How gene therapy clinical trials are addressing retinal diseases at the core


Studies are uncovering a range of potential treatment options for disorders

Gene therapy clinical trials address retinal disease at core

This article is reviewed by Isabelle Audo, MD, PhD.

Research into gene therapy has increased exponentially in recent years, and a number of gene therapy clinical trials for retinal diseases are open/enrolling or recently completed.

Isabelle Audo, MD, PhD, described the highlights in therapies that involve subretinal gene delivery, optogenetics, antisense oligonucleotide (AON), and clustered regularly interspaced short palindromic repeat (CRISPR) Cas9.

Isabelle Audo, MD, PhD

Audo is a professor of ophthalmology in the Department of Genetics at Institut de la Vision, CHNO des Quinze-Vingts in Paris, France.

Subretinal gene therapy

Choroideremia, an X-linked disorder that has a frequency of about 1/50,000 individuals, is linked to a mutation in the CHM gene. Several studies have been performed to evaluate gene replacement therapy using vectors designed for subretinal delivery to treat this disease. One phase 1/2 study conducted by Spark Therapeutics is evaluating sub­retinal injection of the adeno-associated virus (AAV2) vec­tor; no results have been forthcoming thus far.

A few phase 1/2 studies have been conducted in the US and in Europe. One such study conducted by Biogen (formerly NightStar Therapeutics) in the UK reported results obtained with a subretinal injection of a low-dose vector (AAV2) to treat 6 patients. The investigators reported a mean visual gain of 3.8 letters and a dark-adapted increase in sensitivity of 2.3 dB with no significant visual loss.1 Longer follow-up at 3 to 5 years in the 6 patients showed improved vision by 21 and 18 letters in 2 patients and stable vision in 3 patients. One patient treated with the lowest study dose lost 29 let­ters in the treated eye and 18 letters in the fellow eye.2,3

Three studies of choroideremia are ongoing. The phase 2 with early-stage disease with normal vision and large areas of preserved central retina. The study is testing the long-term efficacy of the AAV2-REP1 vector in 2 patient cohorts. The multicenter phase 2 GEMINI trial in the US and Europe is evaluating the safety and efficacy of treatment and includes 15 patients treated bilater­ally. The phase 3 STAR trial includes 140 patients with more advanced choroideremia who received low or high doses or remained untreated; the primary endpoint is the best-corrected visual acuity (BCVA) at 1 year, and the secondary endpoints are the status of the functional and structural parameters


Retinitis pigmentosa (RP) treatment is being evalu­ated in 2 studies in which gene therapy is used to induce a new function in the cells (optogenetics). The idea behind this technology is to transform the relatively well-preserved bipolar and mainly retinal ganglion cells into photoreceptor cells using a very basic photopigment that upon activation can change the polarity of the cells, Audo explained.

Two studies currently are testing the safety and efficacy of this approach. In the first, a phase 1/2 nonrandomized dose-escalation study, Allergan, in conjunction with RetroSense Therapeutics, LLC, is testing 1 injection of 3 doses of AAV2 vector into the vitreous cavity in 21 patients; the vector is over­expressing a channelrhodopsin that is sensitive to a short wavelength of light. The primary outcome in this ongoing trial is safety; no results have been released.

GenSight Biologics is conducting a second ongoing phase 1/2a nonrandomized dose-escalation study of 1 intravitreal injection of the rAAV2.7m8 vector, which overexpresses channelrhodopsin in a long wavelength of light. Patients wear goggles that amplify light to increase the sensitivity and the effect of the opsin used to transduce the ganglion cells.

Thus far, no major side effects have been reported in either study.

AON therapy

Studies of RP, RP in Usher syndrome, and Leber congenital amaurosis (LCA) currently are enrolling patients in which AON therapy is being evaluated. This technology, which specifically targets gene defects, uses small RNA molecules that can target a specific sequence and hybridize to the messenger RNA (mRNA), which results in either masking or silencing of a mutation or modifying the splicing of the mRNA and producing an exon skip,4 Audo explained.

