient themselves (“autologous therapy”) which significantly limits clinical use and adds time and cost that will be increasingly difficult to implement in cost-contained health care systems worldwide. Finally, induced pluripotent stem cells cannot be used for hereditary diseases therapy because of bearing the same genetic defects.

Adult stem cells are rare cells found in various organs or tissues in a person that have a limited ability to differentiate into cells with specific functions. They are older and less powerful than other types. While these stem cells do not require use or destruction of a fertilized egg or extensive manipulation of gene expression, they are rare and hard to identify and they generally proliferate poorly, thus making it hard to produce therapeutic amounts.

Parthenogenetic stem cells are derived from activated human oocytes. Parthenogenesis is a form of asexual reproduction in some amphibians and plants but does not occur naturally in mammals, including humans. ISCO scientists have discovered a process for chemical activation of human eggs, similar to what the sperm does in normal fertilization but without any involvement of a male sperm. ISCO claims that this process results in hpSCs that are as pluripotent and proliferate as embryonic stem cells, yet avoid the ethical, political and religious controversy around use or destruction of human embryos with potential for viable human life. Furthermore, since there is no forced change of gene expression patterns, hpSCs are not likely to face the same safety and regulatory hurdle as induced pluripotent stem cells. Most importantly and unique relatively to all other stem cell classes, hpSCs can be produced in a simplified immunogenetic (“homozygous”) form that enables each line to be an immune match for many millions of people (ISCO’s first line is an immune match for an estimated 75 million people worldwide).

International Stem Cell Corporation has kindly provided the table below that describes the characteristics of the various types of stem cells.

Table 1. Characteristics of the Four Types of Stem Cells 

(By clicking onto the table and opening it into a new tab or window, it will can be enlarged for easier reading.)

(Editors Note: Please take into account that the company specializes in Parthenogenetic stem cells.)

What are the Applications for Stem Cells in Ophthalmology?

The Front of the Eye

Scarred and degenerative corneas represent one prime area of research for the use of stem cells. Because of a lack of donated human cornea bank corneas for transplantation, especially in populous nations such as India and China (and the third World countries), the use of stem cells to regenerate damaged corneal tissues could become lifesavers in those countries where blindness due to damaged corneas is prevalent.

The Middle of the Eye

There are only a few research programs using stem cells for the middle areas of the eye, specifically in treating glaucoma. NeoStem has said that they are working with Schepens Research Institute in using the company’s VSELs (very small embryonic-like stem cells) in the treatment of glaucoma (and AMD), and Stemedica claims to be working with the Fyodorov Eye Institute in Moscow on a glaucoma program.

I know of no programs targeting the lens.

The Back of the Eye

Most of the research efforts appear to be focused on the back of the eye, specifically retinal tissue and diseases. Areas of interest that I have identified include regeneration of retinal epithelial (RPE) cells for the treatment of both dry and wet forms of age-related macular degeneration (AMD); replacement of damaged photoreceptors; the growth of artificial retinas, again for treating AMD; and direct treatments for diseases such as retinitus pigmentosa (RP), retinopathy of prematurity (ROP), diabetic retinopathy (DR), Stargardts disease (Stargardt Macular Dystrophy) (SMD), and retinal veinr occlusions (RVO).

Who is Involved and What are They Doing?

In the following section, are short reviews of the seven companies identified as doing research with stem cells in ophthalmology, including who they are collaborating with, what type of stem cells they are using, and what ophthalmic diseases/eye structures they are attempting to treat.

The table at the end of this section summarizes the results.

Advanced Cell Technology Incorporated (Santa Monica, CA)

Advanced Cell Technology (ACT) is currently focused on using its proprietary technologies to generate stable cell lines including retinal pigment epithelium (RPE) cells for the treatment of retinal diseases such as age-related macular degeneration (AMD).

ACT has demonstrated the ability to rescue visual function in rats through implantations of RPE cells derived from hESCs, in collaboration with Raymond Lund at the University of Utah. The rats, blinded because of RPE degeneration, were injected with embryonic stem RPE cells into the subretinal space, which resulted in the restoration of their ability to see light and attained approximately 70% of the spatial acuity of a normal, healthy rat. In addition, the hESC derived RPE cells did not appear to cause any side effects in the animals.

The company subsequently entered into a sponsored research agreement with Oregon Health and Science University (OHSU). The company is collaborating with Drs. Lund, Richard Weleber and Peter Francis at the Casey Eye Institute to conduct preclinical studies for its RPE program. The company is also in discussion with the OHSU team to conduct a Phase I human clinical trial in this area.

