Saturday, March 28, 2015

Gene Therapy in Ophthalmology Update 16: Current Tables Now Online

My current gene therapy tables are now online for anyone interested to access. Here is a brief description of what is available and how to access them:

Gene Therapy

Gene Therapy Companies/Institutions Active in Ophthalmology

The table lists more than thirty-eight companies and institutions actively pursuing gene therapy solutions to ophthalmic diseases. The table shows the delivery viral platform, the gene type being used (where known), the application, and clinical status.

Gene Therapy in Ophthalmology by Application
This table lists the twenty-one ophthalmic indications, the company/institutions involved, the clinical status, and the clinical trial number. (Twenty-two active clinical trials are listed, with live links.)

Gene Therapy in Ophthalmology -- Ongoing Clinical Trial Details
This table lists the twenty-two active and completed clinical trials, the number of patients to be treated and the number of patients treated to date (that I'm aware of).

Updated March 28, 2015

Friday, March 27, 2015

Avalanche Update 2: Avalanche and Univ. Of Washington Collaborate to Defeat Color Blindness

Avalanche Biotechnologies and the University of Washington Enter Into Exclusive License Agreement to Develop Gene Therapy Approach to Treat Color Blindness

As reported by NPR’s health blog, Shots, on March 25th, Avalanche Biotechnologies in Menlo Park and the University of Washington in Seattle announced a licensing agreement to develop the first treatment for colorblindness. The deal brings together a gene therapy technique developed by Avalanche with the expertise of vision researchers at the University of Washington.

"Our goal is to be treating colorblindness in clinical trials in patients in the next one to two years," said Dr. Thomas Chalberg, the founder and CEO of Avalanche. The company will be entering IND-enabling studies this year.

The agreement has its roots in a scientific breakthrough that occurred six years ago. That's when two vision researchers at the University of Washington used gene therapy to cure a common form of colorblindness in squirrel monkeys.

"This opened the possibility of ultimately getting this to cure colorblindness in humans," says Jay Neitz, who runs the Color Vision Lab at UW along with his wife, Maureen Neitz.

The company also announced, that outside of the scope of the license agreement, Drs. Jay and Maureen Neitz, faculty in the UW's Department of Ophthalmology and color vision deficiency (CVD) experts, have joined its Scientific Advisory Board. They will be technical advisors to the company on the science of vision.

"This agreement with the University of Washington and world-renowned vision scientists Drs. Jay and Maureen Neitz will help us further advance our goal of developing therapeutic products for the millions of people who suffer from CVD," said Dr. Chalberg. "Our proprietary technology enables us to target the retina through intravitreal adeno-associated virus delivery, presenting, for the first time, the opportunity to pursue previously untreatable ophthalmic conditions such as CVD."

Avalanche will build on gene therapy research conducted by the Neitz research team, who used gene therapy to confer color vision in two adult male squirrel monkeys that had been color blind since birth. This groundbreaking work demonstrating proof-of-concept for treating CVD was published in the journal Nature (1).

Curing color blindness involves delivering new genes to cells in the retina that respond to color. That's how Jay and Maureen Neitz cured the squirrel monkeys six years ago. But the technique they used involved a surgical procedure on the retina.

For people, they desired a nonsurgical approach, something that had eluded researchers for years. Then a team at the University of California, Berkeley found a way to deliver genes using a simple injection into the vitreous, the clear gel that fills most of the eyeball.

Avalanche Biotechnologies has been working to improve and commercialize the Berkeley technique, said Chalberg.

So, Avalanche will combine the CVD gene therapy approach discovered by Drs. Jay and Maureen Neitz, with the licensed technology from the University of California at Berkeley and improved by Avalanche which will allow treatment via an intravitreal injection, similar to how wet AMD treatments are currently delivered in ophthalmologist’s offices, in a simple in-office procedure.

(I described this latter new virus vector delivery system in an article written in June 2013 entitled: Gene Therapy in Ophthalmology Update 19: A New Virus Vector for Safer Delivery of Gene Therapies)

According to Dr. Samuel Barone, Avalanche’s Chief Medical Officer, in response to my query if they were going to use the specific Berkeley vector research that I wrote about in Update 19, Dr. Barone said, “We licensed that intellectual property from Berkeley, and it serves as the basis for the delivery.  However, we have improved and optimized the technology, in better cone-specific transduction and protein expression.”

About CVD/Color Blindness and Avalanche's Targeted Development Program

Color vision deficiency (CVD), also known as red-green color blindness, is among the most common genetic diseases. CVD affects approximately 8 percent of males and 0.5 percent of females, or more than 10 million people in the U.S alone. CVD is a visual impairment that impacts many aspects of everyday life, resulting in limitations in professional choices, compromised health and safety, and the inability to perform many activities of daily living.

A simulation from the Neitz lab of what color blindness looks like, with normal color vision on the left and red-green color blindness on the right.

Photopigments in the retina are crucial for perceiving color. People with normal color perception have three different types of photopigments. These photopigments are tuned to perceive either long wavelengths (red), middle wavelengths (green) or short wavelengths (blue), respectively.

The most common forms of CVD are due to genetic defects that lead to missing either the L-opsin (Type 1, or protan defects) or the M-opsin (Type 2, or deutan defects). Affected individuals have trouble distinguishing between red and green and between colors that contain red or green hues.

Ishihara plate, a typical test for red-green colorblindness.

Avalanche has two drug candidates targeting these areas. AVA-322 carries the gene for L-opsin and is being developed for the treatment of Type 1 color vision deficiency. AVA-323 carries the gene for M-opsin and is being developed for the treatment of Type 2 color deficiency.

Avalanche expects to file an IND in the second half of 2016 to support advancement of these drug candidates into clinical trials, using Avalanche’s breakthrough non-surgical intravitreal injection method to deliver genes directly to cone cells at the back of the eye. The company recently launched for patients with color blindness to receive information about the condition and potential research study opportunities.

To read more about Avalanche Biotechnologies and its research programs, please see:


1. Gene therapy for red-green colour blindness in adult primates, Mancuso, K. et al, Nature, 2009; 461:784-787.

Saturday, February 21, 2015

Stem Cells in Ophthalmology Update 24: Current Tables Now Online

My current stem cell/cell therapy tables are now online for anyone interested to access. Here is a brief description of what is available and how to access them:

Stem Cell/Cell Therapy Companies/Institutions Active in Ophthalmology

A list of forty-one companies and institutions working with stem cells/cell therapies for ophthalmic applications. The table lists collaborators, the cell type being used, and the applications for which the cells will be used.

Stem Cell/Cell Therapy in Ophthalmology by Application

A list of eighteen ophthalmic applications being studied and/or in clinical trials. The table includes the companies/institutions involved, the clinical trial status, and an active link for the clinical trial for those listed. (Fifty-three active and completed clinical trials are shown.)

Stem Cell/Cell Therapy in Ophthalmology -- Ongoing & Completed Clinical Trial Details

A list of the the eighteen ophthalmic applications and the fifty-three clinical trials showing the number of patients to be studied in each trial and the number studied to date (that I am aware of). Active links are provided for each ongoing or completed trial.


Updated February 21, 2015. 

Thursday, January 15, 2015

Oraya IRay Update 3: Oraya Now Operating at Nine European Centers and Partnership with Carl Zeiss Meditec

The last time I checked in on Oraya, in March 2013 (Oraya IRay Update 2: INTREPID Two-year Results Meet Primary Clinical Endpoint - Results in At Least 35% Fewer anti-VEGF Injections), the company had just announced the two-year results of the INTREPID clinical study, showing favorable results in requiring fewer anti-VEGF treatments to treat wet AMD.

With the recent announcement (January 7, 2015) of a collaboration agreement between Oraya and Carl Zeiss Meditec, to provide funding to Oraya over a period of up to two years for the implementation of Oraya's growth strategy, and a report of the three-year INTREPID safety results last September, I decided to publish this update.

First, the three-year INTREPID trial safety results.

The three-year safety results were presented on September 13, 2014, at a EURETINA seminar where physicians also discussed their clinical experiences treating patients with Oraya Therapy.