Several studies evaluating this technology are ongoing. The trials address the CEP290 deep intronic mutation, which is a common mutation between exons 26 and 27 that leads to LCA. The mutation produces a missplicing of the gene resulting in truncation of the protein. The goal of AON therapy is silencing of the mutation, thus restoring the splicing and protein.

A phase 1/2, multiple-dose, dose-escalation study has been completed. The study5 included adult and pediatric cohorts treated with low and mid doses. The main adverse events included development of cataract, cystoid macular edema, and retinal thinning. The investigators reported functional efficacy resulting from delivery of the AON with improvement in the BCVA, retinal sensitivity, and mobility tests in patients with LCA.

The ILLUMINATE study is a phase 2b/3 trial that involves multiple sequential injections in 1 eye of sepofarsen (ProQR Therapeutics) with the second treated after 1 year in patients with LCA. Two doses of sepofarsen are being evaluated and compared with sham dosing. Recruitment is completed; results are not expected until 1 year after the first injection.

Another AON study also conducted by ProQR Therapeutics, the STELLAR study, is evaluating the technology to treat RP in Usher syndrome by triggering USH2A mRNA. Exon 13 is the site of very frequently occurring mutations.

“With delivery of AON therapy QR-421, the idea is to modify the slicing of exon 13 to cause the exon to be skipped and therefore avoids its mutation,” Audo said.

Using this technology, some functional recovery has been reported in a zebrafish model (unpublished data). In the ongoing phase 1/2 STELLAR clinical trial involving patients with Usher 2a, patients receive 1 low, mid, or high dose and the results are compared to sham treatment. Patient enrollment is complete and results are expected at the end of 2021.

Another ongoing study by ProQR Therapeutics triggers the most common mutation in the US in autosomic-dominant RP and the rhodopsin gene, the P23H mutation. The goal is to inactivate this mutation responsible for a dominant-negative effect.


This technology is used to correct the genomic sequence. The BRILLIANCE study, conducted by Editas Medicine and Allergan, is using AV vectors to deliver CRISPR to trigger a deep intronic mutation on the CEP290 gene. The goal is to correct the mutation by creating a specific double-strand break to silence the mutation/correct the mutation. This is the first human trial to use CRISP/Cas9 in vivo.

“This is a very exciting moment,” Audo said.


  1. 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(9923):1129-1137. doi:10.1016/S0140-6736(13)62117-0
  2. Edwards TL, Jolly JK, Groppe M, et al. Visual acuity after retinal gene therapy for choroideremia. N Engl J Med. 2016; 374(20):1996-1998. doi:10.1056/NEJMc1509501
  3. Xue K, Jolly JK, Barnard AR, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018;24(10):1507-1512. doi:10.1038/s41591-018-0185-5
  4. Goffrey C, Desviat LR, Smedsrød B, et al. Delivery is key: lessons learnt from developing splice-switching antisense therapies. EMBO Mol Med. 2017;9(5):545-557. doi:10.15252/emmm.201607199
  5. Cideciyan AV, Jacobson SG, Drack AV, et al. Effect of an intravitreal antisense oligonucleotide on vision in Leber congenital amaurosis due to a photoreceptor cilium defect. Nat Med. 2019;25(2):225-228. doi:10.1038/s41591-018-0295-0
Isabelle Audo, MD, PhD
Audo is a consultant for Novartis, Biogen-Nightstar, MeiraGTX-Janssen, Roche, SparingVision, and ViGeneron.
Related Videos
Video 4 - "Treating Geographic Atrophy in Patients with Concurrent Neovascular AMD"
Video 3 - "Managing a Patient with Bilateral Geographic Atrophy"
Video 2 - "FDA-approved Therapies for Geographic Atrophy"
Video 1 - "Geographic Atrophy: Overview, Diagnosis, and Progression"
Retinal Inner Layer Disorganization and OCT in Uveitic Macular Edema: Insights from Dr. Amitha Domalpally
ARVO 2024: Study Reveals Faricimab's Potential for Extended Dosing in nAMD
TENAYA, LUCERNE year 2 data reveals promising results for faricimab
© 2024 MJH Life Sciences

All rights reserved.