Retinal gene therapy clinical trials are addressing disease at core

Ophthalmology Times EuropeOphthalmology Times Europe June 2021
Volume 17
Issue 05

Investigators are conducting retinal gene therapy trials that offer potential new treatments for inherited causes of vision loss.

Retinal gene therapy clinical trials are addressing disease at core

This article was reviewed by Dr Isabelle Audo.

Research into gene therapy has increased exponentially in recent years and several gene therapy clinical trials for retinal diseases are open, enrolling or have recently been completed. Dr Isabelle Audo recently described the highlights in therapies that involve sub-retinal gene delivery, optogenetics, antisense oligonucleotide (AON) and clustered regularly interspaced short palindromic repeat (CRISPR) Cas9. Dr Audo is a professor of ophthalmology in the Department of Genetics at Institut de la Vision, CHNO des Quinze-Vingts in Paris, France.

Sub-retinal gene therapy

Choroideraemia, which involves damage to the blood vessels of the choroid and degeneration of the photoreceptor cells, is an X-linked disorder that has a frequency of about 1/50,000 individuals. The disorder 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 sub-retinal injection of the adeno-associated virus (AAV2) vector; no results have been forthcoming thus far.

Related: Gene therapy heralds new era for inherited retinal diseases

A few Phase 1/2 studies have been conducted in Europe and the United States. One such study, conducted by Biogen (formerly NightStar Therapeutics) in the United Kingdom, reported results obtained with a sub-retinal injection of a low-dose vector (AAV2) to treat six 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 3–5 years in the six patients showed improved vision by 21 and 18 letters in two patients and stable vision in three 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

Related: Non-viral gene therapy eases treatment burden in wet AMD

Three studies of choroideraemia are ongoing. The Phase 2 REGENERATE trial in the UK includes 30 patients 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 two patient cohorts.

The multicentre Phase 2 GEMINI trial in Europe and the US 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 choroideraemia 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 end points are the status of the functional and structural parameters.

Intravitreal delivery


Retinitis pigmentosa (RP) treatment is being evaluated in two studies in which gene therapy is used to induce a new function in the cells (optogenetics). Dr Audo explained that 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.

Related: Initial data from AGTC-501 subretinal gene therapy for X-linked RP demonstrates safety, efficacy

Two studies are currently testing the safety and efficacy of this approach. In the first, a Phase 1/2 non-randomised dose-escalation study, Allergan, in conjunction with RetroSense Therapeutics, is testing one injection of three doses of AAV2 vector into the vitreous cavity in 21 patients; the vector is over-expressing 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 non-randomised dose-escalation study of one intravitreal injection of the rAAV2.7m8 vector, which over-expresses 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

Patients are currently being enrolled in studies of RP, RP in Usher syndrome and Leber congenital amaurosis (LCA) in which AON therapy is being evaluated. As Dr Audo explained, this technology, which specifically targets gene defects, uses small RNA molecules that can target a specific sequence and hybridise to the messenger RNA (mRNA), which results in either masking or silencing of a mutation or modifying the splicing of the mRNA to produce an exon skip.4

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 mis-splicing of the gene, resulting in truncation of the protein. The goal of AON therapy is silencing of the mutation, thus restoring the normal splicing and protein.

Related: Treatment with voretigene neparvovec-rzyl results in foveal morphologic changes in LCA

One Phase 1/2, multiple-dose dose-escalation study has been completed. The study5 included adult and paediatric cohorts treated with low and medium doses. The main adverse events included development of cataract, cystoid macular oedema 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 one eye of sepofarsen (ProQR Therapeutics), with the second eye 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 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 splicing of exon 13 to cause the exon to be skipped and therefore avoid its mutation,” Dr Audo reported.

Related: Linking patient imaging to AAO IRIS Registry clinical data

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 are receiving one low, medium or high dose and the results are being compared to sham treatment. Patient enrolment is completed 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, which is 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 create a specific double-strand break that will silence or correct the mutation. This is the first human trial to use CRISPR/Cas9 in vivo. “This is a very exciting moment,” Dr Audo said.

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.
Edwards TL, Jolly JK, Groppe M, et al. Visual acuity after retinal gene therapy for choroideremia. N Engl J Med. 2016; 374:1996-1998.
Xue K, Jolly JK, Barnard AR, et al. Beneficial effects on vision in patients undergoing retinal gene therapy for choroideremia. Nat Med. 2018;24:1507-1512.
Godfrey C, Desviat LR, Smedsrød B, et al. Delivery is key: lessons learnt from developing splice-switching antisense therapies. EMBO Mol Med. 2017;9:545-557.
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;25:225-228.
Isabelle Audo, MD, PhD
Dr Audo is a consultant for Novartis, Biogen-Nightstar, MeiraGTX-Janssen, Roche, SparingVision and ViGeneron.

Related Content: Gene Therapy | Retina | Inflammation & Infection

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