Retinal Gene Therapies in Clinical Trials

A proliferation of clinical trials means hope for patients.


With the approval of Spark Therapeutics’ Luxturna (voretigene neparvovec) in December 2017, we are living in a new era where the possibility of treatment for inherited retinal disease now exists. The field of retinal gene therapy has been expanding exponentially over the past few years, with multiple ongoing phase 1/2 gene therapy trials and another ongoing phase 3 gene therapy trial for choroideremia.

Within the broad concept of gene therapy, there are multiple categories of treatment modalities. The most common type of gene therapy is referred to as replacement gene therapy, or augmentation therapy, which is useful for autosomal recessive disease (Table 1).

Table 1: Gene Therapies by Disease Type and Therapy Technique
Disease Type Gene Therapy Technique
Recessive disease Augmentation (replacement)
Dominant disease
  • Suppression/inactivation (short interfering RNA)
  • Gene editing/CRISPR
Multifactorial disease (eg, AMD) Addition/growth factor:
  • Oxford Biomedica: subretinally injected RetinoStat, a lentiviral vector expressing endostatin and angiostatin (NCT01301443)
  • Genzyme/Sanofi: Intravitreal delivery of AAV2-soluble FLT-1 (NCT01024998)
Non–genotype-specific disease Neuromodulation (optogenetics): genetically alter ganglion cells

The active retinal gene replacement phase 1/2 trials are targeting Stargardt disease, Usher syndrome, retinitis pigmentosa (RP; both autosomal recessive and X-linked recessive disease), X-linked retinoschisis, choroideremia, achromatopsia, and Leber congenital amaurosis type 2 caused by RPE65 mutations (LCA2). These trials use either adeno-associated virus (AAV) or lentivirus as viral vectors. In this article, we will briefly discuss each of these trials (Table 2).

Table 2: Selected Trials in the IRD and Dry AMD Clinical Trial Pipeline
Achromatopsia (CNGB3) — AGTC Phase 1/2 AMD-dry (RPE) — Astellas Phase 1/2
Achromatopsia (CNGB3) — MeiraGTx Phase 1/2 AMD-dry (RPE) — Cell Cure Phase 1/2
Achromatopsia (CNGA3) — AGTC Phase 1/2 AMD-dry (RPE on scaffold) — Regen Patch Phase 1/2
Achromatopsia (CNGA3) — Tubingen Hospital Phase 1/2 RP, Usher (retinal progenitors) — jCyte Phase 2b
Choroideremia (REP1) — Nightstar Phase 3 RP, Usher (retinal progenitors) — ReNeuron Phase 2
Choroideremia (REP1) — Spark Phase 1/2 Stargardt (RPE) — Astellas Phase 1/2
Choroideremia (REP1) — Tubingen Hosp Phase 2
LCA and RP (RPE65) — MeiraGTx Phase 1/2 Molecules, Proteins, AONs, CRISPR Progress
LCA and RP (RPE65) — Spark FDA Approved AMD-dry (C3 inhibitor) — Apellis Phase 3
RP (PDE6B) — Horama Phase 1/2 AMD-dry (C5 inhibitor) — Ophthotech Phase 2
RP, Usher, others (optogenetic) — Allergan Phase 1/2 Bardet-Biedl (metformin) — Tubingen Hosp Phase 2 pending
RP, Usher, others (optogenetic) — GenSight Phase 1/2 LCA (CEP290, AON) — ProQR Phase 1/2
RP (RLBP1) — Novartis Phase 1/2 LCA (CEP290, CRISPR) — Editas Phase 1/2 pending
Retinoschisis (RS1) — AGTC Phase 1/2 Stargardt disease (emixustat) — Acucela Phase 3
Retinoschisis (RS1) — NEI Phase 1/2 Stargardt disease (deuterated vit A) — Alkeus Phase 2
Stargardt disease (ABCA4) — Sanofi Phase 1/2 Stargardt disease (C5 inhibitor) — Ophthotech Phase 2
Usher syndrome 1B (MYO7A) — Sanofi Phase 1/2 Usher syndrome 2A (AON) — ProQR Phase 1/2 pending
X-linked RP (RPGR) — AGTC Phase 1/2
X-linked RP (RPGR) — MeiraGTx Phase 1/2
X-linked RP (RPGR) — Nightstar Phase 1/2