Furthermore, after discussions with the FDA, ACT has contracted with a leading contract research organization to commence work on an extensive preclinical program. The company has conducted safety studies necessary for the initiation of a clinical trial. The protocols utilize therapeutic dosage levels of RPE cells, based on the rat studies, for the treatment of retinal disease. The company has been able to produce an unlimited amount of RPE cells for this clinical use. In addition, the company has developed novel methodology to cryopreserve the RPE cell products.

In late July 2010, ACT announced that it had submitted documentation to address FDA concerns with the company’s plans to initiate a Phase I/II multicenter study using its line of hESC RPE cells to treat patients with Stargardt’s Macular Dystrophy (SMD).

Editors Note: Stargardt's disease (also known as fundus flavimaculatus and Stargardt's macular dystrophy) is the most common form of inherited juvenile macular degeneration. Inherited as an autosomal recessive trait, it is a severe form of macular degeneration that begins in late childhood, leading to legal blindness. Stargardt's disease is symptomatically similar to age-related macular degeneration, and it affects approximately one in 10,000 children.

Unanswered Questions:

I asked a company spokesperson the following questions and received a few answers:

In the study of treating Stargardt’s, who will be heading the clinical work?

That information is not currently available.

How many patients will be enrolled?

Twelve.

How many clinical centers will be participating?

Multiple, but the exact number has not yet been announced.

When will the first results be reported?

Again, that has not yet been announced.

I guess that we will just have to await further details.

AstraZeneca (London, UK and Wilmington, DE (US))

AstraZeneca and University College London (UCL) have announced a research partnership, to develop medicines that use stem cells to repair damaged eyesight in people with diabetes. Under the three-year partnership, funded by the drugmaker, researchers from AstraZeneca will team up with scientists at the UCL Institute of Ophthalmology to work on new medicines that use the regenerative capacity of stem cells. They hope to come up with a compound in three to five years, which could then undergo clinical development and possibly be on the market in 10 years' time.

Dr Marcus Fruttiger of the UCL Institute of Ophthalmology, who is leading the project, said: "These tools could be used either to manufacture transplantable material or to directly stimulate new cell growth in the eye to help restore or improve the vision of those with diabetic retinopathy (DR)."

AstraZeneca's U.S. rival Pfizer also has a partnership with Professor Pete Coffey of the UCL Institute of Ophthalmology, aimed at another eye condition, macular degeneration. Coffey said: "It's great that 'Big Pharma' is considering regenerative medicines as a serious possibility." He added: "This is British science being developed into a commercial entity with the pharmaceutical industry. It's a good example why the government shouldn't cut funding for biomedical research."

While this is the first time that AstraZeneca has worked on medicine for retinopathy, diabetes has been an area of focus. The company has a new diabetes treatment on the market called Onglyza, which was developed with Bristol-Myers Squibb, and the companies are developing a second diabetes drug that could be submitted to regulators for approval later this year.

International Stem Cell Corporation (Oceanside, CA)

On August 19, 2010, International Stem Cell Corporation announced that its stem cell therapeutic programs, focused on protective, transparent corneas (CytoCor) in the front of the eye and the light-sensitive retinal tissue (CytoRet) in the back of the eye would be formalized into a new business unit, Cytovis. Together these programs will leverage external and internal development, regulatory, and commercial expertise in cellular ophthalmology to form a focused portfolio of complementary product candidates designed to address high unmet medical needs with apparent pharmacoeconomic and quality of life benefits.

CytoCor is the brand name for ISCO's corneal tissue that can be derived from the company's proprietary parthenogenetic stem cells or commonly used embryonic stem cells. Research and development with partners Absorption Systems in the US, Sankara Nethralaya in India and Automation Partnership in the UK will continue for the purpose of optimizing the tissue for transplantation in the 10 million people worldwide suffering from corneal vision impairment and as an alternative to the use of live animals and animal eyes in the $500+M market for safety testing of drugs, chemicals and consumer products. ISCO's goal in the coming months is to establish funding and infrastructure in India for accelerated development of CytoCor for the therapeutic application and to advance and implement the chemical testing application with partners in the US and Europe.

