Saturday, November 06, 2010

The Use of Gene Therapy in Treating Retinitis Pigmentosa and Dry AMD

A short while ago, I received a message from someone I did not know, who said that he enjoyed the writeups on my online Journal and was wondering if I might be interested in writing about the use of gene therapy as an approach to vision restoration. Since I knew absolutely nothing about gene therapy, the writer got my attention.

After several discussions with Sean Ainsworth, the founder of RetroSense, and much online research, I think I have learned a little about what gene therapy is about, and its application in ophthalmology, especially in the possible restoration of vision in those who suffer from retinitis pigmentosa (RP). Thanks to Sean for whetting my appetite -- here is what I have learned.


In an article in Review of Ophthalmology in August 2009, Mark Abelson et al, wrote, “Instead of waiting for a disorder to occur and then treating it with a drug, imagine if we could prevent it from ever happening in the first place. This is the promise of gene therapy, and it's a new frontier for ophthalmic therapies that will be increasingly relevant in the decades to come. As appealing as prevention is, however, gene therapy's efficacy can be very difficult and costly to demonstrate, as  it requires large numbers of patients enrolled in long-term studies. Nevertheless, great strides are being made in the development of gene therapy treatment methods, including vector choice, targeting, selectivity and stability.”

Well, I don’t know about the use of gene therapy for prevention of a disease – I guess that would come when everyone has their genome mapped, and can identify which genes need to be fixed  or replaced. But, in the meantime, the idea of using gene therapy to give back sight to those who have lost it sounds like an idea whose’ time has come – or will come in the near future. And, as for gene therapy’s efficacy being difficult and costly to demonstrate, the facts haven’t borne this out in ocular studies.

A Phase I/II clinical trial in Leber Congenital Amaurosis (LCA) (more on this later) was done using gene therapy with 12 patients and the researchers saw signs of efficacy in as little as two weeks. Upon completion of their first trial, they headed straight into a Phase III clinical trial with 12 patients.

In this comprehensive overview of the use of gene therapy in the treatment of retinitis pigmentosa and dry AMD, I would like to introduce you to RetroSense Therapeutics and the work they have underway to develop a gene therapy treatment to restore vision in those who have lost it due to RP or dry AMD.

The Company: RetroSense Therapeutics

RetroSense Therapeutics was founded in 2009 by a team of seasoned veterans, to develop a novel gene therapy approach to vision restoration. The company is located in Ann Arbor, Michigan, a short drive from Wayne State University, where the approach was pioneered. RetroSense has secured exclusive, worldwide rights to relevant intellectual property from Wayne State University and Salus University.

The company was formed as a result of a commercialization assessment Sean Ainsworth was performing for Wayne State University. Ainsworth found that not only was this game-changing technology, but there was also high unmet need in the marketplace. And, while gene therapy, as a field, has seen some difficult times, tremendous advances were being made, particularly in ocular applications. According to Ainsworth, the intellectual property is also solid, as the primary inventor, Dr. Zhuo-Hua Pan was first to invent using channelrhodopsin-2 in vision restoration.

Ainsworth secured the rights to the intellectual property from Wayne State University and quickly found there was tremendous interest from leaders in the ophthalmology and biotechnology communities. He was able to bring together an impressive management team and advisory committee in short order.

RetroSense's management team has commercial and scientific experience across all phases of drug development, as well as startup success. The company operates virtually in order to secure top industry talent for its diverse, specialized needs in an efficient and effective manner.

The Management Team:

Sean Ainsworth, CEO

The management team is led by Sean Ainsworth who has fifteen years of experience in pharmaceuticals and biotechnology. His experience includes research at Medical Biology Institute (now Avanir Pharmaceuticals developers of Abreva, the leading cold sore medication) in San Diego, intellectual property at Koyama and Associates in Tokyo, and international corporate development consulting at The Mattson Jack Group in St. Louis, MO.

In 2004  Ainsworth launched Ainsworth BioConsulting to provide licensing, strategic planning, and business planning services to the life science and entrepreneurial community. Ainsworth has also had deep involvement in the launch of two previous startup companies, Compendia Bioscience, Inc. and GeneVivo, LLC where he assisted in licensing technologies, securing capital and first customers. Compendia BioScience is a profitable and growing company.