The three year safety evaluation consisted of detailed image analysis looking for the presence of microvascular changes related to radiotherapy. Although small localized changes were identified by the reading center in a quarter of the patients, they did not significantly affect vision.

Commenting on the INTREPID study, Professor Ian Rennie, Consultant Ophthalmologist and Professor of Ophthalmology and Orthoptics and International Expert in Treatments of Ocular Cancers at Sheffield Teaching Hospitals NHS Foundation Trust said, "Of the cases I reviewed that were identified by the study expert panel as having microvascular changes attributable to radiation, most cases were so subtle that I would consider them clinically insignificant."

The INTREPID study was the first to evaluate the safety and efficacy of Oraya Therapy in conjunction with as-needed anti-VEGF injections for patients with wet AMD, and is the only sham-controlled double-masked trial to assess stereotactic radiotherapy for wet AMD. The study met primary and secondary endpoints and showed that Oraya Therapy significantly reduces the need for anti-VEGF injections while maintaining vision in the presence of a favorable safety profile. A total of 21 sites in five European countries participated in the trial. Two-year results showed that a broadly inclusive cohort of previously treated Wet AMD patients continued to receive the benefits of a 25 % mean reduction in anti-VEGF injections over two years. Additionally, the targeted patient population maintained an impressive 45 % mean reduction in injections through the two-year visit, with stable vision.

In simpler terms, as explained by Oraya President and CEO Jim Taylor, “The INTREPID trial enrolled a broad spectrum of patients, with some diagnosed out to 3 years prior (average ~15-18 months), and including many who's disease process had progressed to central scarring and other related conditions. In this broad cohort, we saw the 25% reduction of injections with equivalent vision outcomes to the controls.”

Further, “In a subset of patients who had active leakage and lesions that had not grown so large as to extend outside the Oraya treatment zone, we saw the far more significant 45% reduction; and some suggestion of potential for positive vision benefit as well. This becomes our "target patient population" for commercial/clinical use, and it is important to note that our research suggests these patients make up 60%-70% of the patient population under wet AMD management in a typical clinic.”

These impressive results coupled with increasing interest from physicians and patients, have led the Heart of England NHS Foundation Trust to become the second NHS center to install the technology. Patient treatment at the Trust was due to commence in October 2014. The Heart of England closely follows the Royal Hallamshire Trust in Sheffield, which began offering this innovative therapy in July 2014. The commercial use of Oraya Therapy has been rapidly expanding in Europe, with the treatment available in a total of eight centers (see note below) across the United Kingdom, Germany and Switzerland. It is covered by insurance in all three countries.

“As we conclude this ground-breaking three-year study of Oraya Therapy, results are showing that treatment can, and is, maintaining patients’ vision while significantly enhancing their quality of life,” said JimTaylor. “This result, coupled with the rapid expansion of the availability of the Oraya Therapy in the UK, and indeed across Europe, makes this a very exciting time for the company.”

(Editor’s Note: As of January 2015, there are now nine centers treating patients; four in the UK, one in Switzerland, and four in Germany. See the company website for additional information.)

On January 7, 2015, Carl Zeiss Meditec AG and Oraya Therapeutics, Inc. (Oraya) jointly announced that the companies had entered into a collaboration agreement under which Carl Zeiss Meditec will provide funding to Oraya over a period of up to two years for the implementation of  Oraya's growth strategy, and in turn receive rights in the company reaching up to a majority stake after two years.

The Oraya Therapy is available commercially in Germany, the UK and Switzerland, and the collaboration is intended to accelerate and expand these initial European market developments. While specific terms of the agreement were not disclosed, the companies noted that Carl Zeiss Meditec will be making a meaningful strategic investment in Oraya, and that further opportunities to leverage the companies' respective technical and market expertise and resources will be reviewed.

In discussing the transaction, Dr. Ludwin Monz, President and CEO of Carl Zeiss Meditec AG, stated, "The current pharmaceutical treatment regimens for wet AMD are exceptionally costly and burdensome, and Oraya's unique therapy offers a significant potential to positively impact the management of this debilitating disease." He went on to add that, "ZEISS has a long tradition of bringing new and innovative technologies to the ophthalmic market, from the earliest slit lamps, to category leading products such as glaucoma field analyzers, Optical Coherence Tomography (OCT) and innovative femtosecond laser platforms. These types of technology innovations, all offering significant provider and patient benefits, are part of the core strategy of Carl Zeiss Meditec AG."

Commenting on the agreement, Jim Taylor, CEO of Oraya, stated, "It is exceptionally rewarding to have the support and validation that are inherent in this commitment by Zeiss, a company universally recognized for its commitment to excellence in science as well as in patient-focused and physician-focused products and innovations. As a result of this collaboration, we have effectively enhanced our potential to positively impact patient outcomes, while significantly reducing the therapy burden for clinicians and providers as well."

In the USA the Oraya IRay is still an investigational device and is not yet available for sale.

Wednesday, January 07, 2015

Iluvien Update 9: Additional Marketing Approvals; A New Ophthalmic Application; and An Interesting Human Interest Story

Since I last wrote about Iluvien back in September (Iluvien Update 8: Alimera Sciences Receives FDA Approval of Iluvien for Treatment of DME), when Alimera Sciences and pSivida announced the FDA approval of Iluvien for treating chronic DME, adding the U.S. to the approvals or pending approvals obtained in seventeen European countries – approved in thirteen and pending approval in an additional four others, the product has become commercially available in the UK and Germany and is scheduled to become available in Portugal shortly.

With the FDA approval, Iluvien should also become commercially available in the U.S. in early 2015.

In a recent news release, Dr. Paul Ashton, President and CEO of pSivida, said, "We continue to be pleased as Iluvien gains additional marketing approvals in Europe. We believe Iluvien’s efficacy and three-year duration make it an attractive treatment option for many DME patients, particularly in the U.S. where the drug has broader labeling."

In addition to the application of Iluvien for the treatment of DME licensed to Alimera, pSivida is independently developing the product for the treatment of posterior uveitis. The FDA recently cleared the company's Investigational New Drug (IND) application to treat posterior uveitis with its injectable, sustained-release micro-insert, permitting pSivida to move directly to two Phase III trials under which it would enroll a total of 300 patients. However, the FDA approval of Iluvien for DME opens up the potential for pSivida to seek FDA approval on Medidur for uveitis with only one Phase III clinical trial, similar to what occurred with Allergan’s Ozurdex and its FDA approvals. The FDA is allowing pSivida to reference much of the data, including the clinical safety data, from the clinical trials of Iluvien for DME previously conducted by Alimera. Under the terms of its collaboration agreement with Alimera, pSivida has joint ownership of, and reference rights to, all clinical data and regulatory filings generated by Alimera, including its New Drug Application (NDA) for DME.

pSivida’s injectable micro-insert (Medidur) to treat posterior uveitis is a tiny tube about the size of an eyelash. It releases the off-patent steroid fluocinolone acetonide at a consistent rate over a period of approximately 36 months. The micro-insert is injected into the back of the eye during an office visit through the use of a fine gauge needle.

And, An Interesting Human Interest Story

What caught my attention, and brought me back to Iluvien (and the company, pSivida, that produces it and licenses it to Alimera Sciences for marketing) was a story that recently appeared in the Kansas City Star:

This is a story about a software engineer from Olathe, Kansas.

David Jiang was in danger of losing vision in his left eye when his eye specialist tracked down the inventor of a tiny eye implant that releases an anti-viral drug.

Jiang was examined recently by Siddhartha Ganguly (left) at the University of Kansas Cancer Center. 

David Jiang (left) says his vision remains slightly blurry but his retina is recovering after receiving the implant.

A year ago, after a routine physical, Jiang got the disturbing news that he had leukemia.

"I was shocked," he said, when his doctor called him with the diagnosis. His life was in danger, the doctor warned him. Jiang had been heading out the door to lunch. He changed his destination to the University of Kansas Cancer Center. The next morning, he started chemotherapy.

