I last wrote about the status of gene therapy in ophthalmology in the April 2013 issue of Retinal Physician.1 In that article, I provided an introduction to the use of gene therapy for eye disease. Now, I’d like to bring you up to date on where the field stands two-and-a-half years later.

I continue to monitor the field and update the Gene Therapy in Ophthalmology Tables that describe the companies and institutions involved, the applications being researched and pursued, and the status of ongoing and completed clinical trials.

According to my latest update (September 1, 2015), there are currently 42 companies and institutions actively pursuing gene therapy solutions to ophthalmic diseases, working on 21 applications, resulting in 26 clinical trials either under way or completed and more than 180 eyes treated to date, including some second eyes.

The latest versions of the three tables listing this information can be accessed via my online blog.2

I’d like to discuss where I believe the field of gene therapy in ophthalmology stands today, in trying to get this therapy into your hands to treat several important retinal diseases, most of which lack good treatment modalities.

Leber Congenital Amaurosis

Currently, there are at least eight gene therapy clinical trials of treatments for Leber congenital amaurosis (LCA) under way or completed, with the most advanced being undertaken by Spark Therapeutics (Philadelphia, PA), a spin-off of the Children’s Hospital of Philadelphia (CHOP).

Spark has completed recruitment for its phase 3 trial (ClinicalTrials.gov number NCT00999609), following encouraging results to date from their two phase 1 trials (NCT00516477 and NCT01208389), with some patients now at four years following treatment. The company plans to announce the phase 3 results to date, before the end of this year.

With the increase in the understanding of the genetic underpinnings of diseases, the diagnosis of what are referred to as inherited retinal dystrophies (IRDs), such as LCA, has begun to shift from traditional clinical nomenclature to a diagnosis based on the specific underlying causal gene. In the case of Spark’s LCA trials, SPK-RPE65 has been studied in subjects with LCA due to RPE65 mutations, as confirmed by genetic testing.

However, with the broad availability of genetic testing and the corresponding shift from clinical to genetic diagnosis, Spark believes SPK-RPE65 will have broad application to IRDs caused by autosomal-recessive RPE65 gene mutations.

A controversy arose this summer, when the results of two clinical trials were reported in the New England Journal of Medicine. The two studies, conducted at the University of Pennsylvania3 (NCT00481546) and at University College of London4 (NCT00643747), both reported that an initial improvement in vision was seen, which then began to decrease after one to three years. These results have led to questions regarding whether the vision improvements seen with adeno-associated virus (AAV) gene therapies for LCA might not last long in the eye.

This controversy was quickly resolved, however. Analysis of the methods used for the two reported studies, compared to the method used by Spark Therapeutics, which reported no such loss of vision following long-term analysis of its data, placed the potential blame on differences in the makeup of the vectors used and the delivery methods, among other factors.

An analyst’s analysis of the differences in the three trials,5 including the makeup of the vectors used, the different gene promoters, and the methods of delivering the therapy subretinally, including the use of a surfactant by Spark to prevent clumping of AAVs within the needle used during subretinal injection (see Figure 1), clearly favored Spark’s approach.

Further, as stated by Spark in a statement,6 “SPK-RPE65 continues to demonstrate long-lasting effects, with subjects reported to date from [Spark’s] Phase I study of the contralateral eye maintaining improvements in function, vision, and retinal sensitivity through their latest follow-up visit, which ranges from two to four years post-injection.”

In addition, Jean Bennett, MD, PhD, who leads the LCA clinical trials at CHOP, said that her study, which used a somewhat different gene promoter than the other two trials, has not found the evidence of photoreceptor degeneration that the other two did.

Dr. Bennett said, “I wouldn’t say one administration of treatment is going to totally stop the disease in its tracks. Who cares how many photoreceptors you have if you’re still seeing? The numbers don’t mean anything if the person is still benefitting from the intervention.”7

Thus, it appears that we are on course, particularly in the case of LCA, to accomplish the “forever fix,” ie, the name so aptly given by Ricki Lewis8 to a single treatment to restore vision in patients with genetically caused retinal diseases.


As I noted in my last update on this topic, there are several companies at the forefront of research into the use of gene therapy for wet AMD. These companies include: Genzyme (Cambridge, MA; now a Sanofi [Bridgewater, NJ] company); Avalanche Biotechnologies (Menlo Park, CA), working with the Lions Eye Institute of Perth, Australia; and Oxford BioMedica (Oxford, United Kingdom). The three companies each have initiated clinical trials using gene therapy.