Ainsworth holds a BS in Microbiology from University of California, San Diego and an MBA in strategy and finance from Washington University in St. Louis.

Thomas Marten, COO

Thomas Marten has over twenty years of experience in pharmaceutical and biotechnology commercial operations with functional responsibilities including strategic planning, brand marketing, U.S. and global market research, business analysis, sales administration, and field sales.  Marten has had leadership roles with both large pharma and specialty biopharma companies including Glaxo Inc., Glaxo Wellcome, Bayer Biological Products, and Talecris Biotherapeutics.  Marten has significant experience in new product planning, brand strategy development, pricing and reimbursement strategy development, licensing related commercial due diligence, marketing, market research and sales force planning. Marten also has significant experience launching biologics into niche therapeutic areas and has worked with rare diseases including primary immunodeficiencies, hemophilia, and alpha-1 antitripsin deficiency.

In 2007  Marten founded Pharmacision LLC, a management consulting firm working with both large and small pharmaceutical companies to support strategic planning, drug development, and medical communications efforts. While at Pharmacision, Marten was instrumental in developing business plans, evaluating new product strategic opportunities, and coordinating with CROs and medical communications agencies to develop operational plans for numerous early stage pharma clients.

Marten has a BS in Medicinal Chemistry from the State University of NY at Buffalo and an MBA in Finance from the William E. Simon School of Business at the University of Rochester.

Edward "Ted" McGuire, PhD, Head of Pre-Clinical Development

Dr. McGuire has over 35 years of experience in pharmaceutical research and development, playing instrumental roles in the submission of numerous INDs, NDAs, and MAAs, including those for Lopidr, Accuprilr, Neurontinr, Lipitorr, and Rezulinr. Dr. McGuire's most recent positions include, Senior Director, Toxicological Sciences and Development at Parke-Davis, and Senior Scientific Advisor, Drug Safety Evaluation at Pfizer. During Dr. McGuire's tenure within pharma companies, he has supervised discovery and development teams - including gene therapy programs - coordinated and developed global toxicology plans, designed, conducted, and interpreted preclinical safety studies and study results, and led the resolution of issues impacting drug development.

Dr. McGuire received BSc and MSc degrees from the University of Windsor, Canada, and a PhD from The University of Michigan. He received a Distinguished Dissertation Award for his PhD thesis addressing hepatic effects of marketed lipid-regulating agents. He has published extensively and presented at numerous scientific meetings.

The Advisory Committee:

George A. Williams, MD, Scientific Advisor

George Lasezkay, PharmD, JD, Business Advisor

Dale Pfost, PhD, Business Advisor

The Diseases to Be Treated:

Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a group of inherited genetic retinal degenerative disorders characterized by progressive peripheral vision loss and night vision difficulties followed by eventual central vision loss and blindness in many cases. RP is typically diagnosed in adolescents and young adults. The rate of progression and degree of visual loss varies from person to person.

Approximately 100,000 people living in the U.S. and between 0.03% and 0.04% of the global population suffer from RP. An estimated 25,000 people in the U.S. with RP have progressed to a more advanced form of the disease and are legally blind with 20/200 or worse vision. Currently, there are no FDA approved therapies for the prevention or treatment of RP. Future treatments may involve retinal implants, gene therapy, stem cell therapy, and/or drug therapies.

RetroSense will pursue RP as a lead indication for its RST-001 photosensitivity gene and seek orphan drug status.

Dry Age Related Macular Degeneration

Dry AMD occurs when the light-sensitive cells in the macula break down, gradually blurring central vision. The macula is located in the center of the retina, the light-sensitive tissue at the back of the eye. Over time, as more photoreceptors in the macula atrophy and die, central vision is lost.

Dry AMD is the most common type of macular degeneration and affects 90% of the people with AMD.

Advanced late-stage dry AMD, or geographic atrophy, is characterized by progressive loss of photoreceptors causing profound vision loss and in some cases, blindness. Nearly 1 million people in the U.S. suffer from advanced dry AMD. Of them, an estimated 200,000 people with advanced dry-AMD are legally blind and suffer from 20/200 vision or worse.