CytoRet is the brand name for ISCO's stem cell-derived retinal tissue. ISCO is using its parthenogenetic stem cells to develop individual retinal pigmented epithelial ('RPE') cells and layered retinal structures internally and in collaboration with the laboratory of Dr. Hans Keirstead, Professor of Anatomy and Neurobiology at the University of California, Irvine. ISCO recently commenced a new research collaboration with UC Irvine to launch the next phase of its retinal studies with that institution, including preclinical trials. Potential therapeutic applications include retinitis pigmentosa, an untreatable inherited disease affecting about 100,000 Americans, and the dry form of age-related macular degeneration, a major cause of blindness in the elderly of the Western world. ISCO's goal is to establish functional proof of concept for RPE cellular therapy in models of human disease in the next twelve-eighteen months.

(Editors Note: An extensive writeup about the work being done in building an artificial retina from human embryonic stem cells by the team at UC Irvine, is contained in AMD Update 12. That writeup describes the use of human embryonic stem cells as the starting point. It is not known at this time who is the supplier of the hESCs used by UCI for this program, since ISCO does not supply this type of stem cells.)

Jointly referred to as Cytovis ('cyto' for cellular, 'vis' for vision), these two cellular ophthalmology programs share a number of features and benefits. First, with the aging of the population worldwide and the growing number of work-related eye injuries in India, China and other major countries, the market opportunity is growing steadily. Second, there are strong pharmacoeconomic and quality-of-life rationales for full or partial vision restoration or delay of vision impairment diseases. Third, delivery of cells and tissues to the confined anatomy of the eye inherently provides for better safety and efficacy than, for example, the systemic circulation or the central nervous system. This will likely result in lower regulatory barriers and shorter and less costly development paths compared to that of anatomically deeper and more widespread diseases. Fourth, a number of eye diseases cannot be treated with surgery or traditional small molecule or protein therapeutics, yet cell and tissue therapy is proven to work but currently limited by availability of safe and sufficient cells and tissue from human donors. Finally, eye care development programs like CytoCor and CytoRet share a number of regulatory, development and commercial aspects that make it feasible for a relatively small team to produce substantial clinical outcomes and achieve competitive presence in the marketplace alone or in collaboration with dedicated partners.

Brian Lundstrom, ISCO's President, said, “ISCO's proprietary parthenogenetic stem cell technology continues to form the foundation for the company's long term regenerative medicine therapy programs. In the nearer term, CytoCor and CytoRet's unique benefits in the field of cellular ophthalmology offer the potential for partnering and funding at a relatively early stage. Combined with the current and future revenue of Lifeline Cell Technology and the revenue potential of Lifeline Skin Care, scheduled for launch in the 4th quarter, Cytovis adds significantly to ISCO's diversity and value creation potential for its investor base in a cost-efficient fashion.”

According to Lundstrom, both CytoCor and CytoRet are currently at the discovery research stage with proof-of-concept testing ongoing in various model systems in India and the US. The company has not yet met with the FDA or similar regulatory bodies overseas, and there are no clinical paths as yet.

NeoStem Incorporated (New York, NY)

On August 10, 2010, NeoStem Inc. announced that it had entered into a sponsored research agreement with the Schepens Eye Research Institute, an affiliate of Harvard Medical School. NeoStem will collaborate with the Schepens Institute and sponsor research in the laboratories of principal investigators Drs. Michael Young, Ph.D., Director of the Institute's Minda de Gunzburg Center for Ocular Regeneration, and Kameran Lashkari, M.D. The focus of the research will be on the development of therapies for both age-related macular degeneration (AMD) and Glaucoma.

The research will examine in animal models the regenerative potential of NeoStem's VSEL technology in the visual system through the engraftment of the very small embryonic-like stem cells. VSELs (adult stem cells) are small embryonic-like stem cells are a heterogeneous population of stem cells found in adult bone marrow that have properties similar to those of embryonic stem cells. NeoStem has shown that their VSELs can be mobilized into the peripheral blood, enabling a minimally invasive means for collecting what NeoStem believes to be an important population of stem cells that may have the potential to achieve the positive benefits associated with embryonic stem cells without the ethical or moral dilemmas or the potential negative effects associated with embryonic stem cells.

"Our research team is looking forward to leveraging our adult stem cell expertise to advance the understanding and development of very small embryonic like stem cells for the treatment of age-related macular degeneration and glaucoma through our collaboration with the Schepens Institute," said Robin Smith, M.D., Chairman and CEO of NeoStem. "We are excited to gain access to the expertise in ocular regeneration offered by Drs. Michael Young, Kameran Lashkari and the Schepens Institute through this important project."

Unanswered Questions:

(Posed to the company and awaiting answers.)

Since this is one of the first programs to study stem cells in the treatment of glaucoma, exactly what is going to be done?

What kind of glaucoma will be treated – open-angle or closed-angle?

Also, will this research be done in animal or human models?