Stargardt disease is one of the most common inherited retinal dystrophies, with a prevalence of approximately 1 in 8,000 to 10,000. Typical autosomal recessive Stargardt disease is associated with mutations in the ABCA4 gene expressing the photoreceptor-specific ABCA4 protein, a member of the superfamily of ATP-binding cassette (ABC) transporters. Clinically, patients typically develop central visual loss as a result of progressive accumulation of lipofuscin in the retinal pigment epithelium (RPE) with the development of yellowish pisciform flecks and eventual macular atrophy. Depending on the severity of the mutations in the ABCA4 gene, there can be a wide spectrum of phenotype, ranging from relatively mild and late-onset localized macular disease to earlier-onset diffuse cone-rod disease.

A 48-week phase 1/2a dose escalation study sponsored by Sanofi is currently investigating SAR422459 (a lentiviral vector gene therapy carrying the ABCA4 gene formerly known as StarGen), for the treatment of Stargardt disease at the Casey Eye Institute and Centre Hospitalier Nationale d’Ophtalmologie des Quinze-Vingts. Eligible patients must have 2 pathogenic ABCA4 gene variants confirmed by segregation analysis of parental samples.

Several patient groups with advancing disease are being tested in the study (NCT 01367444), the inclusion criteria of which are listed below:

  • Group A (Cohort 1): Age ≥18 years, visual acuity (VA) ≤20/200 in the worst eye, and ERG with severely abnormal responses.
  • Group B (Cohorts 2-4): Age ≥18 years, VA ≤20/200 in the worst eye, and ERG with abnormal responses.
  • Group C (Cohort 5): Age ≥18 years, VA ≤20/100 in the worst eye, and ERG with abnormal responses.
  • Group D (Cohort 6): Symptomatic patients (6-26 years old) with early or childhood-onset Stargardt macular degeneration (age at disease onset <18 years), VA ≥20/200 in both eyes at the time of the screening visit, and patients are anticipated to experience rapid deterioration in visual function and/or retinal structure.
  • Group E (Cohort 7): Symptomatic patients (between 6 years and 17 years old) with early or childhood-onset Stargardt macular degeneration, VA ≥20/100 in both eyes at the time of the screening visit, and patients are anticipated to experience rapid deterioration in visual function and/or retinal structure.

This study involves a vitrectomy with subretinal injection of SAR422459. The primary objective of the study is to assess the safety and tolerability of SAR422459 and the secondary objective is to evaluate biologic activity. After 48 weeks, patients are encouraged to continue follow-up in a long-term safety study. At the time of publication of this article, 27 patients have been treated, with cohorts 1 to 5 complete and 5 patients enrolled in cohorts 6 and 7. The plan is to continue enrollment of cohorts 6 and 7, which will include subjects from 6 years to 26 years old with early-onset Stargardt disease and evidence of rapid progression of disease, either by deterioration in VA, or demonstration of disease progression by optical coherence tomography, microperimetry, or static perimetry.


Usher syndrome refers to a clinically and genetically heterogeneous group of autosomal recessive disorders, which account for the most frequent cause of combined deafness and blindness in humans, with an estimated prevalence of 3 to 6 per 100,000. There are 3 clinical subtypes (USH1, USH2, and USH3), distinguished by the severity and progression of hearing loss and the presence or absence of vestibular dysfunction. USH1 is the most severe form in terms of the onset and extent of hearing loss and RP. The most common genetic mutation in USH1 is MYO7A (Usher 1B), accounting for approximately 60% of all USH1. MYO7A encodes an actin-based protein that performs critical motility functions in both the inner ear and retina. Patients with USH1B are born with profound neurosensory deafness, have vestibular dysfunction (often report history of delay in walking) and develop early retinal degeneration in childhood.