Currently there are no FDA approved therapies for the prevention or treatment of dry AMD. Future therapies may include stem cell therapy, gene therapy, drug therapy – including sustained-release drugs, and retinal regeneration using lasers or combined with stem cell therapy.

RetroSense will pursue Advanced Dry-AMD as a second indication for RST-001.

The Therapeutic Approach: Gene Therapy to Restore Vision in Retinitis Pigmentosa and Dry AMD

RetroSense Therapeutics is pioneering an innovative gene therapy approach to restore vision in people with retinal degenerative conditions where the loss of photoreceptors has led to blindness. Photoreceptors (rods and cones) are light sensitive cells in the eye that convert light signals to nerve impulses which are sent to the brain where they are interpreted and create the vision we sense. As photoreceptors die in retinal degenerative conditions such as retinitis pigmentosa (RP) and dry AMD, visual acuity and the ability to see in dimly lit rooms is diminished. Progressive loss of photoreceptors leads to blindness.

RetroSense is employing a gene therapy approach to deliver a new photosensitivity gene to retinal cells to restore the ability of eyes to sense light. As RP is caused by over 100 different gene defects, addressing each individually is not feasible with current technologies. RetroSense's approach is designed to "install" new photosensors, restoring vision irrespective of which gene defect is responsible for vision loss. What this means is, their approach promises application across a broad spectrum of RP patients.


RetroSense's lead candidate, RST-001 employs a photosensitivity gene, channelrhodopsin-2 (Chop2), to create new photosensors in retinal cells and restore vision in retinal degenerative conditions such as RP and advanced dry-AMD.

Channelrhodopsin-2 is supported by a strong body of published literature on its efficacy and safety in animal models.(1) Numerous studies have demonstrated the ability of channelrhodopsin-2 to restore light perception and vision in animals with naturally occurring or induced blindness due to loss of photoreceptors. In primate studies, the administration of channelrhodopsin-2 was well tolerated. This approach to vision restoration was pioneered by Dr. Zhuo-Hua Pan at Wayne State University and Dr. Alex Dizhoor at Salus University.(2)

RetroSense is currently at the pre-clinical stage of development and working toward human clinical trials. RST-001 will be developed initially for retinitis pigmentosa, with advanced dry-AMD as a follow-on indication. The company currently anticipates filing an IND for RST-001 for RP by the end of Q3 2012 and commencing human clinical trials in Q4 2012.

How Gene Therapy Works

Gene therapy is the addition of new genes to a patient’s cells to restore or impart new function in order to overcome a disease – usually of genetic origin. Researchers typically deliver new genes to cells in modified virus vectors, as viruses have evolved to deliver genetic materials to cells.

(There is a second method of gene therapy – gene interference or silencing. In this technique, interfering or silencing of  a defective protein of a pair can be done using RNA interference. Since this technique is not used in treating either RP or AMD (or Leber’s), it is not discussed in this article.)

Gene therapy seems to be emerging as a viable means of treating diseases, after two decades of experimentation and trials, some of which was hallmarked by catastrophic results.

As Mark Abelson succinctly pointed out in his article, noted in the introduction, “Many fears surround gene therapy, stemming from concerns about inadvertently activating an autoimmune response, transfecting the wrong cells, activating oncogenes, or stimulating viral disease or tumor growth. While the blood-retina barrier provides some protection against such mishaps and decreases the likelihood of transfected cells spreading systemically, there are no guarantees.”

With regard to ocular gene therapy, Abelson also noted, “When other areas of the body receive gene therapy, rejection of viral capsids carrying the payload is a concern. The eye however, experiences reduced chances of vector rejection, just as foreign tissue in the eye experiences extended, if not indefinite, survival where it would be rapidly rejected in other parts of the body.”

“The eye is also relatively easy to monitor, both for potential side effects and for treatment benefit, with methods such as electroretinography, visual acuity, optical coherence tomography, and perimetry. Ophthalmoscopy and fundus photography also provide an easy way to directly visualize and document therapeutic effects.”