Finally, what will Schepens be doing in the treatment of AMD?

Pfizer Regenerative Medicine (Cambridge, UK)

Pfizer Ophthalmics (San Diego, CA)

As reported in the June 2010 issue of Retina Today, Pfizer, Inc. launched the Pfizer Regenerative Medicine research unit in 2008 to lead investigative efforts in stem-cell therapies throughout the company. Building on Pfizer's experience in the field of regenerative medicine, this independent research organization aims to discover and develop a new generation of medicines for major medical needs across several therapeutic areas. Specific to ophthalmology, Pfizer’s Ophthlamics division hopes to develop stem-cell therapies for patients with severe vision loss due to late-stage age-related macular degeneration (AMD) and other retinal diseases. Additionally, Pfizer's research unit is sampling stem cells in an effort to understand how retinal diseases progress.

Pfizer is partnering with academia and industry to understand new technologies and accelerate innovation in the area of retinal regenerative medicine. Pfizer and its most recent partner, University College London (UCL), are examining how human embryonic stem cells differentiate into retinal pigment epithelium, with the goal of developing stem-cell-based therapies for wet and dry AMD. The collaboration marries the pioneering work of Professor Peter Coffey, UCL Institute for Ophthalmology and Director of the London Project (The London Project to Cure Blindness), and colleagues in the field of cell-based therapies with Pfizer's expertise in the design and delivery of therapeutics.

Under an agreement between the company and the University, Pfizer will provide funding to UCL to enable research into the development of human embryonic stem-cell-based therapies for AMD and other retinal diseases. Pfizer's contributions will include expertise in the design and execution of clinical studies, interaction with global regulators, and product manufacturing techniques – specifically the membrane containing the stem cell structure that will be implanted into the retina..

(Editors Note: As discussed in the introduction to this Primer, I have written extensively about the London Project – see my writeups beginning with AMD Update 5 in April 2009, followed by the latest information about the London Project in my AMD Update 7 in April 2010. Professor Coffey expects to begin human clinical trials in early 2011, based on safety studies being submitted to the UK’s National Health Service later this year.)

Pfizer is also investing in EyeCyte, Inc., a company that is advancing adult stem-cell approaches developed at the Scripps Research Institute in La Jolla, CA. EyeCyte's regenerative medicine technologies are under development to treat acquired and inherited retinal diseases that include diabetic retinopathy, retinopathy of prematurity, retinal vascular occlusive disease, AMD, and retinitis pigmentosa.

Pfizer officials realize that it will take time to develop a practical and effective stem-cell therapy in ophthalmology, as there are many scientific and clinical barriers that must be overcome, Dr. Eveleth, Vice President of Pfizer Ophthalmics, said. "In order to achieve the best outcomes and minimize the risk of stem-cell transplant rejection, researchers are working to develop culture and differentiation protocols that produce the purest possible populations of stem cells." Such protocols are not yet established; however, researchers are making progress.

Dr. Eveleth admits that there is still much to learn about how and when these new cells integrate and grow, but he is confident that Pfizer will be a leader in developing stem-cell therapies for ophthalmology. "With the expertise of Pfizer's Regenerative Medicine group, the clinical and disease area knowledge of Pfizer Ophthalmics, the talents of our academic and industry partners, and the scientific know-how and resources of the world's largest biopharmaceutical company, we have the experience and the staying power required to develop practical applications of this exciting new science."

StemCells Incorporated (Palo Alto, CA)

StemCells, Inc. hopes to build upon the promising results of its research through the initiation in 2012 of clinical trials for patients with retinal degenerative diseases. The company has already engaged the FDA in discussions regarding a pathway to clinical testing of its human neural stem cells for retinal indications and additional preclinical studies are underway in pursuit of that goal.

StemCells is developing its HuCNS-SC product candidate (purified human neural stem cells) as a potential therapeutic product to treat several disorders of the central nervous system (CNS). These tissue-derived “adult stem cells” are currently in clinical development for two fatal neurodegenerative diseases in children; Neuronal Ceroid Lipfuscinosis (NCL or Batten disease) a lysosomal storage disorder, caused by inheritance of a recessive genetic mutation, and Pelizaeus-Merzbacher disease (PMD) a myelination disorder caused by a mutation in the gene controlling the production of proteolipid protein (PLP), which is integral to the formation of myelin. StemCells recently completed a Phase I clinical trial of its HuCNS-SC cells in NCL. Data from this trial demonstrated the safety and tolerability of these cells, and the company plans to initiate a second NCL trial later this year. StemCells is also currently conducting a Phase I trial in PMD at the University of California, San Francisco (UCSF) Children’s Hospital.