A clinical trial is currently investigating SAR421869 (UshStat), a lentiviral gene therapy administered by a subretinal injection for the treatment of RP in patients with Usher syndrome type 1B (Myosin 7A gene defect). All patients must have 2 confirmed mutations in Myosin 7A. This study is a phase 1/2a dose-escalation study sponsored by Sanofi, enrolling at the Casey Eye Institute and Centre Hospitalier Nationale d’Ophtalmologie des Quinze-Vingts (NCT01505062).

As of the date of this publication, a total of 9 patients have been treated over cohorts 1 to 3. The plan is to continue enrollment of cohort 3 for dose finding.


X-linked retinoschisis (XLRS) is an X-linked disorder that affects approximately 1 in 5,000 to 1 in 20,000 individuals. The disease begins early in childhood, and affected males typically have best-corrected VA of 20/60 to 20/120 at initial diagnosis. Severe complications, such as retinal hemorrhage or retinal detachment, occur in up to 40% of patients, especially in older individuals. The causative gene was identified in 1997 and named retinoschisin 1 (RS1). The gene codes for the retinoschisin protein, which normally provides lateral adhesion that holds retinal cells together. Mutations in the RS1 gene alter the protein and thereby interfere with the ability of cells to maintain proper structure of the retina. Without normal retinoschisin, the layers of the retina split. Affected individuals typically have early central vision loss and can develop peripheral schisis, exudate, or retinal detachment. This damage often forms a “spoke-wheel” pattern in the macula, which can be seen during an eye exam/OCT. Likely due to the diffuse expression of RS1 throughout the retina, as well as the relative increased permeability of the retina due to the nature of the degeneration, it has been shown that intravitreal AAV delivery can rescue the condition in the mouse model of XLRS. This is the first replacement gene therapy trial for an inherited retinal dystrophy that is investigating the safety and efficacy of intravitreal gene delivery.

Two phase 1/2 studies are currently ongoing investigating intravitreal gene therapy in XLRS. A study at the National Eye Institute is evaluating 3 increasing dose levels of an AAV-RS1 vector in up to 24 patients greater than 18 years old with VA of 20/63 or worse in 1 eye. A study sponsored by AGTC is being conducted at 7 sites in the United States in up to 27 patients. Three initial groups of patients older than 18 years old will receive increasing dose levels of an AAV-RS1 vector, followed by evaluation of the maximum tolerated dose level in patients older than 6 years old. In both studies, the vector is being administered by intravitreal injection. Results from the AGTC study were recently released in a press release in December 2018, and show that rAAV2tYF-CB-hRS1 is generally safe and well tolerated, but no signs of clinical activity were observed at 6 months. As per the study protocol, AGTC will continue to monitor enrolled patients at scheduled visits through the end of the study.


Choroideremia is an X-linked recessive disorder involving a genetic defect in RAB escort protein 1 (REP1) that causes degeneration of the RPE and photoreceptors, leading to severe and diffuse chorioretinal degeneration. Patients experience gradual progressive loss of vision from chorioretinal degeneration starting from the periphery and advancing toward the fovea. Multiple phase 1/2 trials are currently ongoing at several sites. A recently completed phase 1 investigator-sponsored trial (NCT02077361) studied subretinal injection of the rAAV2.REP1 vector. Spark Therapeutics is currently sponsoring a phase 1/2 study of AAV2-hCHM (NCT02341807).

Nightstar Therapeutics completed a phase 1/2 dose escalation trial on 14 patients in 2017 investigating subretinal rAAV2.REP1 (NCT01461213). MacLaren et al published initial 6-month results of this phase 1/2 study in 2014.1 Two patients with advanced choroideremia, who had low baseline best-corrected visual acuity (BCVA), gained 21 letters and 11 letters in their vision. Four other patients with near-normal BCVA at baseline recovered to within 1 to 3 letters. Maximal sensitivity measured with dark-adapted microperimetry increased in the treated eyes. In all patients, over the 6 months, the increase in retinal sensitivity in the treated eyes was correlated with the vector dose administered per area of surviving retina. The early improvement observed in 2 of the 6 patients was sustained at 3.5 years after treatment, despite progressive degeneration in the control eyes.2 In this trial, subretinal AAV2 encoding REP1 was delivered to the macula. Final 2-year outcomes for this phase 1/2 study were published in 2018.3 Despite complications in 2 patients, VA improved in the 14 treated eyes compared to controls (median 4.5 letter gain vs 1.5 letter loss, P=.04), with 6 treated eyes gaining more than 1 line of vision (>5 letters). These results suggest that retinal gene therapy can sustain and improve VA in a cohort of predominantly late-stage choroideremia patients in whom rapid VA loss would ordinarily be predicted. Nightstar Therapeutics is currently conducting a phase 2 study (NCT03507686; GEMINI), which involves bilateral treatment, and the company is also currently conducting the first phase 3 trial in choroideremia (NCT03496012; STAR).