In the retina, photoreceptor cells convert light signals to electrical signals that are then relayed through second- and third-order retinal neurons to higher visual centers in the brain. The severe loss of photoreceptor cells caused by congenital retinal degenerative diseases, such as retinitis pigmentosa (RP), often results in complete blindness. RetroSense is exploring the possibility of genetically converting the surviving inner retinal neurons into directly photosensitive cells – thus imparting light sensitivity to retinas that lack active photoreceptors.

In the RetroSense approach, the company uses a virus, that has been stripped of its ability to replicate, as the delivery mechanism for the gene of interest, in this case, channelrhodopsin-2 (or Chop2) into the target cell – in the case of RP, being the ganglion cells and bipolar cells, as shown in the accompanying figure of the detailed makeup of the retina.

(This illustration taken from the RetroSense website and used with permission of Webvision)

The target cell's machinery reads the gene and creates the encoded Chop2 protein, which provides light sensitivity to these inner retinal cells, replacing the photosensitivity previously provided by the rods and cones that have become degenerated because of the disease.

In ocular gene therapy, the virus containing the gene of interest is injected into the eye, either subretinally, or intravitreally. Some distinct advantages of gene therapies in the eye are 1) the eye is an enclosed space, so the virus/gene is not distributed widely throughout the body, 2) smaller doses can be administered, 3) while the eye is not completely immune privileged, the immune response within the eye is muted in comparison to systemic administration of a virus.

Potential problems with gene therapies come primarily in the body’s immune response to the virus being used. Immunogenicity can be elicited, which eliminates the virus before it reaches its target and can also cause major side effects.

Early on in gene therapy developments a patient, Jesse Gelsinger, died in a clinical trial and regulatory bodies have since been very cautious with the approach.

Adeno-associated viruses (AAV) are not known to cause any human disease, and illicit a muted immune response. They have been well characterized in human studies. Safety and efficacy has been substantiated in ocular studies. For these reasons, RetroSense will advance with an AAV vector.

Status of Development

Channelrhodopsin-2 is a very well characterized protein. Numerous studies have been published supporting the protein’s efficacy(2, 3, 4) and safety (5, 6)  in vision restoration. Published mouse, rat, and marmoset studies support efficacy. Additional published studies support the safety – including neurotoxicity and immunogenicity. In order to enter into human clinical trials, however, RetroSense will be required to perform a battery of safety tests under “Good Laboratory Practices” as established by FDA guidelines.

While RetroSense cannot divulge details on just where they are in the pre-clinical process, the company suggests they could be in human clinical trials in less than two years. Much like the LCA trials recently published, RetroSense expects to see signs of efficacy in a short time frame (as little as two months), with a small number of patients. As drug development goes, this is actually a very short timeline.

Alternative Therapies Under Development for RP and Dry AMD

As a means of putting gene therapy into perspective as one of the many approaches that are being developed for the ophthalmologist’s armamentarium for treating RP and dry AMD, I have included the following information about the state of research for other experimental techniques/therapies that may find use in treating these diseases.

For RP:

The prime therapies for treating RP are gene therapy, described above; retinal implants; and the use of stem cells. The two latter therapies will be discussed below. Plus, at least one drug therapy is under evaluation, as noted below.

Retinal Implants (7, 8)

This discussion is taken almost entirely from Wikipedia. For more information about retinal implants and their technology, please see the excellent review article by Dr. Raymond Iezzi, recently published in Review of Ophthalmology (Reference 8).

A retinal implant is a biomedical device meant to partially restore useful vision to people who have lost theirs due to degenerative eye conditions such as retinitis pigmentosa or macular degeneration. Retinal implants are currently being developed by more than fifteen companies and research institutions in more than six countries worldwide.

The various technologies used in the implants consist of : 1) an array of electrodes implanted on the retinal surface; 2) a digital camera worn on the user's body and, 3) a transmitter/image processor that converts the image to electrical signals and beams them to the electrode array in the eye. The technologies, while still rudimentary, allow the user to see a scoreboard type image made up of bright points of light viewed from about arm's length. The developments are currently aimed only at the disabled, however, this technology once perfected, could revolutionize the personal computing and cyborg industries.

There are two types of retinal implants currently showing promise in clinical trials: Epiretinal Implants (on the retinal surface) and Subretinal Implants (within or behind the retina).