But the chemo wasn't doing the job of ridding Jiang's body of his cancerous bone marrow and the abnormal white blood cells they were producing. Doctors decided he needed a bone marrow transplant, a tough and sometimes risky course of treatment. A bone marrow donor was found, and Jiang received the transplant in April.

So, what does this have to do with Jiang's eyesight?

Before cancer patients undergo a bone marrow transplant, they must go through a rigorous course of chemotherapy or radiation to eliminate their own diseased marrow from their bones. The donated marrow is infused into their bloodstream and migrates to their bones, where it grows and begins producing healthy blood cells.

But bone marrow cells are also the source of the body's immune system. Until new marrow can renew patients' immune systems, they're exceedingly vulnerable to all kinds of infections. And as with other kinds of transplants, there's the potential for rejection, which can slow recovery.

When kidneys, livers and other organs are transplanted, the immune system of their new owner may sense them as foreign objects and launch a search and destroy mission. But with bone marrow transplants, rejection comes with a twist. It's the bone marrow itself, the person's new immune system, that sees its new home as the alien and attacks the patient. It's called graft versus host disease.

That's what happened to Jiang. "After the transplant, I was exhausted," he said. "I had one complication after another." There were headaches and stomach pain. To keep his graft versus host reaction in check, Jiang had to take drugs to suppress his immune system.

And that is how his eyesight was put in jeopardy.

Like most adults, Jiang is a carrier of cytomegalovirus, also called CMV. It's scary-sounding, and the virus can be life-threatening. But people with healthy immune systems generally keep it in check and never know they carry it. But in people with compromised immune systems, such as those with AIDS or bone marrow transplants, cytomegalovirus can cause big trouble.

Depending on which organs CMV attacks, it can cause inflammation of the brain, seizures, coma, ulcers in the digestive tract, pneumonia or inflammation of the liver. The virus also can attack the eyes.

For Jiang, it began a painful attack on the retina of his left eye, blurring his vision.

"We needed to stop this virus where it was or it was going to eat away the center of his vision," said Ajay Singh, Jiang's eye specialist at the University of Kansas Hospital. Singh started twice weekly injections of an anti-viral drug (ganciclovir) directly into Jiang's eyeball. The injections were painful and risked causing an infection. Singh couldn't give Jiang an oral version of the drug because it could damage his new bone marrow.

But Singh knew that during the AIDS epidemic, CMV eye infections were so common that a tiny device was created that could be loaded with medication and implanted directly into a patient's eye where it would slowly release the drug. Singh wanted one of these implants for Jiang - his patient was an ideal candidate - but they were nowhere to be found. It turned out that AIDS treatment had advanced so far that people with AIDS no longer were developing CMV eye infections. The implant manufacturer had pulled it off the market about a year or two ago, he found.

Singh was worried: The infection was a millimeter from the center of vision of Jiang's retina. If he didn't get an implant within a month, his vision could be lost. "The odds were stacked against him."

Early in October, Singh started making calls to Singapore, India and Mexico City, searching for an implant. He emailed the CEO of the company that discontinued the device but never received an answer. Eventually, the people Singh was contacting told him of an eye doctor in Kentucky who knew the original inventor of the implant. The Kentucky doctor put the two in touch. And it is here that the inventor-entrepreneur enters the picture.

"Dr. Singh somehow rooted me out," said Paul Ashton, CEO of Massachusetts-based pSivida. While pSivida had licensed its CMV implants to another company, it was still making other drug-dispensing eye implants.

Its newest is the size of an eyelash and can hold enough medication to treat diabetic eye disease for three years. Ashton offered Singh a slightly larger implant, about the size of a grain of rice, that would hold enough of the ganciclovir anti-viral drug.

"It was simply a matter of putting in a different drug," Ashton said. "We were changing the ammunition but keeping the same gun."

Singh recalled Ashton saying: "If you can send me the drug and get approval from the Food and Drug Administration, I will make you the implant." So Ashton went to his laboratory, testing the permeable ends of the tiny tube to be sure they would allow the drug to ooze out at the right speed. "It was a month of many sleepless nights. It was a race against time," Ashton said. "You can't keep injecting someone in the eye. Something bad is going to happen." Singh marveled at the speed with which Ashton's laboratory worked. "It's not like a car engine part" off the shelf, Singh said. "They have to test it. To do it in four weeks is a big deal."

In early November, the implant was ready. Singh called the FDA for emergency approval for the implant. "The FDA responded at lightning speed," he said. "I got an answer in four hours."

On Nov. 5, Singh implanted the device in Jiang's eye at KU Hospital.

"Now his cancer doctors can keep working on getting his bone marrow up and running," Singh said. The implant will continue delivering the drug to Jiang's eye for nine months to a year. "By that time, his immune system can recover and get the virus under control again."

Jiang said his vision is still a bit blurry, but his retina is recovering. Singh has assured him that in a few months, with new prescription glasses, he will be seeing well again. So far, his cancer hasn't returned and his graft versus host disease is well-controlled.

Jiang is grateful to the far-flung team that saved the vision in his left eye. "They all worked together. They worked so well together. I'm so fortunate."

To read more about how the pSivida drug delivery system works, please take a look at my initial writeup of Iluvien: Iluvien and the Future of Ophthalmic Drug Delivery Systems.


Tiny device and lots of teamwork save Olathe leukemia patient's sight, Alan Bailey, The Kansas City Star, January 2, 2015.

Wednesday, December 24, 2014

Stem Cells in Ophthalmology Update 28: First Ophthalmic Stem Cell Treatment Recommended for Approval

On December 19th, the European Medicines Agency's (EMA's) Committee for Medicinal Products for Human Use (CHMP) recommended the stem cell product Holoclar (Chiesi Farmaceutici S.p.A.)  as a first-ever medicinal treatment for severe limbal stem cell deficiency, a condition caused by physical or chemical burns to the eye or eyes in adults, which can result in blindness.

The EMA has designated Holoclar as both an orphan medicine and an advanced therapy medicinal product, which enabled the manufacturer to receive free scientific advice and protocol assistance for drug development. The CHMP recommendation was based on an assessment by the expert Committee for Advanced Therapies. Such steps are taken to promote the development of medicines for rare diseases and to encourage innovative medicinal products, according to the EMA statement.

Holoclar is produced by Chiesi under an agreement with Holostem Terapie Avanzate, an Italian biotechnological company devoted to the development, manufacture, registration and distribution of Advanced Therapy products based on cultures of epithelial stem cells both for cell therapy and gene therapy. Holoclar was designed specifically for the treatment of severe limbal stem cell deficiency (LSCD).

The transparency of the cornea is essential to ensure the ability to see properly. Corneal cell renewal and repair are dependent upon the cells present in the limbus, which is found in a small area of the eye between the cornea and the conjunctiva.

Thermal or chemical burns to the eye can destroy the corneal surface (epithelium) and the limbus, causing a deficiency of limbal cells. If this happens, the cornea is covered by a different epithelium following an invasion of cells from the conjunctiva. This process leads to neovascularization, chronic inflammation and stromal scarring, rendering the cornea opaque and results in subsequent loss of vision. Conventional corneal transplants are an ineffective treatment in such cases.

Fig 1 Damaged eye before treatment

The therapy is based on cultures of limbal cells taken from the patient, which, once they have successfully grafted, regenerate the corneal epithelium and restore its functions. Limbal cell cultures even allow the possibility of treating patients with a loss of corneal epithelium in both eyes, provided that a small portion of limbus remains in one of the eyes.

Holoclar, is an autologous culture of limbal stem cells. It is made from a biopsy taken from a small undamaged area (minimum of 1-2 mm2) of the patient's cornea and grown in the laboratory using cell culture, and transplanted in the affected eye or eyes after removal of the damaged area. Such cultures engraft and permanently regenerate a functional corneal epithelium allowing recovery of visual acuity. replacing damaged limbal stem cells.

Fig 2 A cultured sheet of corneal epithelium

Holoclar can offer an alternative to corneal transplantation for replacing altered corneal epithelium in some cases, and it has been shown to increase the chances of a successful corneal transplant where the injury has caused extensive eye damage. It reduces the risk of rejection compared with transplanting tissue from a donor and does not require surgery on the patient's other eye as only a small biopsy is performed to collect the cells, thus reducing the risk of damage to the healthy eye. Therefore, Holoclar may also be suitable where both eyes are affected by moderate to severe LSCD.