Achromatopsia (ACHM) is an autosomal recessive disease that affects approximately 1 in 30,000 individuals and is associated with the complete loss of cone function.10 This congenital-onset disease is relatively stationary, with clinical findings of poor central VA (usually 20/200), nystagmus, severe photophobia, and complete loss of color discrimination. On electrophysiology testing, patients have nonrecordable cone-mediated responses. The 2 most common genes associated with ACHM are CNGB3 and CNGA3. A phase 1/2 dose escalation study sponsored by AGTC evaluating subretinal delivery of an AAV-CNGB3 vector in patients with CNGB3 achromatopsia is currently ongoing at several sites in the United States. A phase 1/2 dose escalation study sponsored by AGTC for treatment of CNGA3-achromatopsia with AAV (using the same AAV vector and promoter as used in the CNGB3 study) is also currently enrolling at several sites in the United States and internationally.


One form of autosomal recessive RP is currently being studied in a gene therapy trial. Receptor MER tyrosine kinase proto-oncogene (MERTK)-associated autosomal recessive RP is very rare, with isolated patient populations identified in the Middle East and most recently the Faroe islands. A phase 1 open-label dose-escalation clinical trial using an AAV2 vector with an RPE-specific promoter driving MERTK was recently completed in Saudi Arabia. Results were published in Human Genetics in 2016.11 Six patients were treated with rAAV2-VMD2-hMERTK with a submacular injection. Three patients showed improvement in VA; however, this effect was lost by 2 years. Ocular and systemic safety profiles were acceptable.


Because of its early onset and the availability of multiple animal models, a tremendous amount of attention has been focused on developing a gene-based therapy for RPE65-associated Leber congenital amaurosis (LCA), or LCA2 (prevalence 1:100,000).4 Multiple national and international phase 1/2 trials have been either completed or are still ongoing for RPE65-associated LCA. The phase 1/2 clinical trials investigating gene therapy for RPE65-associated LCA have suggested that improvement in retinal function as measured by cone and rod sensitivity is detectable within the first month after treatment5-7 and there is persistence at 1 year8 and 3 years.9

The recently completed phase 3 trial for RPE65-associated LCA was sponsored by Spark Therapeutics. The trial included 29 subjects who were treated after randomization 2:1 to an early treatment arm vs a treatment delayed by 1 year arm. Both eyes were treated with subretinal injection of AAV in this trial, with surgeries separated by approximately 1 week. The primary endpoint for this trial was a novel functional vision outcome measure known as the multiluminance mobility test (MLMT), which consisted of mobility testing in an obstacle course. Treated patients scored 1.6 light levels better than controls with a P value of .004, meaning that these treated patients could navigate the maze in lower light conditions. Sixty-five percent of treated patients vs none of the control patients passed the MLMT at the lowest luminance level tested (1 lux), demonstrating maximum improvement. The secondary outcome was full-field light sensitivity testing, which was done with both eyes open. Treated patients shown in yellow displayed improved sensitivity to dim light compared to controls. The sensitivity improved 2.1 log units, equivalent to a 100-fold improvement, significant at P=.001 compared to controls.12 No serious adverse events were found to be related to treatment. All ocular events were mild (eg, transient elevated IOP in 4 subjects, cataract in 3 subjects, retinal tears that resolved after laser in 2 subjects, transient mild eye inflammation in 2 subjects).