The human safety data that StemCells is accumulating for its HuCNS-SC product candidate through these clinical trials is expected to facilitate future clinical testing in other CNS disorders including spinal cord injury and retinal degenerative diseases such as AMD and retinitis pigmentosa. The status of its HuCNS-SC product development programs is shown below:

● NCL (Phase I Clinical Trial completed; Second Trial planned for second half of 2010)

● PMD (Phase I Clinical Trial underway)

● Spinal cord injury (Phase I Clinical Trial planned for 2011)

● Retinal disorders (Phase I Clinical Trial planned for 2012)

Work in the Eye

In January 2008, StemCells entered into a research collaboration with the Casey Eye Institute at Oregon Health & Science University (OHSU) to evaluate it neural stem cells as a potential treatment for retinal diseases. These studies showed that, when transplanted into the sub-retinal space of the RCS (Royal College of Surgeons) rat, a well-established animal model of retinal degeneration, the company’s human neural stem cells protected the retina from progressive degeneration and preserved visual function long term as measured by two separate visual tests. The transplanted cells also exhibited robust, long-term protection of both rod and cone photoreceptors. The ability to protect cones, in particular, is significant in regard to AMD, since it is the progressive deterioration of these specific cells that ultimately results in the devastating vision loss caused by this disease. The protection of both rods and cones is important in considering the potential of using human neural stem cells as a treatment for retinitis pigmentosa and other retinal degenerative disorders.

In May 2009, preclinical data showing the ability of the company’s human neural stem cells to protect the retina from progressive degeneration were presented at the Association for Research in Vision (ARVO) Annual Meeting.

More recently, additional preclinical data showing photoreceptor protection and ability to preserve long term visual function was presented at the Society for Neuroscience 2009 Annual Meeting and at the International Society for Stem Cell Research (ISSCR) 2010 Annual Meeting.

“We have long recognized that a number of eye disorders may be suitable candidates for stem cell-based therapies,” stated Stephen Huhn, MD, FACS, FAAP, vice president and head of the CNS program at StemCells, Inc. “The demonstrated ability of our human neural stem cells to preserve cones is very meaningful, because it is the progressive deterioration of these specific cells that ultimately results in vision loss in AMD. These data support our hypothesis that our neural stem cells may provide neuroprotection to existing cells, and it is our hope that we will be able to replicate these promising results in the clinic.”

The encouraging results of its latest studies follow previously reported data showing that StemCells’ neural stem cells engraft, survive long term, and can protect the retina from progressive degeneration in the RCS rat. StemCells is pursuing additional preclinical studies of its neural stem cells in the hope of one day achieving a breakthrough in treating AMD.

Stemedica (San Diego, CA)

I first learned about Stemedica’s involvement in the use of stem cells to treat retinal disease in January 2007, upon seeing a news release announcing the company’s collaboration with Lumenis to use the latter’s new retinal laser to produce a non-damaging “wound” the retina to create a signaling proteins focal source to attract stem cells to “heal” the retinal disorder. The work was to be undertaken at the Fyodorov Eye Institute in Moscow.

That collaboration fell through, but Stemedica continued to study the use of stem cells (and lasers) in treating retinal diseases at the Fyodorov Eye Institute.

In July 2009, Stemedica announced a breakthrough in the use of human stem cells and stem cell factors for the potential treatment of retina and retinal pigmented epithelium degeneration, including diseases such as Retinitis Pigmentosa. The results of these studies were presented at several major conferences.

According to one of the study's Principle Investigators, Dr. Paul Tornambe, "The results from this pre-clinical experiment are exciting. It allows researchers and clinicians to push the envelope in the quest to use stem cells to modulate diseases like Retinitis Pigmentosa." There is currently no medical treatment that can completely cure Retinitis Pigmentosa - an eye disease that affects approximately 1,500,000 people on a worldwide basis each year.

The 18 month pre-clinical study was implemented at the Fyodorov Eye Institute using Stemedica's proprietary multiple cell technology. Three different types of adult human stem cells (hSC) were used in the study - retinal pigment epithelium (RPE), neural (NSC) and cilliary body (CB) - all obtained from human donor tissue. Cells were injected into rats with hereditary pigmented degradation of retina. One eye of each participating rat served as the treatment eye and the other eye served as the control eye. Healthy non-dystrophic and non-treated (normally dystrophic) animals were also used as independent control groups. Electroretinography (ERG) and immunohistochemical (ICH) analysis was performed on both eyes.