Several other companies are in the research stage, including: Eyevensys (Paris, France); Applied Genetics Technologies (Alachua, FL), partnered with 4D Molecular Therapeutics (Emeryville, CA); and the Alberta Ocular Gene Therapy Team of the University of Alberta (Edmonton, Canada).

The trial undertaken by Genzyme and Sanofi (NCT01024998) has completed recruiting with no results reported to my knowledge. I also believe that the trial was stopped by Sanofi as of April of this year.

In June, Avalanche presented its phase 2a top-line data (NCT01494805), which apparently did not meet the results expected, causing its share price to drop. The company reported reaching its primary endpoint of safety, but it failed to reproduce the promising efficacy (secondary endpoints) seen in a prior phase 1 trial of its product AVA-101.

Notably, in the phase 2a trial, AVA-101 patients demonstrated a smaller mean change in best-corrected visual acuity from baseline, and it required more rescue injections than hoped for. In addition, there was an increase in retinal thickness from baseline in the treated population compared to the controls.

These results seem to differ from the previous phase 1 trial, potentially due to differences in the patient populations. Specifically, patients in the phase 1 trial started the study with lower baseline vision on average, thus allowing for more vision to be gained. There was also more end-stage disease, which might have impacted the results on optical coherence tomography.

On the basis of these results, the company stated that it would not initiate a phase 2b clinical trial in the second half of 2015, as expected, but it would conduct additional preclinical studies to investigate optimal dose and delivery of AVA-101 and AVA-201 vs the standard of care of anti-VEGF therapy, to select the best gene therapy product candidate for wet AMD to advance back into the clinic.

This decision was based on more detailed analyses of the phase 2a clinical trial data, which included individual subject-level assessment of anatomic and functional outcomes, treatability of the phase 2a subjects, and product administration.

The Oxford BioMedica trial (NCT01301443) has completed recruitment, and the data reported at this year’s ARVO conference showed that this therapy (RetinoStat, the first lentiviral gene therapy administered to the eye) was safe and well tolerated in all patients following subretinal administration, with no vector biodistribution or immune response detected.

Overall, there was a reduction in vessel leakage and stabilization in VA over the one-year trial, with encouraging signs of clinical benefit seen in several patients. According to the company, these data demonstrate robust and dose-dependent expression of both therapeutic genes (endostatin and angiostatin) over the course of the study, which is a first for a gene therapy trial.

It is my understanding that both Avalanche and AGTC are working on advanced or novel AAV-based therapies (AAV2.7m8), originally developed at the University of California–Berkeley and now being licensed by 4D Molecular Therapeutics (a spin-off from UC Berkeley), which might enable delivery of gene therapies intravitreally, rather than subretinally (see Figure 2, page 40).9



Choroideremia is an X-linked inherited retinal disease that affects both men and boys, with the loss of the retinal pigment epithelium/choriocapillaris, photoreceptor degeneration, retinal remodeling, and profound loss of vision within three decades. Female carriers may exhibit pigmentary fundus changes.10

Choroideremia can have a variable onset, often late in childhood, with night blindness and slow progression of peripheral field loss. The majority of patients will have some central vision until their fifth decade.

There are several companies (Spark Therapeutics and NightstaRx [London, United Kingdom]) and universities (Alberta Ocular Team/University of Alberta and the University of Oxford/Moorfields Eye Hospital/University College London) with research efforts under way, including four clinical trials and pre-clinical research at GenSight Biologics (Paris, France).

According to my latest information, several of these clinical trials are under way, and some patients have been treated, but few results have been published. In the NightstaRx clinical trial (NCT01461213), results published in the Lancet in January 2014 reported that, six months after treatment with this therapy, the first six patients showed improvement in their vision in dim light, and two patients with impaired VA at the start of the trial were able to read more lines on the eye chart.11

In June of this year, NightstaRx announced12 that the University of Alberta had begun enrolling and dosing subjects in a phase 2 clinical trial (NCT02077361) of the company’s gene therapy for the treatment of choroideremia. In this open-label study, six patients have received a single dose of AAV2-REP1 via subretinal injection.

The Spark Therapeutics clinical trial (NCT02341807), which started in January 2015, has completed enrollment of its cohort 1 dosing level. The study at the University of Oxford (NCT02407678) has yet to begin recruiting patients.