Epiretinal Implants sit on top of the retina, directly stimulating ganglia using signals sent from the external camera and power sent from an external transmitter, whereas Subretinal Implants sit under the retina, stimulating bipolar or ganglion cells from underneath. Some subretinal implants use signals and power from external circuitry, while others use only incident light as a power source and effectively replace damaged photoreceptors leaving all other structures within the eye untouched.

Clinical trials with chronic or semi-chronic (one-month) implant durations are currently under way in the United States and Europe. Patients with epiretinal stimulators have the ability to detect light, can ambulate along a white line painted on the floor, have demonstrated object avoidance, and some subjects can identify large letters on a computer screen with high accuracy. In addition, subretinal devices tested in Europe have provided 20/1200 visual acuity in a single subject.

Retinal prosthesis technology has been in development for more than two decades. Early devices are currently in clinical trials and are demonstrating exciting results.

A few of the major efforts in this field include:

●    The Boston Retinal Implant Project - external objective (eyeglasses) and subretinal implant
●    Retina Implant AG, in Germany - subretinal implant
●    Second Sight Medical Products - epiretinal implant

Retinal Implant AG

Retina Implant AG presented its latest clinical results at the recent American Association of Ophthalmology Meeting’s Retina Subspecialty Day on October 16th, “Subretinal Implants for Retinitis Pigmentosa”. The presentation discussed findings from Retina Implant's first clinical trial which began in November 2005 and involved implanting 11 patients with a 1500 electrode microchip subretinally. Dr. Walter Wrobel, CEO of the company, explained how the trial was carried out, the subretinal technique to implantation, and the visual results achieved by patients including the ability to recognize foreign objects and read at a basic level.

The company also discussed the technical and clinical results obtained during that first human clinical trial following the results being published in the Proceedings of the Royal Society B on November 2, 2010. That study titled, "Subretinal electronic chips allow blind patients to read letters and combine them to words," (9) details the visual results achieved during the first clinical trial. Patients in the trial were able to recognize foreign objects and read letters to form words. The study concluded that the implantation of Retina Implant's microchip was successful in restoring useful vision in patients previously blind due to retinitis pigmentosa.

Implant position in the body. (a) The cable from the implanted chip in the eye leads under the temporal muscle to the exit behind the ear, and connects with a wirelessly operated power control unit. (b) Position of the implant under the transparent retina.

Editors Note: The photograph can be enlarged for easier reading by opening it in a new tab or browser window.

"The stellar results achieved during our first clinical trial validate our subretinal approach to implantation which we believe is the key to restoring useful vision for patients blinded by retinitis pigmentosa. As we continue on with our second clinical trial, we look forward to expanding on the lessons learned during our first trial by following patients as they return home."

Retina Implant began their second clinical trial earlier this year in Germany with plans to expand the trial to other European countries including the U.K. and Italy. In this clinical trial patients will receive the 1500 electrode implant permanently. Pending positive results from their second clinical trial, Retina Implant intends to submit the results for CE mark approval (for marketing in Europe).

Early Development Project

One other interesting project, in the early stages of development, involves  research  based at Boston College and the University of Massachusetts Medical School, that is attempting to create nano-structured retinal implants. The visual prosthesis is based on a novel, nanostructured, biocompatible energy conversion device whose dimensions enable the density of implanted stimulating electrodes to exceed 100 million/cm2.  This constitutes by far the highest pixelation for a retinal implant, tens of thousands of times higher than any competing device, comparable even to the rods and cones in the retina that the implant will replace. Moreover, the novel "nanocoax" architecture of the neuroprosthesis enables unprecedented light-to-energy conversion efficiency.  It also establishes a new paradigm for retinal implant technology: ambient light operation, without the need for implanted batteries or wires.

According to the latest information from the inventor of the above nanostructered device, the research team is still awaiting funding to get this concept off of the ground.

Stem Cells

In my recently published Primer on the Use of Stem Cells in Ophthalmology, I pointed out that at least three of the seven companies targeting the use of stem cells for retinal diseases had mentioned RP as one of their targets. The three specific references were the programs at Scripp’s Research Institute, sponsored by Pfizer Regenerative Medicine; the program at Oregon Health & Science University, sponsored by Stem Cells, Incorporated; and the program at the Fyodorov Eye Microsurgery Center in Moscow, sponsored by Stemedica. (All three programs, by the way, are using adult stem cells.) No further information is available at this time.