Limbal stem cell deficiency is estimated to affect about 3.3 per 100,000 people in the EU, causing pain, photophobia, inflammation, corneal neovascularization, loss of corneal transparency, and eventually blindness.

The recommendation was made by the Committee for Medicinal Products for Human Use (CHMP) based on a robust assessment carried out by the Committee for Advanced Therapies (CAT), the Agency's expert committee for ATMPs.

“This recommendation represents a major step forward in delivering new and innovative medicines to patients,” says Enrica Alteri, Head of EMA's Human Medicines Evaluation Division. “EMA has used all available support tools to facilitate the development and assessment of Holoclar. It is an advanced therapy medicinal product that has been designated as an orphan medicine. This allowed the Agency to provide support including several rounds of free scientific advice to the applicant during Holoclar's development.”

The Committee for Advanced Therapies and the CHMP panels determined that although the product's benefits outweigh its risks, the marketing authorization should be conditional because the data thus far are retrospective and not yet comprehensive. Therefore, the EMA says, "an additional study on the use of Holoclar should be conducted."

The opinion adopted by the CHMP at its December 2014 meeting is an intermediary step on Holoclar's path to patient access. The CHMP opinion will now be sent to the European Commission for the adoption of a decision on an EU-wide marketing authorization. After that, decisions about price and reimbursement will take place at the level of each member state,  taking into account the potential role/use of this medicine in the context of the national health system of that country.

Update: On February 20, 2015, the EMA approved European marketing for Holoclar. Chiesi said that Holclar would be available to all suitable patients in Europe "in the near future".


1. First stem-cell therapy recommended for approval in EU, European Medicines Agency Press Release, December 19, 2014

2. First-Ever Stem Cell Therapy Recommended in EU, Miriam E. Tucker, Medscape, December 19, 2014

Wednesday, October 15, 2014

Stem Cells in Ophthalmology Update 27: ACT Interim Clinical Results Are Outstanding

Having treated 36 patients in two clinical trials for Stargardt’s Macular Dystrophy (SMD - 24 patients to date) and for dry Age-Related Macular Degeneration (AMD - 12 patients to date), Advanced Cell Technology reported the interim results obtained with 18 of these patients (9 in each trial) in the US-based studies. Both trials (NCT01345006 - Stargardt’s, and NCT01344993 - AMD) began in July 2011, giving the company up to three-year’s data for the earliest patients, and a median of 22 months followup for all. The interim results were reported in The Lancet, published online October 14, 2014 in: “Human embryonic stem cell-derived retinal pigment epithelium in patients with age-related macular degeneration and Stargardt’s macular dystrophy: follow-up of two open-label phase 1/2 studies”.

An additional Stargardt’s trial, being conducted at two clinics in the United Kingdom, with 12 patients enrolled (NCT01469832), along with 3 of the 4 patients treated in each of two trials with better vision candidates, as part of the two clinical trials in the publication (Phase IIa), were not included in The Lancet results.

As noted by Paul K. Wotton, Ph.D., President and Chief Executive Officer of Advanced Cell Technology, "These study results represent an important milestone and strengthen our leadership position in regenerative ophthalmology. We would like to thank the patients for their willingness to participate in these studies. Our findings underscore the potential to repair or replace tissues damaged from diseases. We plan to initiate comprehensive Phase 2 clinical trials for the treatment of both AMD and SMD, two disease states where there is currently no effective treatment."

Editors Note: As announced on October 15th by the company, the Phase II dry AMD clinical trial (50 Patients) will start during the 1st Half of 2015 and is expected to be completed in the middle of 2016, taking place at 10 Trial Sites across North America. The Phase II SMD clinical trial (100 patients) will start during the 4th Quarter of this year or by the end of the year. It will take 18-24 months to complete, taking place at 30 sites across North America and Europe.

Robert Lanza, M.D., Chief Scientific Officer of ACT and co-senior author of the paper, commented, "Diseases affecting the eye are attractive first-in-man applications for this type of investigational therapy due to the immune-privileged nature of the eye. Despite the degenerative nature of these diseases, the vision of 10 of 18 patients showed measurable improvement at the six month follow up, after transplantation of the RPE cells. Furthermore, the cells have been well tolerated for a median period of 22 months with two of the patients treated more than three years ago. We are pleased that there have been no serious safety issues attributable to the cells observed in any of the patients."

Steven Schwartz, M.D., Ahmanson Professor of Ophthalmology at the David Geffen School of Medicine at UCLA and retina division chief at UCLA's Jules Stein Eye Institute, principal investigator and co-lead author of the publication said, "The data published in The Lancet support the potential safety and biological activity of stem cell-derived retinal tissue. Once again, surgical access to the subretinal space has proven safe. However, for the first time in humans, terminally differentiated stem cell progeny seem to survive, and do so without safety signals. Combined with the functional signals observed, these data suggest that this regenerative strategy should move forward. This is a hopeful and exciting time for ophthalmology and regenerative medicine."

These two studies provide the first evidence of the mid- to long-term safety, survival, and potential biologic activity of pluripotent stem cell progeny into humans with any disease. In addition to showing no adverse safety issues related to the transplanted tissue, anatomic evidence confirmed successful engraftment of the RPE cells, which included increased pigmentation at the level of the RPE layer after transplantation in 13 of 18 patients.

There was no evidence of adverse proliferation, rejection, or serious ocular or systemic safety issues related to the transplanted tissue. Adverse events were associated with vitreoretinal surgery and immunosuppression. Thirteen (72%) of 18 patients had patches of increasing subretinal pigmentation consistent with transplanted retinal pigment epithelium. Best-corrected visual acuity, monitored as part of the safety protocol, improved in ten eyes, improved or remained the same in seven eyes, and decreased by more than ten letters in one eye, whereas the untreated fellow eyes did not show similar improvements in visual acuity. Vision-related quality-of-life measures increased for general and peripheral vision, and near and distance activities, improving by 16–25 points 3–12 months after transplantation in patients with atrophic age-related macular degeneration and 8–20 points in patients with Stargardt’s macular dystrophy.

Figure 3: Change from baseline in best-corrected visual acuity in patients with age-related macular degeneration (A) and Stargardt’s macular dystrophy (B) Median change in best-corrected visual acuity was expressed as number of letters read on the Early Treatment of Diabetic Retinopathy Study visual acuity chart in patients with age-related macular degeneration (A) and Stargardt’s macular dystrophy (B). Red lines show treated eyes and blue lines show untreated eyes of patients during the first year after transplantation of the cells derived from human embryonic stem cells. Green lines show the difference between the treated and untreated eyes. Patients who underwent cataract surgery after transplantation are not included in the graph. There was a significant difference in the letters read in transplanted eyes of patients with age-related macular degeneration versus non-transplanted controls at 12 months (median 14 letters vs –1 letter; p=0·0117). There was an increase in letters read in transplanted eyes of patients with Stargardt’s macular dystrophy versus non-transplanted controls at 12 months (median 12 letters vs two letters, although the sample size was too small to allow reliable calculation of the Wilcoxon signed-rank test).
The SMD and dry AMD trials are prospective, open-label studies designed to evaluate the safety and tolerability of human embryonic stem cell (hESC)-derived RPE cells following sub-retinal transplantation into patients at 12 months, the studies' primary endpoint. Three dose cohorts were treated for each condition in an ascending dosage format (50,000 cells, 100,000 cells, and 150,000 cells). Both the SMD and dry AMD patients had subretinal transplantation of fully-differentiated RPE cells derived from hESCs.