Luxturna is the first FDA-approved retinal gene therapy product. Undoubtedly, this historic contribution will pave the way for future FDA approvals for retinal gene therapies, and it certainly will raise awareness of the necessity of accurate clinical diagnosis of retinal dystrophies and genetic confirmation of disease.


Three companies are concurrently investigating subretinal delivery of AAV therapy for RPGR-associated X-linked retinitis pigmentosa (XLRP). Nightstar Therapeutics is conducting a phase 1/2 study investigating an AAV8 vector for RPGR-associated XLRP (NCT03116113; XIRIUS). AGTC is enrolling a study investigating an AAV2-RPGR vector for XLRP (NCT03316560). Lastly, MeiraGTx UK II Ltd is also enrolling for a phase 1/2 trial investigating AAV2 for XLRP. (NCT03252847). No results have been published to date on these studies.


Optogenetics is an exciting and innovative new field that involves genetically modifying neurons to express light-sensitive ion channels. This may be beneficial for multiple retinal dystrophies regardless of the specific causative genetic defect. Additionally, optogenetics may still be useful even when photoreceptors are severely damaged or even missing, as the target cell for this form of gene therapy may be ganglion cells or inner retinal cells (bipolar cells), obviating the necessity for remaining viable photoreceptor cells as a target population. This form of gene therapy opens a new frontier of possibility — and it may be able to offer a broader treatment for a variety of retinal degenerations with a possibly larger window of opportunity for successful intervention in progressive disease.

Retrosense Therapeutics LLC (recently acquired by Allergan) is currently sponsoring a study of Optogenetics in RP at a single site, Retina Foundation of the Southwest, Dallas. In this study, a photosensitive gene (channelrhodopsin2) is delivered via intravitreal injection. The primary endpoint is safety. This is a dose escalation study investigating 3 doses. Fifteen subjects greater than age 18 with advanced RP will be treated. Visual acuity can be no better than hand motions. The first patient was treated in 2016.

Another new and innovative field for retinal inherited disease is the field of antisense oligonucleotide therapy (AON). Although not classic gene therapy, AON therapy approaches retinal degenerative disease at the level of shutting down gene expression using an antisense drug to bind to RNA sequences and prevent translation of disease-causing proteins. ProQR Therapeutics has developed a phase 1/2 trial to investigate the safety and tolerability of product QR-110 administered intravitreally in patients with LCA10, caused by a specific intronic mutation in CEP290.

Lastly, CRISPR/CAS9-based therapy is a new and exciting field within the spectrum of retinal gene therapy, involving gene editing techniques to repair mutations in DNA in living cells. Editas is developing a CRISPR-based therapy for LCA10 (the same form of LCA also being investigated by the AON approach described above). Editas is currently completing a natural history trial studying CEP290-related retinal degeneration (LCA10) caused by a compound heterozygous or homozygous intron 26 c.2991+1655A>G mutation. This knowledge will inform the interventional clinical trial design for EDIT-101, Editas Medicine’s preclinical product candidate to treat LCA10.


The historic FDA approval of Luxturna has dawned a new era of promise and possibility regarding treatments for inherited retinal diseases previously thought to be untreatable. The LCA2 trials have established safety and efficacy of gene replacement for monogenetic retinal disease. With multiple ongoing phase 1/2 trials, other therapies may move toward FDA approval in the next few years, further advancing retinal gene therapy. With innovations within the field of retinal gene therapy including the new and exciting frontier of optogenetics, we can imagine a future where various diseases can be treated with a larger window of opportunity for therapeutic effect. Accurate and early diagnosis, appropriate workup and clinical characterization, genetic testing, and up-to-date counseling of these patients is increasingly critical as these clinical trials progress. There is work to be done in retinal gene therapy and there are multiple questions and issues that have yet to be resolved, but we are finally at a point that realistic hope can be offered. There are few things as satisfying as offering hope to a patient, and we are now at a point that hope can be offered, albeit within the confines of educated and realistic counseling. With gene therapy, as well as countless other emerging therapeutic fields (stem cell therapy, artificial vision, and retinal prostheses), it is critical to stay up-to-date in our own knowledge to provide the best possible care to our patients. RP


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