Drug Therapy

At least one drug therapy is under evaluation for treating RP.  Neurotech Pharmaceuticals, Inc., has announced that the company's lead product candidate, NT-501 has demonstrated a strong biologic effect in two Phase 2 clinical trials in the treatment for retinitis pigmentosa (RP).

NT-501 is an intraocular implant that consists of human cells that have been genetically modified to secrete ciliary neurotrophic factor (CNTF). CNTF, a growth factor capable of rescuing and protecting dying photoreceptors, is delivered directly to the back of the eye in a controlled, continuous basis by means of the company's proprietary Encapsulated Cell Technology (ECT) platform.  Delivery via ECT bypasses the blood-retinal barrier and overcomes a major obstacle in the treatment of retinal disease.

"CNTF has the potential to help people with retinitis pigmentosa and other photoreceptor degenerations," said Dr. Paul Sieving, Director of the National Eye Institute and Principal Investigator of Neurotech's Phase 1 study of NT-501 in RP. "These studies are important as they present an opportunity to move the field forward."

However, it was noted in the news release about the test results that no visual benefit was seen in the treated eye relative to the control eye over this relatively short 12-month time period. So, it appears that photoreceptor preservation occurs, but no regeneration or improvement in sight using this implant – at least to date.

For Dry AMD:

The treatment of dry AMD is under study from many fronts, because of it’s presence in so many patients. The main approaches, in addition to gene therapy discussed briefly above, are both externally applied drops and injected drugs, including sustained release types; stem cells; and retinal regeneration using both a laser to stimulate regeneration of retinal pigmented epithelial (RPE) cells, and a combination of laser and stem cells. These will be discussed briefly below.

Therapeutic and Sustained Drug Release

I have published two articles in my online Journal on the subject of drug therapies for retinal diseases, including dry AMD, one of which is specific for the treatment of dry AMD. My AMD Update 6: An Overview of New Treatments for Dry AMD, by Dr. Philip Rosenfeld, addresses the preclinical and Phase I drugs in development for dry AMD; while my writeup on Iluvien and the Future of Ophthalmic Drug Delivery Systems discusses sustained-release drug delivery systems, a few of which are aimed at treating dry AMD.

The three FDA-approved sustained-release systems are Vitasert (for cytomegalovirus retinitis); Retisert (for uveitis); and Ozurdex (for macula edema following branch or central retinal vein occlusion). Iluvien (for diabetic macula edema) is expected to achieve FDA marketing approval before the end of this year. It is also being tested as a treatment for both dry AMD and geographic atrophy, which occurs during the latter stages of dry AMD.

Several other drugs, mentioned in both of the articles noted above, are under evaluation for treating dry AMD, and at least one, from Neurotech, as noted above in the RP writeup, for treating RP

Stem Cells

Again, as noted in my recently published Primer on the Use of Stem Cells in Ophthalmology,  six of the seven companies are targeting the dry stage of AMD with their stem cell programs. Two of the efforts are with human embryonic stem cells, one uses induced pluripotent stem cells, and the remainder are using adult stem cells. It is interesting to note that one program, that sponsored by Stemedica, at the Moscow-based Fyodorov Eye Institute, is attempting to use the injection of stem cells following spot laser damage of the retina.

It should be noted that to date, no FDA-approved human clinical trials using stem cells to treat retinal diseases has begun. However, this is about to change. The first human trials for retinal diseases are scheduled to begin, either in the fourth quarter of this year (for Stargart’s by Advanced Cell Technology) or in the first quarter of next year (for dry AMD by The London Project to Cure Blindness, sponsored by Pfizer Regenerative Medicine).

Retinal Regeneration

In late 2007, I learned of a new, potential laser treatment, under development for treating retinal diseases. It was the Ellex 2RT program, using  a specially designed laser to treat retinal pigment epithelial cells, to stimulate the RPE cells to release enzymes that are capable of “cleaning” Bruch’s membrane, thereby rejuvenating the retina by allowing the increased transport of water and chemicals across this important membrane. In doing so, it is hoped that this will alleviate some of the debris (drusen) associated with the early stages of dry AMD. The technology behind this therapy is described in more detail in my first writeup, Ellex 2RT Retina Regeneration Therapy: A First Report.