Dr. Anthony Atala, a surgeon and director of the Wake Forest Institute for Regenerative Medicine at Wake Forest University in an accompanying commentary in The Lancet said:

"It really does show for the very first time that patients can, in fact, benefit from the therapy.
That allows you to say, 'OK, now that these cells have been used for patients who have blindness, maybe we can also use these cells for many other conditions as well, including heart disease, lung disease and other medical conditions.' "

Human embryonic stem cells have the ability to become any kind of cell in the body. So scientists have been hoping the cells could be used to treat many diseases, including Alzheimer's, diabetes and paralysis. But the study is the first human embryonic stem cell trial approved by the Food and Drug Administration that has produced any results.

"It is really a very important paper."

The co-authors of the study summarized their interpretation of their results in this way:

“The results of this study provide the first evidence of the medium-term to long-term safety, graft survival, and possible biological activity of pluripotent stem cell progeny in individuals with any disease. Our results suggest that human-embryonic-stem-cell-derived cells could provide a potentially safe new source of cells for the treatment of various unmet medical disorders requiring tissue repair or replacement.”

My takeaway from reading The Lancet article (and several of the accompanying writeups about the study) is, the use of RPE derived from embryonic stem cells is safe and efficacious, particularly in the eye. But most of all, this important study shows that Advanced Cell Technology is able to safely stop the progression of to-date untreatable dry AMD and SMD retinal diseases (17 of 18 patients) and to improve the vision in those who have lost considerable sight (10 of 18 patients).

Finally, the two clinical trials that are reported on in The Lancet, were done on patients with nothing to lose (with vision no better than 20/400), whereas patients in the Phase IIa study, still in progress, have vision no worse than 20/100. It is anticipated that even better results will be shown with this better vision group.


Other Resources:

Encouraging New Paper on ACT Stem Cell-Based Trial for Macular Degeneration, Paul Knoepfler, Knoepfler Lab Stem Cell Blog, October 14, 2014

Embryonic Stem Cells Restore Vision In Preliminary Human Test, Rob Stein, NPR Health Blog, October 14, 2014

Disclosure: As of September 17, 2014, I own a small number of shares of the company’s stock.

Friday, September 26, 2014

Iluvien Update 8: Alimera Sciences Receives FDA Approval of Iluvien for Treatment of DME

After several attempts to gain approval for its NDA for Ilunien, the FDA has finally seen the light (after approval in the UK, Germany, and marketing or pending approvals in seventeen other EU countries).

I first began writing about Iluvien in July 2010 – see my comprehensive writeup about the technology behind this and other sustained delivery drug systems – Iluvien and the Future of Ophthalmic Drug Delivery Systems. In addition I have written about the products progress in seven updates, the latest in August 2012, Iluvien Update 7: Alimera Sciences to Re-File for FDA Approval of Iluvien for Chronic DME

Here are the statements from the two companies involved in bringing Iluvien to the market, Alimera Sciences, the marketing arm, and pSivida the licensor of the technology to Alimera:

Alimera Sciences announced that the U.S. Food and Drug Administration (FDA) has approved ILUVIEN for the treatment of diabetic macular edema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure (IOP). Alimera currently intends to begin selling ILUVIEN in the U.S. in the first quarter of 2015.

"We are very excited with this news from the FDA and thank the many people who contributed to this outcome and believed in ILUVIEN, including the retinal specialists, clinical site personnel, reading centers, and the many patients and their caregivers for helping us bring this long-term treatment to people in the U.S. with DME," said Dan Myers, president and chief executive officer of Alimera. "The approval of ILUVIEN under this broader label brings a DME treatment to the U.S. that lasts years, not months, after a single injection and greatly expands the addressable market opportunity in the U.S."

"The approval of ILUVIEN is wonderful news for the retinal community, as recent studies have indicated that as many as 50 percent of DME patients are not optimally managed with today's standard of care known as anti-VEGF therapies," said Pravin Dugel, M.D., Retinal Consultants of Arizona and clinical associate professor, Doheny Eye Institute, Keck School of Medicine, University of Southern California. "Having a multi-year delivery, low-dose corticosteroid drug will provide an additional treatment option for patients with this disease."

ILUVIEN (fluocinolone acetonide intravitreal implant) 0.19 mg is a sustained release intravitreal implant approved in the U.S. to treat diabetic macular edema (DME) in patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure. Each ILUVIEN implant is designed to release submicrogram levels of fluocinolone acetonide (FAc), a corticosteroid, for 36 months. The ILUVIEN approval was based on clinical trial data that showed that at month 24 after receiving the ILUVIEN implant, 28.7 percent of patients (p value .002) experienced an improvement from baseline in their best corrected visual acuity on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart of 15 letters or more. Patients treated with ILUVIEN experienced a statistically significant improvement in visual acuity compared to the control group by week three of follow up, and maintained a statistically significant advantage over the control through completion of the trial at month 36.

"As the role of inflammation in DME becomes more clearly understood, the use of a continuous, long-term, low-dose anti-inflammatory, such as ILUVIEN, is an important option for patients who have DME that persists," said Barry Kuppermann, M.D., Ph.D., professor and chief of the Retina Service at University of California, Irvine.

"As the glaucoma specialist on the FAME Study Data Safety Monitoring Board, I have extensive familiarity with the IOP data related to ILUVIEN," said Richard Parrish, M.D., Professor and Director of the Glaucoma Service at the University of Miami Miller School of Medicine, Bascom Palmer Eye Institute.  "I am confident that the benefits of this important treatment for DME will outweigh concerns related to elevated IOP in the indicated patients."

And, from pSivida:

pSivida today announced that the U.S. Food and Drug Administration (FDA) has approved ILUVIENr for the treatment of diabetic macular edema (DME). It is indicated for patients who have been previously treated with a course of corticosteroids and did not have a clinically significant rise in intraocular pressure (IOP). A single injection of the ILUVIEN micro-insert provides sustained treatment of DME for 36 months. Approximately 560,000 people in the U.S. are estimated to have clinically significant DME, the most frequent cause of vision loss in individuals with diabetes and the leading cause of blindness in young and middle-aged adults in developed countries. ILUVIEN is expected to be commercially available in the U.S. in early 2015.

FDA approval of ILUVIEN entitles pSivida to a $25 million milestone from its licensee Alimera Sciences. pSivida will also be entitled to 20% of the net profits from sales of ILUVIEN in the U.S.

"FDA approval of ILUVIEN, our third FDA-approved product for retinal disease, provides an important treatment option for DME patients in the U.S., the majority of whose DME, despite anti-VEGF intra-ocular injections as frequently as monthly, is not optimally managed. ILUVIEN's clinical trials showed that ILUVIEN can actually reverse vision loss in many DME patients. Another advantage of ILUVIEN over existing therapies is that a single injection provides sustained therapy for three years," said Paul Ashton, Ph.D., president and chief executive officer of pSivida.

"The $25 million milestone will help finance our ongoing product development program, including MedidurT for posterior uveitis and TethadurT for the sustained delivery of biologics," added Dr. Ashton. pSivida is independently developing Medidur, an injectable, sustained release micro-insert of the same design and delivering the same drug as ILUVIEN, for the treatment of chronic posterior uveitis, the third largest cause of blindness in the U.S. The Company plans to seek FDA approval of this product on the basis of its ongoing single Phase III clinical trial. Enrollment of this study is expected to be completed by the end of the first quarter of calendar 2015.

ILUVIEN is already commercially available in the U.K. and Germany, and has received or is pending marketing approval in seventeen other EU countries, for the treatment of patients with the chronic DME insufficiently responsive to available therapies. "We are very pleased that the FDA's approval of ILUVIEN is not limited, as in the EU, to the subset of patients with chronic DME, patients who have failed other therapies, or patients who have had cataract surgery," continued Dr. Ashton.

ILUVIEN is an injectable micro-insert that provides sustained treatment through continuous delivery of a submicrogram dose of the corticosteroid fluocinolone acetonide for 36 months. Current standard-of-care therapy requires anti-VEGF injections into the eye as frequently as monthly, and studies show that over 50 percent of patients are not optimally managed with this treatment. FDA approval was based on clinical trial data that showed that at month 24, 28.7 percent of patients receiving ILUVIEN experienced an improvement from baseline in their best corrected visual acuity on the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart of 15 letters or more. This improvement in vision was maintained through 36 months, the end of the trials. 