The research team compared the efficacy of each of the three cell types. The study showed statistically significant gain (77%) in the treated eye (with RPE cells) over the control eye of the same animal. Of interest, both the treated eye and the control eye were approximately 10 times more active (response to ERG) compared to non-treated (normally dystrophic) control animal. It was also shown that the RPE and NSC cells were effective in preserving the thickness of the outer nuclei layer of the retina.

A contra lateral effect was observed between the test and control eyes. As a result, both eyes exhibited significant improvement. It is believed that the positive outcome in the control eye was achieved through the systemic release of cytokines; growth and other important factors; peptides; and, molecules from stem cells transplanted into the treated eye. This phenomenon is referred to by Stemedica as "The Factor Release Effect" and branded by the company as StemedicaFRET. These factors, circulating in the blood flow, effect and mobilize endogenous stem cells. Stemedica believes improvement in the contra lateral eye is a 'Factor Release Effect' rather than a Sympathetic Ophthalmic effect which is very rare.

At the Laser Florence 2009 Meeting, Drs. Alexei Lukashev and Eugene Baranov (Stemedica); Natalia Gavrilova (Fyodorov Eye Institute); Irina Saburina and Alexander Revischin (Russian Academy of Medical Science); and Paul Tornambed (Retina Specialists, San Diego) presented a paper, “Combination of a Laser and Stem Cells in Posterior Eye Ophthalmology” (AIP Conf. Proc. -- May 31, 2010 -- Volume 1226, pp. 82-90), that described the use of the combination of laser and stem cells in treating the retina of a rabbit model.

An argon laser at 514nm and a dye laser at 577nm were used to provide a controlled damage on the rabbit retina. Two type of human progenitor stem cells(hPSC) were tested: Mesenchymal and Neural. Four cell delivery methods were compared: Retrobulbar, Introvitreous, Subconjuctival and Suprachoroidal injections. Electroretinography(ERG) was used as a diagnostics of retina functionality. Selective immunohystochemical analysis was performed to assess cells migration and viability.

Controlled laser damage on the retina provided a strong attracting signal for the stem cells. The team concluded that, the application of laser light enhances the results of stem cells injection in the posterior eye and may have benefits for treatment of different types of retinopathy and macular degeneration.

According to the company’s website, both clinical and pre-clinical work is currently underway
at the Fyodorov Eye Institute in Moscow, in using stem cells (and lasers) In treating diabetic retinopathy, macular degeneration, retinitis pigmentosa, and in the treatment of glaucoma.

Some questions posed to company management:

What is the current status of these clinical studies?

We have not started ophthalmic clinical studies (on humans) using stem cells as an IND (Investigational New Drug) approved by FDA. We plan to do this under an existing IND using  allogeneic bone marrow derived stem cells for intravenously administration in patients with retinal ischemia with and without laser treatment of retina.  

Are they being conducted in human eyes?

Eight human subjects with different kinds of retinopathy were treated by human adult progenitors stem cells manufactured by Stemedica (clinical case studies). Three years follow up show the safety and preliminary efficacy of adult stem cells for ophthalmic applications, and warrant further investigation in clinical trials which are planned for initiation in the U.S.

And, exactly what is being done in the glaucoma work?  This is the second time I have heard of stem cells being applied to glaucoma. Can you provide some further explanation?

We are double checking and analyzing our preliminary results, preparing our intellectual property (IP) filings, but this is not yet ready for public release.

Table 2, Stem Cell Companies Active in Ophthalmology

(By clicking onto the table and opening it into a new tab or window, it will can be enlarged for easier reading.)

A Brief History of Stem Cells in Ophthalmology

Stem Cells in Medical Research

Until recently, scientists primarily worked with two kinds of stem cells from animals and humans: “embryonic stem cells” and non-embryonic or “adult” stem cells. Scientists discovered ways to derive embryonic stem cells from early mouse embryos nearly 30 years ago, in 1981. The detailed study of the biology of mouse stem cells led to the discovery, in 1998, of a method to derive stem cells from human embryos and grow the cells in the laboratory. The embryos used in those studies were created for reproductive purposes through in vitro fertilization procedures. When they were no longer needed for that purpose, they were donated for research with the informed consent of the donor. In 2006, researchers made another breakthrough by identifying conditions that would allow some specialized adult cells to be “reprogrammed” genetically to assume a stem cell-like state. This new type of stem cell was called induced pluripotent stem cells (ipSCs).