In two later reports, I wrote about the first clinical results with this laser treatment (Ellex 2RT Retinal Regeneration Laser: An Update – First Clinical Results), which showed improved visual acuity in patients treated with newly diagnosed diabetic maculopathy and/or macula edema; and then earlier this year, following the ARVO meeting, the results of two key pilot studies, one on patients with proliferative diabetic retinopathy, and the other on patients with early (dry) AMD (Ellex 2RT Updated Clinical Results: ARVO 2010). In the latter study, of interest to this program,  after six months, ten of fourteen eyes had improved in visual function (six eyes) or drusen reduction (ten eyes). One-year results were expected to be reported at the AAO Meeting in late October. (As of the date that this report is being written, I have not received any verification that this occurred.)

Other Applications of Gene Therapy in Ophthalmology

Significant advancements have been made in understanding the genetic pathogenesis of ocular diseases, and gene replacement and gene silencing are being shown as potentially efficacious therapies. Recent improvements have been made in the safety and specificity of vector-based ocular gene transfer methods. Proof-of-concept for vector-based gene therapies has also been established in several experimental models of human ocular diseases. After nearly two decades of ocular gene therapy research, preliminary successes are now being reported in phase 1 clinical trials for the treatment of Leber congenital amaurosis.

The review article, “Gene Therapy for Ocular Diseases” (British Journal of Ophthalmology, August 2010) (BJO), describes current developments and future prospects for ocular gene therapy.

“Novel methods are being developed to enhance the performance and regulation of recombinant adeno-associated virus- and lentivirusmediated ocular gene transfer. Gene therapy prospects have advanced for a variety of retinal disorders, including retinitis pigmentosa, retinoschisis, Stargardt disease and age-related macular degeneration. Advances have also been made using experimental models for non-retinal diseases, such as uveitis and glaucoma. These methodological advancements are critical for the implementation of additional gene-based therapies for human ocular diseases in the near future.”

During my research for this writeup, I discovered a unique program underway at Genzyme, that combines the anti-VEGF properties of a drug like Lucentis (Genentech) with gene thearapy, to produce, hopefully, a longer acting effect of the anti-VEGF factor in treating the wet form of AMD.

As described in Technology Review (10), Lucentis binds to and neutralizes a wound-healing growth factor known as VEGF. This binding action stalls the excess growth of blood vessels in the eye that characterizes (the wet form of) age-related macular degeneration. Genzyme's gene therapy drug, officially called AAV2-sFLT01, would insinuate itself into the patient's retinal cells to produce the same VEGF-binding protein as Lucentis over far longer periods – (perhaps) up to several years.

A phase 1 clinical trial of Genzyme's gene therapy treatment began at the end of May. Three patients received the treatment, according to Sam Wadsworth, a Genzyme group vice president in charge of gene and cell therapy. Preliminary results should be available in about a year.

Genzyme  is collaborating with Applied Genetic Technologies Corp., in developing the gene therapy drug.

The only other ocular disease that I will discuss in detail in this article is Leber’s congenital amaurosis. I will leave the others for another time.

Lebers Congenital Amaurosis (11, BJO))

Leber’s congenital amaurosis (LCA), is a rare form of inherited blindness caused by retinal degenerative disease that strikes in infancy and causes a severe loss of vision. Leber congenital amaurosis (LCA), an autosomal recessive disorder that affects both rods and cones, has been linked to at least 14 genes. Several have been demonstrated as potentially efficacious gene therapy targets. The use of the gene RPE65 in an adeno-associated virus (AAV2/2) vector or carrier has been shown to restore rod photoreceptor function and vision-dependent behavior in some of the patients so treated.

Researchers in the United States (12)(13) and the United Kingdom (14) have injected one eye of LCA patients with a harmless virus carrying a gene coding for an enzyme needed to make a lightsensing pigment. In the first completed trial, the light sensitivity of all 12 partially blind patients improved. Four children gained enough vision to play sports and stop using learning aids at school. (Another team using a similar approach gave full color vision to squirrel monkeys born with red-green colorblindness.(15))

At least three Clinical Trial are currently underway (BJO). In one  dose-escalation study involving 12 patients and performed by Malone et al (reference 102 in BJO) safety and efficacy were sustained for at least 2 years post-treatment.