Stargardt Macular Dystrophy

Regarding treatments for Stargardt macular dystrophy, only Oxford BioMedica, with its partner Sanofi, which has now fully licensed the product, has initiated a phase I/2a clinical trial (NCT01367444) with at least 16 of 28 patients treated to date. At last report, cohort 3 dosing was under way.

According to ClinicalTrials.gov, the study is ongoing and recruiting participants. In addition, Sanofi has initiated a long-term (15 years) follow-up clinical trial (NCT01736592) for those patients treated in the initial trial established by Oxford BioMedica. Again, the results of this trial were reported at this year’s ARVO conference.

The cohort 4 dose escalation phase has been completed with follow-up ranging from nine to 42 months in the 16 patients treated.

Subretinal administration of Oxford’s SAR 422459 (StarGen) has been well tolerated, causing no ocular inflammation in any patients to date. Immune response to a capsid protein has been observed in two of 14 patients treated with SAR 422459. No significant changes in functional or structural tests were observed after treatment. As a result, Sanofi intends to add an additional cohort 6, with patients at least six years old.

Additionally, the Alberta Ocular Gene Therapy Team has noted that it is conducting preclinical research for autosomal-dominant Stargardt.

Retinitis Pigmentosa

There is much work being done to develop a gene therapy treatment for retinitis pigmentosa (RP). I have noted at least eight companies or institutions working toward clinical trials for this disease.

One institution, Kyushu University Hospital in Japan, has a clinical trial under way,13 with at least four of the 20 patients to be treated enrolled, but no results have yet been released.

One company, RetroSense (Ann Arbor, MI), which is working on an optogenetics approach, has a clinical trial (NCT02556736) set to begin by the end of this year. Optogenetics is the use of either light-activated proteins or photoswitches, inserted into the remaining live tissue of the vision chain (ganglion and bipolar cells or other retinal tissue), which upon activation send electrical signals along the optic nerve to the brain, providing rudimentary vision that was lost with the death or damage of the photoreceptors.

In addition, at least three other companies (Bionic Sight [Cornell University; Ithaca, NY], GenSight Biologics, and LambdaVision Inc. [Farmington, CT]) and at least eight institutions (Friedrich-Miescher Institute, Basel, Switzerland; Institut de la Vision, Paris, France; Institute for Physiology at University of Bern, Switzerland; Newcastle University, Newcastle-Upon-Tyne, United Kingdom; Okayama University, Okayama, Japan; the University of Genoa, Genoa, Italy; and two separate programs at UC Berkeley) are involved in optogenetic approaches for treating RP.

Usher Syndrome 1b

There is only one clinical trial under way to treat Usher syndrome, which is being conducted by Sanofi (NCT01505062), now that it has fully licensed the product, SAR 421869, from Oxford BioMedica.

To date, four of the contemplated 18 patients have been treated in the phase 1/2a study, with three patients completing the first cohort and one patient treated in cohort 2 at a higher dose level.

As reported at ARVO, there have been no drug-related complications or sustained surgical sequelae, with subretinal administration of SAR 421869 well tolerated, causing no significant ocular inflammation in any patients to date.

As with the other Sanofi gene therapy trial (for Stargardt disease), licensed from Oxford BioMedica, Sanofi has opened a long-term follow on study (NCT02065011) for safety and tolerability, which is intended to follow the patients treated in the original study for up to 15 years.

In my April 2013 article, I raised the question of cost for an ophthalmic gene therapy treatment. At that time, no one knew what such a treatment might cost. The only gene therapy approval (in Europe) was for alipogene tiparvovec (Glybera, UniQure NA, Amsterdam, the Netherlands) with an estimated cost of treatment of as much as $1.6 million.

No one expected that any of the ophthalmic therapies would cost that much, because the populations to be treated were several orders of magnitude larger than for the very rare disease (lipoprotein lipase deficiency) of a few hundred people. I gave this question considerable thought at the time and began working on a proposed pricing model. However, I had no idea how the healthcare community could afford to pay for the high costs proposed.

Since then, several authors, myself included, have suggested a payment method that makes sense — an annuity program model, based on performance and duration of efficacy.14-16

With the likelihood of a gene therapy and/or stem cell treatment for retinal diseases to be approved for marketing within the next two to three years, it is time for the ophthalmic and healthcare communities — the suppliers, practitioners, patients, and payers — to start thinking about how much these regenerative medicine treatments are likely to cost and how patients and the healthcare system will pay for them.