Stem Cells in the Eye

(With thanks to Dan Roberts, Director, the MD Support Group)

2000

Stem cell work in the eye started with the discovery that stem cells have certain characteristics of photoreceptor cells, reported in the year 2000 by Dr. Derek van der Kooy (University of Toronto) and Dr. Iqbal Ahmad (University of Nebraska).

2001

In 2001, President George W Bush limited government funding for research using embryonic stem cell lines. In the same year, Dr. Michael Young (Schepens Eye Institute) showed that transplanted cells from a mouse retina were able to reproduce, and that some of them contained the photoreceptor-specific protein, rhodopsin, which initiates the visual cycle (phototransduction).

2002

In 2002, the Scripps Research Institute (TSRI) in La Jolla, California reported success in forming new retinal blood vessels in mice with ocular disease. The process uses pluripotent adult stem cells derived from bone marrow and injected into the vitreous of the eyeball. Not only could adult bone marrow stem cells be used to form new vessels, but they could also be used to deliver powerful antiangiogenic drugs to prevent neovascularization. This was promising news to people with wet AMD.

2004

In 2004, Advanced Cell Technology (Alameda, California) announced that they had engineered human embryonic stem cells which could be used to repair a damaged retina. Dr. Robert Lanza (Scientific Director) said the results illustrate the need to use cloning technology to eliminate the risk of rejection by the patient's immune system.

A month later, the Department of Medical Biophysics (University of Toronto, Ontario, Canada) announced that their researchers had cultured and transplanted stem cells from human retinas into the healthy retinas of young mice. After four weeks, most of the cells had migrated to the new retinas and successfully differentiated themselves into photoreceptor cells.

Later that year, California became the first state to circumvent the federal government’s restriction on funding for stem cell research by passing Proposition 71 with a majority vote of 69%. This allowed nearly three billion dollars to be put aside for stem cell research in that state over the next 10 years.

Almost simultaneously, scientists from Harvard's Schepens Eye Research Institute successfully, and for the first time, improved the vision of mice with transplanted progenitor stem cells from day-old mice. The procedure had preserved existing cells and restored health to those that were degenerating--a major step toward the therapeutic use of stem cells for people with all forms of retinal degeneration.

2006

Work with humans began in 2006. In April, a research team in India (Dr Rajender Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences) reported that 50 patients severely affected by age-related macular degeneration or retinitis pigmentosa showed significant improvement in vision after one month of injecting stem cells, and that there was further improvement after a gap of three months.

In August, researchers at the University of Washington used a mix of growth factors to coax embryonic cells into becoming retinal cells. This was the first use of human stem cells using the technique for the retina. The team then began injecting the new cells into the eyes of retina-damaged mice, measuring nerve reactions to see whether there was actual vision improvement.

In September, scientists from Moran Eye Center (University of Utah, Salt Lake City) and Advanced Cell Technology reported that cells grown from human embryonic stem cells safely slowed vision loss when injected into the eyes of rats with a disease similar to macular degeneration.

2007

The year 2007 was full of breakthroughs, as researchers continued to look for ways to avoid harming embryos during the production of new stem cell lines. In January, for example, researchers at the Institute for Regenerative Medicine (Wake Forest University School of Medicine) discovered yet another potential source of embryonic stem cells in the amniotic fluid of the womb. These cells appeared to be almost as malleable as those in the embryo itself, and the advantage would be that harvesting them would be harmless. On another front, Advanced Cell Technology developed a technique for harmlessly removing a blastomere from an eight-cell human embryo (blastocyst). A blastomere is a cell resulting from the first few divisions of the ovum (egg) after fertilization. In June of 2007, ACT issued a press release announcing successful production of a human embryonic stem cell line (hESC) using that method.

Meanwhile, research was also beginning in the United Kingdom at the University College London, Moorfields Eye Hospital and Sheffield University, in a cooperative effort called the London Project to Cure Blindness. The London Project is a five year research project that began in June of 2007 to develop stem cell therapy for AMD hopefully by the year 2012. Doctors at Moorfields had some success with human subjects using adult stem cells from the patients' own eyes. Embryonic cells, however, had been shown by the Sheffield scientists to be more malleable and easier to transplant than adult stem cells. Laboratory-grown cells from the blastocyst of a 5-day old embryo require only one injection (a 45-minute procedure), whereas the Moorfields experiments took two hours and two surgical procedures. This protocol would be very expensive and impractical in general practice, so embryos are being used at Sheffield, and that will take a little longer to get into human trials.