Monday, September 15, 2014

Retina Revealed

Over the weekend, I read an excellent account of how the various parts of the retina work. Ben Shaberman, the senior science writer for the Eye on the Cure blog (Foundation Fighting Blindness), put together an easy to read and understand overview of what the various cell layers of the retina do and how they interact. Since the retina is the focus of most of what I write about, I asked Ben for his permission to reproduce the writeup in this space. Permission was granted and here is what he wrote:

By Ben Shaberman,  September 8, 2014
Eye on the Cure - Foundation Fighting Blindness

Your eyes are not just windows to your soul, but to your health as well. People rarely pay attention to their eyes, until something goes wrong. The eye is a delicate organ, and vision is a complex process involving various components.

Photoreceptors, in particular, get a lot of attention from researchers because they're the main cells in the retina that make vision possible. They convert light into electrical signals, which are sent to the brain and used to construct the images we see. Also, many retinal diseases begin with loss of photoreceptors.

However, the retina is like a multi-layer cake, with each layer comprised of different types of cells, all playing important roles in retinal health and vision. While preserving and restoring photoreceptors is often job number one for scientists, they also explore ways to protect other retinal cells from deterioration and even harness them to restore vision.

Here's a summary of the major retinal cell types, their functions and their potential roles in future treatments of diseases:

Choroid - The choroid is a layer of blood vessels that supplies oxygen and nourishment to the retina. Defects in the CHM gene cause choroideremia, a disease characterized by deterioration of the choroid, retinal pigment epithelium (RPE) and photoreceptors. In the wet form of age-related macular degeneration, leaky blood vessels expand from the choroid into the retina – a process called choroidal neovascularization – which causes loss of photoreceptors and central vision.

Retinal pigment epithelium - Also known as the RPE, this is a single layer of cells above the photoreceptors that provides them with essential nutrition and waste removal. In age-related macular degeneration (AMD) and Stargardt disease (SMD), toxic waste products accumulate in the RPE or between the RPE and photoreceptors. Subsequently, the RPE deteriorates, leading to loss of photoreceptors.

Photoreceptors -These are the retinal cells, known as rods and cones, that initiate the vision process by converting light into electrical signals. Rods provide low-light and peripheral vision. Cones are concentrated in the macula, the central region of the retina, and provide central and color vision. The outer segments of rods and cones are antenna-like projections that absorb light and convert it into electrical signals. Inner segments are the cell bodies where other supportive functions are performed. The adult human retina has approximately 125 million photoreceptors.

Bipolar cells - Their job is to receive electrical information on lighting intensity from photoreceptors and pass it along to other retinal cells. Bipolar cells often survive after photoreceptors are lost to disease. This makes them an attractive target for emerging optogenetic treatments, which are designed to provide light sensitivity and restore vision.

Ganglion cells - Ganglion cells receive input from many different cells in the inner retinal layers and process visual information, including detection of edges, contrast and colors. Ganglion cells extend to form an optic nerve, a million-fiber cable that conveys visual information from the eye to the brain. In people with advanced retinal disease, ganglion cells often survive longer than bipolar cells, making them a potential target for optogenetic therapies. Currently, scientists believe that bipolar cells may provide a more detailed visual experience than ganglion cells when treated with a light-sensing therapy, because they reside in layers of the retina closer to photoreceptors.

Muller glia - Muller cells extend through the retina, like spokes of a wheel, providing structural support and guiding light through the inner retina. They also transport molecules critical to retinal health and vision. Researchers believe Muller cells may even have the capacity to become new photoreceptors, which could lead to restoring vision. The research is still new, but success might someday have a big impact on the vision of people with advanced diseases.

A final note

The processing of visual information in the retina-beginning with 125 million photoreceptors and converging on a one-million-fiber optic nerve-remains a subject of intense research. There's still much that scientists don't know about the retinal cells and their roles. For example, little is known about the processing activities of amacrine and horizontal cells, which reside between bipolar and ganglion cells. However, advancing imaging technologies, including adaptive optics and optical coherence tomography, are helping complete the picture.

For additional information about retinal anatomy and function, please see the Eye on the Cure post "Appreciating the Beauty of the Retina." The University of Utah's Webvision is one of the best online sources for detailed information about the retina. I also want to thank John Flannery, Ph.D., at the University of California, Berkeley, for his editorial input.

Saturday, September 13, 2014

Stem Cells in Ophthalmology Update 26: First Wet AMD Patient Treated With RPE Derived from iPS Cells

Earlier this week, it was reported that Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology (CDB) in Kobe had appeared in front of a 19-member health-ministry committee for the safety of the clinical use of stem cells. She was flanked by Shinya Yamanaka, the biologist who first created iPS cells. Yamanaka shared the 2012 Nobel Prize in Physiology or Medicine for his breakthrough and now heads the Center for iPS Cell Research and Application in Kyoto. Takahashi was seeking approval to implant a retinal pigmented epithelial (RPE) sheet made from induced pluripotent stem (iPS) cells into a human patient.

Takahashi and her collaborators had shown in monkey and mice studies that iPS cells generated from the recipients' own cells did not provoke an immune reaction that causes them to be rejected. There had been concerns that iPS cells could cause tumours, but Takahashi's team found that to be unlikely in mice and monkeys.

To counter further fears that the process of producing iPS cells could cause dangerous mutations, Takahashi's team had performed additional tests of genetic stability. Guidelines covering the clinical use of stem cells require researchers to report safety testing on the cells before conducting transplants. The health ministry said that no problems were found and that the human trial could commence.

Only four days later (Friday, September 12th), the first patient was treated with the implanted sheet of RPE cells. She derived them from the patient's skin cells, after producing induced pluripotent stem (iPS) cells and then getting them to differentiate into retinal cells.

This is a major first for the stem cell and regenerative medicine fields.

Takahashi and her collaborators have been using induced pluripotent stem (iPS) cells to prepare a treatment for age-related macular degeneration. Unlike RPE derived from embryonic stem cells (i.e., as being done by Advanced Cell Technology), iPS cells are produced from adult cells, so they can be genetically tailored to each recipient. They are capable of becoming any cell type in the body, and have the potential to treat a wide range of diseases. The CDB trial will be the first opportunity for the technology to prove its clinical value.

A Japanese woman in her 70s is the world's first recipient of cells derived from induced pluripotent stem cells, a technology that has created great expectations since it could offer the same advantages as embryo-derived cells but without some of the controversial aspects and safety concerns.

In a two-hour procedure starting at 14:20 local time, a team of three eye specialists lead by Yasuo Kurimoto of the Kobe City Medical Center General Hospital, transplanted a 1.3 by 3.0 millimeter sheet of retinal pigment epithelium cells into an eye of the Hyogo prefecture resident, who suffers from age-related macular degeneration.

The procedure took place at the Institute of Biomedical Research and Innovation Hospital, next to the RIKEN Center for Developmental Biology (CDB) where ophthalmologist Masayo Takahashi had developed and tested the epithelium sheets.

Afterwards, the patient experienced no effusive bleeding or other serious problems, as reported by RIKEN.

Another important element to this story is that Japan has a clinical translation pipeline that is now faster with recent changes in regulations than that of the US. For example, this and future iPS cell-based transplants were approved as part of a clinical study, a type of clinical research mechanism that doesn't exist in the US. It is safe to say that the same technology with the same research team and outstanding level of funding would still be at least a few years away from their first patient in the US due to the different regulatory scheme.

As noted by Dr. Paul Knoepfler, in his writeup about the procedure:

 “The patient is clearly a brave hero. The team transplanted a huge (from a bioengineering perspective) 1.3 x 3.0 mm sheet of RPEs into the retina of the patient, who did not have any clear immediate side effects from the procedure. Keep in mind again that this sheet was made indirectly from the patients own skin cells so it is an autologous (or self) transplant, a notion that 10 years ago would have seemed entirely like sci-fi.”

“This is not only a huge milestone, but also an astonishingly fast translation of iPS cell technology from the bench to the bedside.”