RPE65 gene therapy for LCA has been one of the most successful examples of gene therapy for ocular diseases to date.

In Conclusion

To date, there are no approved treatments for retinitis pigmentosa and/or dry AMD. As shown above, gene therapy holds much promise for RP and, hopefully, for dry AMD as well.

With stem cell therapy about to begin human clinical trials for both Stargardt’s (Advanced Cell Technology) and dry AMD (UCL-London Project to Cure Blindness – Pfizer), and Retinal Regeneration not far behind, it will be interesting to see which new technology/therapy wins the race for treatment of these ocular diseases.


The RetroSense Website

Gene Therapy in Ophthalmology
Uthra S, Kumaramanickavel G. “Gene therapy in ophthalmology”, Oman J Ophthalmol 2009; 2:108-10.

Gene Therapy for Ocular Diseases

Liu, Melissa M; Tuo, Jinsheng; Chan, Chi-Chao; “Gene therapy for ocular diseases”; Br J Ophthalmol doi:10.1136/bjo.2010.174912 (BJO)

Gene Therapy Turns Foes into Friends

Abelson, Mark B., Tzekov, Radouil T., Howe, Amanda; “Gene Therapy Turns Foes into Friends”,  Review of Ophthalmology - August 2009


1. Evaluation of AAV-Mediated Expression of Chop2-GFP in the Marmoset Retina, Ivanova E, Hwang GS, Pan ZH, Troilo D, Invest Ophthalmol Vis Sci, May 2010.

2. Ectopic expression of a microbial-type rhodopsin restores visual responses in mice with photoreceptor degeneration, Bi A, Cui J, Ma YP, et al, Neuron 50 (1): 23-33, April 2006.

3. Channelrhodopsin-2 gene transduced into retinal ganglion cells restores functional vision in genetically blind rats. Tomita, et al, Exp Eye Res. 2010 Mar;90(3):429-36. Epub 2009 Dec 27.

4. Evaluation of AAV-mediated expression of Chop2-GFP in the marmoset retina, Ivanova, et al, Invest Ophthalmol Vis Sci. 2010 Oct;51(10):5288-96. Epub 2010 May 19.

5. Evaluation of the adeno-associated virus mediated long-term expression of channelrhodopsin-2 in the mouse retina; Ivanova, et al, Molecular Vision 2009; 15:1680-1689

6. Systematic and Local Responses of Channelrhodopsin-2 Gene Therapy; Sugano, et al, ARVO Poster #A615.

7. Retinal Implants, Wikipedia, February 22, 2010

8. An Inside Look at Retinal Prothesis Technology, Iezzi, Raymond, MD, Review of Ophthalmology, April 2010.

9. Subretinal electronic chips allow blind patients to read letters and combine them to words, Zrenner, Eberhart  M.D et al, Proceedings of the Royal Society B, November 2, 2010.

10. Gene Therapy for Eye Diseases, Weintraub, Karen, Technology Review, July 15, 2010.

11. Gene Therapy Returns, Science, December 18, 2009.

12. Gene Therapy Restores Vision in Leber Congenital Amaurosis, Children's Hospital of Philadelphia news release October 24, 2009

13. Safety and Efficacy Study in Subjects With Leber Congenital Amaurosis, Clinical Trial, NIH, October 21, 2009.

14. Eye gene therapy boost for young, BBC NEWS, August 24, 2009.

15. Colour blindness corrected by gene therapy, Nature, September 16, 2009.

Editors Note: The introduction to this article is now posted in the Special News items on Gene Therapy Net.


At 11:18 PM, Anonymous Anonymous said...

Thanks Dr.Irv,
Really appreciated this overview on RP possibilities. Any further news coming from clinical trials & their impact will be appreciated. Advanced Cell sounds like it is only a safety check. Could any of us, especially the patients expect a change in their vision, or are they beyond that hope ?
Also, I'd like to know whether only one eye is treated ?
How long before a preliminary non conclusive report might be issued ?


Post a Comment

<< Home