Moorfields scientists are also studying the potential transformation of Müller neuroglial cells from the patient's own eyes. These would be removed from the eye, injected with a triggering chemical (either glutamate or aminoadipate, a derivative of glutamate), grown in vitro (i.e. in a petri dish) and transplanted back into the eye as stem cells. Late in 2007, two research groups (one at Kyoto University and the Gladstone Institute of Cardiovascular Disease in San Francisco, and the other at the University of Wisconsin) described a method of creating induced pluripotent stem cells by inserting master regulator genes into the chromosomes of human skin cells. These altered cells appeared to behave like embryonic stem cells, which scientists hoped could eventually eliminate the need for using human embryos for research.

2008

In 2008, President Obama lifted President Bush's restrictions on government funding for using embryonic stem cell lines. This opened the door to the world's first test in people of stem cell replacement therapy.

2009

In February of 2009, Geron, a pharmaceutical company, began enrolling paralyzed patients who could be treated within two weeks of their injury. This move set a precedent for more stem cell research in the low vision field. Then, in August, scientists at the University of Wisconsin-Madison reported that they had reprogrammed skin cells and turned them into different kinds of retinal cells. This added to the growing weight of evidence that stem cells made by reprogramming have similar, if not the same, abilities as embryonic stem cells.

One caveat of the new research, however, was that UW scientists had not yet proved that retinal cells made in a dish can perform all of the functions of those made in the body. But, at least, scientists can now take a skin biopsy from someone with a vision ailment, create retinal cells in a dish, and observe how the disease unfolds and how the cells die over time. Actual stem cell replacement in human retinas is still a little further in the future.

In November, Advanced Cell Technologies filed an IND with the FDA to initiate testing of its embryonic stem cells for treating Stargardt’s Macular Dystrophy.

2010

In the May issue of the AIP Conference Proceedings, a paper given at Laser Florence 2009 was published, providing information about the laser and stem cell programs underway with Stemedica and its research partner, the Fyodorov Eye Institute in Moscow. The paper described using lasers to “wound” the retina of rabbit eyes, followed by stem cell injections to “cure” the wounds.

At the end of July, Advanced Cell Technology (ACT) submitted documentation to the FDA in connection with the company’s plans to initiate a Phase I/II multicenter study using hESCs derived retinal cells to treat patients with Stargardt’s Macular Dystrophy. This followed its filing of an IND in November 2009 to commence treating patients.

In August, International Stem Cell Corp. announced it had reformed its therapeutic stem cell program; with the formation of CytoCor to focus on corneal applications, CytoRet on retinal applications, and all under the wings of Cytovis, the business unit.

Also in August, NeoStem announced that it had entered into a sponsored research agreement with the Schepens Eye Research Institute, whose focus will be on the development of stem cell therapies for both age-related macular degeneration and glaucoma.

In September, AstraZeneca signed a research collaboration with University College London, to develop a stem cell-based treatment for diabetic retinopathy.

Future Promise

As described in the accompanying text, stem cell technology has yet to be tested in controlled human clinical trials. But that test is just around the corner. The hESCs involved in the Pfizer Regenerative Medicine’s London Project to Cure Blindness or in the Advanced Cell Technology program to treat Stargardt’s disease may well be the first clinical trial program to implant embryonic stem cells into human eyes, and that could take place as early as the fourth quarter of this year or the first quarter of 2011.

As shown in the enclosed table of stem cell companies active in ophthalmology, there are a variety of projects underway to treat a multitude of retinal diseases (and a few for glaucoma and cornea).

If any of these projects are successful, and the hopes are high, we may well be on the verge of a new era, and soon have the technology and means to overcome degenerated eye structures to stave off blindness and poor sight for millions of humans.

I will continue to follow new developments in this exciting field and report on them as they happen.

Resources for Stem Cell Information:

1. Stem Cells, International Stem Cell Corporation website.

2. Stem Cell Facts: The Next Frontier?, International Society for Stem Cell Research, 2008.

3. Stem Cell Basics, The NIH Resource for Stem Cells, April 2009.

4. Understanding Stem Cell Therapy, Dan Roberts, and Profs. Claudio Stern and Peter Coffey, MDS Support Library, May 2010.

Citations:

Stem Cells in Ophthalmology, Dr. John Morrow, Newport Biotech, Ophthalmology Times Europe, September 2008.

Version 3, revised September 14, 2010.

Editors Note: This article has been reproduced in two parts in Ophthalmology Times Europe. The first part of the story was reproduced in the October 2010 issue of the magazine, and part two will appear in the November issue of the magazine. The article also appears in online excerpts -- here are the links: for Part 1; and for Part 2 (when it is published).