 “Also, on the positive side we have the encouraging results from the ongoing clinical trials from Advanced Cell Technology (ACT) using a similar approach to macular degeneration, but employing human embryonic stem cells to make the RPEs.”

“For the vision impaired and the broader stem cell field, it is heartening to have two such capable teams working to cure blindness with pluripotent stem cells.”


3. Stem cell landmark: patient receives first ever iPS cell-based transplant, Knoepfler Lab Stem Cell Blog, Paul Knoepfler, Septermber 12, 2014.

Thursday, August 21, 2014

A Potential New Approach to the Treatment of Retinitis Pigmentosa

In a recently published study (1), researchers at the Columbia University Medical Center (CUMC) have come up with a novel approach in developing an individualized treatment for RP patients, using the patients' own cells transformed into an in vitro model for studying the disease and developing a potential treatment.

While RP can begin during infancy, the first symptoms typically emerge in early adulthood, starting with night blindness. As the disease progresses, affected individuals lose peripheral vision. In later stages, RP destroys photoreceptors in the macula, which is responsible for fine central vision. RP is estimated to affect at least 75,000 people in the United States and 1.5 million worldwide.

Mark Hillen, editor of The Ophthalmologist has written about this new approach, and I have reproduced the writeup, with his permission.

Might you soon take a skin cell from a patient with retinitis pigmentosa, roll it back to a pluripotent state, culture it to become retinal cells and trial gene therapy on it in vitro?

By Mark Hillen
The Ophthalmologist, July/August 2014

Personalized medicine is a particularly hot topic in medicine. Take cells from a patient, modify or grow them, and return them to the patient for their therapeutic effects. What a team of Manhattan-based researchers are doing at the Columbia University Medical Center (CUMC) is something rather special. They take skin epithelial cells from patients with retinitis pigmentosa (RP), turn them into induced pluripotent stem (iPS) cells, then differentiate them into retinal cells in cell culture, enabling them to examine what the structural and functional defects of these retinal cells really are - without having to perform a dangerous (and ethically dubious) excision of a section of a patient's retina to do so (1).

More than 60 different genes have been linked to RP, making it a challenge to go to a mouse model to study the disease. Making a genetically-modified mouse is time consuming enough, but there's the additional confounding factor that the retinae of mice and men have enough interspecies differences to induce a great depression in researchers. This is why the ability to study the patient's own retinal cells in culture is so valuable.

Using this approach, the CUMC researchers examined cells from a patient with RP that resulted from a mutation in the MFRP (membrane frizzled-related protein) gene. Analysis of these cells showed that the primary effect of MFRP mutation is to disrupt the regulation of the major cytoskeletal protein, actin (Figure 1). "Normally, the cytoskeleton looks like a series of connected hexagons," said lead researcher, Stephen Tsang. "If a cell loses this structure, it loses its ability to function."

In the next phase of the study, the CUMC team used adeno-associated viruses to introduce normal copies of MFRP into the iPS-derived retinal cells (in cell culture), successfully restoring the cells' function. The team went on to successfully use gene therapy to rescue the "normal" phenotype in mice with MFRP mutation-induced RP.

Does this herald a future of personalized medicine, where patients can have their retinae reproduced from skin cells, their disease state assessed, and potential gene therapy options trialled, all in vitro, in order to choose the most effective gene therapeutic option? Tsang believes so, concluding that, "The use of patient-specific cell lines for testing the efficacy of gene therapy to precisely correct a patient's genetic deficiency provides yet another tool for advancing the field of personalized medicine. iPS cells can help us determine whether these genes do, in fact, cause RP, understand their function, and, ultimately, develop personalized treatments."

Figure 1. a. Normal (wild-type) retinal cells: the protein actin forms the cell's cytoskeleton, creating an internal support structure that looks like a series of connected hexagons; b. This structure fails to form in cells with MFRP mutations, compromising cellular function; c. Diseased retinal cells, when treated with gene therapy to insert normal copies of MFRP, have normal-looking cytoskeletal structures and function.


1. Y. Li, W.-H. Wu, C.-W. Hsu, et al., "Gene Therapy in Patient-specific Stem Cell Lines and a Preclinical Model of Retinitis Pigmentosa With Membrane Frizzled-related Protein Defects", Mol. Ther. Epub ahead of print (2014). doi:10.1038/mt.2014.100.

Sunday, May 25, 2014

Menu 21: A List of Writeups on Gene Therapy Used in Ophthalmology

As with my menu on stem cells used in ophthalmology (Menu 20), here is one for the current articles on the use of gene therapy in ophthalmology, with links to the full writeups.

(Updated May 25, 2014)

Gene Thearpy

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 announcement today, Oxford BioMedica said that it had gained approval from the FDA to begin a Phase I/IIa Clinical Trial for a form of Usher’s Syndrome, Type 1B, which leads to progressive retinitis pigmentosa combined with a congenital hearing defect.

In a news release that I found on the net, I learned that the Foundation Fighting Blindness was going to put $8.25 million into six gene therapy projects, either already underway or about to start. The release contains good information about several projects that I knew about, and others that I did not.

In  another of the presentations made during the Retina SubSpecialty Day Meeting, Dr. Stephen Tsang presented on factors and the genetics of retinitis pigmentosa. His paper was based on the article previously published by he and his co-author, Kyle Wolpert, that appeared in the November 2010 issue of Retinal Physician.

Gene Therapy in Ophthalmology Update 4: Table of Companies and Institutions Participating Nov. 2011

Again, this table is currently out-of-date. See Update 16.

A writeup about a start-up company, Hemera Biosciences, with a gene therapy approach to treating dry AMD.

Thanks to my friends at the Foundation Fighting Blindness, I learned about this first human clinical trial using gene therapy for treating recessive retinitis pigmentosa.

In this opus, I discuss my reasons why I think 2012 is going to be the year for gene therapy and also presented my table of current clinical trials underway. (Again, note there is now an updated table available via Update 16.)

A report on the progress being made in treating Leber’s using gene therapy, as reported by the Foundation Fighting Blindness.

Gene Therapy in Ophthalmology Update 9: Oxford BioMedica/OHSU Preparing to Treat First Usher Syndrome Patient & Oxford BioMedica Ophthalmic Program Update Mar. 2012

A report on the start of the program to treat Usher Syndrome patients at OSHU, and an update on other ophthalmic programs underway by Oxford BioMedica.

Gene Therapy in Ophthalmology Update 10: Gene Therapy Research in Dogs Cures X-Linked Retinitis Pigmentosa – Paves the Way for Similar Treatment in Humans  Mar. 2012

Researchers at several universities and laboratories collaborated to treat dogs afflicted with the x-linked form of retinitis pigmentosa, to deliver the therapeutic RPGR gene specifically to the diseased rods and cones, which led to functional and structural recovery. This is the first proof that this condition is treatable in an animal model and the researchers feel the results are promising and relevant for translation to humans afflicted with this disease.

Gene Therapy in Ophthalmology Update 11: Clinical Trial Details May 2012

In attempting to determine how many patients had been treated with gene therapy for eye disorders, I quickly found that no one was keeping track – at least no one that I could find.

So, I decided to try and get this data. I have now found reliable data for more than two-thirds of the 16 clinical trials underway and present this information in my new table. My latest table (available via Update 16) contains all of the newest data.

Editors Note: See Update 16 for access to the latest versions of the three tables.

Gene Therapy in Ophthalmology Update 12: First Gene Therapy Approval on the Horizon Jul. 2012

As Andrew Pollack writes in today’s NYTimes, “After more than two decades of dashed expectations, the field of gene therapy appears close to reaching a milestone: a regulatory approval. The European Medicines Agency has recommended approval of a gene therapy to treat a rare genetic disease.”

The therapy recommended for approval in Europe, called Glybera, was developed by uniQure, a Dutch company. It treats lipoprotein lipase deficiency, a disease that affects only several hundred people in the European Union and a similar number in North America.

People with the disease have a genetic mutation that prevents them from producing an enzyme needed to break down certain fat-carrying particles that circulate in the bloodstream after meals. Without the enzyme, so much fat can accumulate that the blood looks white rather than red.