In another article,16 I proposed a pricing model for regenerative medicine in ophthalmology, based on the population of patients to be treated, and I suggested that an annuity program model, based on performance and duration of efficacy, could be used to pay for it.

In the Table (page 42), taken from that article, I show the proposed prices for both gene therapies and stem cell treatments for several of the retinal disease states discussed in this article.

Captura de pantalla 2016-10-17 a las 21.18.28.png


To date, the results obtained with gene therapy for treating retinal diseases still appear promising, safe, and long lasting (despite the questions raised, as previously discussed, in the recent NEJM articles about the longevity of LCA results).

Will gene therapy in ophthalmology continue to show the promise seen to date and achieve FDA marketing approval? Will the developing companies and the healthcare community accept the proposed costs of a one-time treatment (the “forever fix”) and agree to pay for the treatment with an annuity-type program? Will intravitreal delivery, with its capacity for larger doses and next-generation vectors, become accepted for some gene therapy approaches, as suggested by Sanford and Shannon Boye?10

Only time will tell.

1. Arons I. The current status of the use of gene therapy in ophthalmology. Retin Physician. 2013;10(7):30-32, 75.
2. Arons I. Irv Arons’ Journal. Gene Therapy in Ophthalmology Update 16: Current Tables Now Online. Available at: http://irvaronsjournal.blogspot.com/2013/01/gene-therapy-in-ophthalmology-update-16.html. Accessed September 1, 2015.
3. Jacobson SG, Cidecyan AV, Roman AJ, et al. Improvement and decline in vision with gene therapy in childhood blindness. N Engl J Med. 2015;372:1920-1926.
4. Bainbridge JWB, Mehat MS, Sundaram V, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med. 2015;372:1887-1897.
5. Fink Z. AAV RPE65 gene therapy: more than meets the eye. BioTerp Partners Web site. Available at: http://www.bioterppartners.com/#!AAV-RPE65-Gene-Therapy-More-Than-Meets-The-Eye/c1d3s/554ba8270cf2adc1ad189f24. Accessed September 1, 2015.
6. Spark Therapeutics reports first quarter 2015 results [press release]. Available at: http://www.streetinsider.com/Press+Releases/Spark+Therapeutics+Reports+First+Quarter+2015+Results/10527334.html. Accessed September 1, 2015.
7. Lewis R. Retinal gene therapy: long-term results less than expected. Medscape Med News. Available at: http://www.medscape.com/viewarticle/844151. Accessed September 1, 2015.
8. Lewis R. The Forever Fix: Gene Therapy and the Boy Who Saved It. New York, NY; St. Martin’s Press; 2013.
9. Arons I. Gene Therapy in Ophthalmology Update 19: A New Virus Vector for Safer Delivery of Gene Therapies. Available at: http://irvaronsjournal.blogspot.com/2013/06/gene-therapy-in-ophthalmology-update-19.html. Accessed September 1, 2015.
10. Boye SL, Boye SE. Genetic therapies for inherited retinal diseases. Retin Physician. 2015;12(4):19-24.
11. MacLaren RE, Groppe M, Barnard AR, et al. Retinal gene therapy in patients with choroideremia: initial findings from a phase 1/2 clinical trial. Lancet. 2014;383:1129-1137.
12. NightstaRx and the University of Alberta announce the start of the first Canadian gene therapy study to treat choroideremia [press release]. Available at: http://www.nightstarx.com/news-events/press-releases/nightstarx-and-university-alberta-announce-start-first-canadian-gene-therapy-study-treat-choroideremia/. Accessed September 1, 2015.
13. UMIN-CTR Clinical Trial. Available at: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000012009&language=E. Accessed September 1, 2015.
14. Timmerman L. Gene therapy lurches ahead, sees thorny future questions on price. Available at: http://www.xconomy.com/national/2014/01/27/gene-therapy-lurches-ahead-sees-thorny-future-questions-on-price/. Accessed September 1, 2015.
15. Brennan TA, Wilson JM. The special case of gene therapy pricing. Nat Biotech. 2014;32:874-876.
16. Arons I. The economics of gene therapy. Ophthalmologist. Available at: https://theophthalmologist.com/issues/eye-robot/the-economics-of-gene-therapy. Accessed September 1, 2015.

Retinal Physician, Volume: 12 , Issue: October 2015, page(s): 38-40, 42, 43, 53



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