The reason I believe that this is important is because it brings “legitimacy” to the whole field of regenerative medicine. As readers of this online Journal are aware, my interest is in the field of ophthalmology. As you may be further aware, I am currently tracking eleven clinical trials involving the use of stem cells to treat ophthalmic disorders and sixteen gene therapy clinical trials. Several of these are showing promising results and the above approval, when it comes, will bring increased attention to the whole of this field, including the ophthalmic trials.

Gene Therapy in Ophthalmology Update 13: New Clinical Site for Usher Syndrome Clinical Trials  Jul. 2012

The Foundation Fighting Blindness and Oxford BioMedica announced funding for a second clinical site to conduct a gene therapy trial for Ushers Syndrome. The site will be the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts in Paris, and will join the ongoing clinical trial being held at the Oregon Health & Science University's Casey Eye Institute.

Gene Therapy in Ophthalmology Update 14: Early Positive Results in Ongoing Gene Therapy Wet AMD and Stargardt’s Disease Studies Aug. 2012

Last week, Oxford BioMedica and its partner Sanofi announced positive results in their ongoing gene therapy clinical trials for wet AMD and Stargardt’s disease. In an interim review of their Phase I (RetinoStat) and Phase I/IIa (StarGen) trials, the Data Safetly Monitoring Board (DSMB), an independent panel of specialists in the fields of ophthalmology, virology and vectorology, gave the go ahead to proceed to a final patient cohort in the Phase I study in the case of the RetinoStat trial, and to a third patient cohort in the Phase I/IIa study of the StarGen trial.

Gene Therapy in Ophthalmology Update 15: First Gene Therapy Treatment Approved! Nov. 2012

As I first wrote back in July (Update 12: First Gene Therapy Approval on the Horizon), the first approval of a gene therapy application in medicine was expected soon. It has now been accomplished. On November 2nd, the European Medicines Agency gave final approval to a gene therapy approach to treat a rare genetic disease.

The therapy, given approval in Europe, called Glybera, was developed by uniQure, a Dutch company. It treats lipoprotein lipase deficiency (LPLD), a disease that affects only several hundred people in the European Union and a similar number in North America.

The reason I am noting this accomplishment in this space, where I normally write about treatments for ocular diseases is, because it brings “legitimacy” to the whole field of regenerative medicine. As readers of this online Journal are aware, my interest is in the field of ophthalmology. As you may be further aware, I am currently tracking twenty one clinical trials involving the use of stem cells (or cell threapy) to treat ophthalmic disorders and sixteen gene therapy clinical trials. Several of these are showing promising results and the above approval will bring increased attention to the whole of this field, including the ophthalmic trials.

Gene Therapy in Ophthalmology Update 16: Current Tables Now Online Jan. 2013/May 2014

Access to the three updated tables of information about the companies and institutions active in gene therapy, the ophthalmic applications being pursued, and the clinical trials underway and completed.

Gene Therapy in Ophthalmology Update 17: Hemera Biosciences Obtains Initial Funding Mar. 2013

Hemera biosciences has obtained initial funding, along with the issuance of a US Patent covering their technology and can now begin manufacturing its drug, soluble CD59 (protectin), perform animal toxicology, and initiate a phase 1 clinical study.

To review, HMR59 is a gene therapy using an AAV2 vector to express a soluble form of a naturally occurring membrane bound protein called CD59 (sCD59), which blocks MAC. Membrane attack complex is the final common pathway of activation of the complement cascade, and is composed of complement factors C5b, C6, C7, C8 and C9 that assemble as a pore on cell membranes. The MAC pore induces ionic fluid shifts leading to cell destruction and ultimate death. 

HMR59 works by increasing the production of sCD59 by ocular cells. The sCD59 released from the cells will circulate throughout the eye and penetrate the retina to block MAC deposition and prevent cellular destruction. By blocking MAC, the remainder of the upstream complement cascade is left intact to perform its normal homeostatic roles.

Gene Therapy in Ophthalmology Update 18: A RetroSense Update  Mar. 2013

Since I first wrote about RetroSense in November 2010, I have learned that they are using a unique technology, called Optogenetic Therapy to treat retinitis pigmentosa and dry AMD. Optogenetics combines gene therapy and optical methods to provide vision where there is none.

The gene therapy allows the delivery of an “opsin” that converts second- or third-order non-light sensitive cells to become light sensitive to mimic the function of rods and cones.

Gene Therapy in Ophthalmology Update 19: A New Virus Vector for Safer Delivery of Gene Therapies Jun. 2013

Researchers at UCal Berkeley have found a gene therapy vector that can deliver genes deep into the retina via intravitreous delivery, instead of using a needle to deliver the virus sub-retinally.

This eliminates the need for a vitrectomy, anesthesia and a hospital stay to treat patients, allowing for a simple short office visit and injection into the vitreous, similar to the way anti-VEGF drugs for age-related macular degeneration are currently delivered.

Gene Therapy in Ophthalmology Update 20: Oxford BioMedica Gene Therapy Clinical Trials Resume Oct. 2013

As I have recently noted, both Oxford BioMedica and Genzyme had stopped recruiting for their respective gene therapy clinical trials this summer. Oxford announced the reason for its stoppage, but no word from Genzyme (and no response to my attempts to find out).

Well, Oxford announced today that it had resumed its clinical trial after receiving clearances from both the FDA and the French regulatory agency, ANSM.

Gene Therapy in Ophthalmology Update 21: New Gene Therapy Company, Spark Therapeutics, Launches Oct. 2013

Children’s Hospital of Philadelphia has spun out a new gene therapy company, Spark Therapeutics, that has taken over CHOP’s gene therapy programs. The new company takes over the advanced clinical trial for treating Leber’s Congenital Amaurosis, as well as an earlier stage trial for treating hemophilia B.

The Phase III clinical trial for Leber’s, is expected to be completed in mid-2015, and could become the first FDA-approved gene therapy treatment in the U.S.


Recently, I encountered a unique referral source, goldenretrevor/pra-research. This piqued my curiosity and I went to the site and took a look. It turns out that the site is run by the owner of a Golden Retriever, named Trevor, along with two Labrador Retriever siblings. It seems that Trevor had been diagnosed with photo receptor cone disease (prcd), associated with progressive retinal atrophy (PRA). This was discovered when the dog was a puppy and the owner decided to look into this disease to see if there was anything that could be done to prevent him from going blind.

In doing extensive research, the owner, Katie McCormick, discovered that there was little research being done in the field of PRA in animals, but that PRA is genetically similar to retinitis pigmentosa (RP) in humans, as one study noted, "Identical mutation in a novel retinal gene causes progressive rod-cone degeneration (prcd) in dogs, and retinitis pigmentosa in man." And, there was lots of research being done on RP.

In her blog entry on PRA Research, Katie describes how she set up a “Google Alert” using the terms “progressive retinal atrophy” and “retinitis pigmentosa” – which is how she found my Journal article on The Use of Gene Therapy in Treating RP and Dry AMD.

A Novel Gene Therapy Approach to Treating the Wet Form of AMD: The BioFactoryTM From Avalanche Biotech  Feb. 2012

I originally contacted this company in November 2010, when they were still in “stealth mode” and weren't able to share details about what they were doing. Recently, the company got back in touch to provide an update, having announced, in December 2011, a clinical trial of their gene therapy approach to treating the wet form of AMD.

Since their approach is unique, and possibly “game changing” for the treatment of the wet form of AMD, I asked if I could prepare a writeup about the company and its technology for publication in my online Journal, and the co-founder and CEO Tom Chalberg agreed to answer my questions, as best as he could. So, here in their own words is what Avalanche Biotech is all about.

An Update on Avalanche Biotechnologies: A Potential Longer-Lasting Wet AMD Treatment? May 2014

With the news of a collaboration between Avalanche and Regeneron, we decided to update our initial report on Avalanche to describe what the collaboration is all about, as well as a brief update of the clinical trial underway using Avalanche’s Ocular BioFactory. Could this approach to treating wet AMD lead to fewer injections – once every 18 months or several years – in controlling this sight-robbing disease?