The IRD Gene Therapy Pipeline

Inherited retinal diseases (IRDs) are a heterogenous group of diseases characterized by dysfunction and degeneration of photoreceptors and/or the retinal pigment epithelium (RPE) stemming from defects in at least 349 genes.¹ Since the 2017 FDA approval of voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics) for the treatment of RPE65-associated Leber congenital amaurosis (LCA), more than 30 gene therapies have entered the pipeline to address LCA, retinitis pigmentosa (RP), Stargardt disease, Usher syndrome, choroideremia, and achromatopsia (Table). Here, we highlight recent updates for many of these clinical trials.

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LEBER CONGENITAL AMAUROSIS

More than 25 genes are associated with LCA,² and gene replacement of GUCY2D and LCA5 is under investigation. The 12-month interim results from a phase 1/2 study (NCT03920007) of subretinal gene augmentation of GUCY2D (ATSN-101, Atsena Therapeutics) report safety and improvements in dark-adapted full-field stimulus testing (FST), multi-luminance mobility testing, and BCVA in patients receiving the highest dose.^3-5

Preliminary reports on the first three adults treated with gene replacement of LCA5 with OPGx-LCA5 (Opus Genetics) showed safety and early signs of biological activity (NCT05616793), with expected treatment of the next escalation dose in mid-2024.⁶

Mutations in CEP290 are associated with an estimated 10% to 30% of LCA cases,^7,8 making it an important target. Rather than attempting replacement of this extremely large gene (~7.5 kB), RNA and gene editing have been employed to target the common intronic mutation, c.2991+1655A>G, that is present in at least one allele in 77% of patients.⁹

Sepofarsan (ProQR Therapeutics) is an antisense oligonucleotide that binds CEP290 mRNA transcript to block aberrant splicing. In the phase 1b/2 dose-escalation study (NCT03140969), five of 11 patients showed a clinically meaningful improvement in BCVA and FST.^10,11 Longer-term analysis of a young patient treated in the contralateral eye in the extension study (NCT03913130) demonstrated a peak biologic response at 3 months, which lasted 3 years, across multiple measures in anatomy and visual function. Further development of sepofarsen, however, is on pause.¹²

CRISPR-Cas9 gene editing has also been used to remove the CEP290 c.2991+1655A>G intronic mutation.¹³ While the phase 1/2 study (NCT03872479) is currently paused, interim results showed promising improvements in FST and an average of 0.21 logMAR BCVA improvement with clinically significant improvement over 0.3 logMAR in four patients.¹⁴

RETINITIS PIGMENTOSA

RP is the most common IRD with a prevalence of one in 4,000 and is associated with more than 100 genes.¹⁵ X-linked RP generally shows a more severe phenotype compared with other inheritance patterns. More than 70% of X-linked RP is caused by the RP3 gene encoding for the RP GTPase regulator (RPGR) protein, in which males show severe vision loss by the third to fourth decade of life.¹⁶

Subretinal AAV5-hRKp-RPGR (MGT009, MeiraGTx/Janssen) demonstrated overall safety and improvement in perimetry in phase 1/2 trials, although three patients on the highest dose showed inflammatory responses and/or a decrease in retinal sensitivity (NCT03252847).¹⁷ The phase 3 study (NCT04671433) is administering the low and intermediate doses with an extension study for a subgroup randomly assigned to delayed treatment (NCT04794101).

rAAV2tYF-GRK1-RPGR (AGTC-501, Beacon Therapeutics) uses adeno-associated virus (AAV) 2 with three tyrosine-to-phenylalanine capsid mutations designed to improve transduction efficiency.¹⁸ The 12-month interim results from the phase 2 study (NCT04850118) show promising improvements in microperimetry, FST, and mobility testing.¹⁹

4D Molecular Therapeutics developed a proprietary R100 AAV capsid variant to widely transduce all retinal layers, including photoreceptors to intravitreally deliver gene replacement of RPGR. The active phase 1/2 clinical trial is testing two doses of 4D-125 (NCT04517149).

Gene replacement for PDE6A-associated RP (STZ Eyetrial) is currently active in a phase 1/2 trial (NCT04611503). However, initial findings showed that two of nine treated patients had moderate to severe vision loss with foveal thinning, and another five had temporary decreases in vision.²⁰

Gene replacement of PDE6B (EyeDNA/Coave Therapeutics) is recruiting in a phase 1/2 trial (NCT03328130) with positive results at 5 years—eyes treated with the low dose showed a 12-letter difference compared with untreated eyes. The 2-year results of six patients with less advanced disease receiving the higher dose showed stability of vision loss and improvements in FST and foveal anatomy.²¹

Gene replacement of RLBP1, currently in a phase 1/2 trial in Sweden, used a self-complementary AAV8 capsid (scAAV8-RLBP1) that has been shown in preclinical models to have greater transduction efficacy than other vectors.²²

To target autosomal-dominant RP caused by mutations in RHO, a dose-escalation phase 1/2 trial administered intravitreal antisense oligonucleotides (QR-1123, ProQR Therapeutics) to block transcription of the common P23H-RHO mutation (NCT04123626). Preliminary results reported safety and improvements in perimetry, with repeated dosing planned in the phase 2 trial.²³

Gene-agnostic strategies expressing neurotrophic factors and modifier genes are being evaluated. One trial is exploring subretinal SPVN06 (SparingVision) to express rod-derived cone viability factor, which promotes cone photoreceptor survival (NCT05748873). Expression of NR2E3 (Ocugen), a nuclear hormone receptor that modulates retinal homeostasis, has been found to rescue retinal degeneration in RP mouse models. A phase 1/2 trial (NCT05203939) is recruiting for RP associated with RHO and NR2E3 mutations and LCA associated with CEP290 mutations²⁴; a phase 3 trial is recruiting for RP associated with RHO and any other gene (NCT06388200).

STARGARDT DISEASE

Stargardt disease, associated with autosomal-recessive mutations in ABCA4, has an incidence of one in up to 10,000.²⁵

A gene-agnostic strategy (Ocugen) is currently underway with AAV5 expressing human retinoic acid receptor-related orphan receptor alpha, thought to regulate lipid metabolism, oxidative stress, and inhibition of the complement system. A phase 1/2 trial is enrolling with safety reported in the phase 1 dose-escalation cohort (NCT05956626).²⁶

An optogenetics approach is ongoing (NCT05417126) with intravitreal injection of AAV2 expressing multi-characteristic opsin (MCO-010, Nanoscope) under the mGluR6 promoter for patients with Stargardt disease associated with ABCA4, PROM1, and ELOVL4 mutations. Preliminary phase 2a results showed clinically significant improvements in BCVA and a 3 dB gain in mean sensitivity in perimetry.^25,27

Gildeuretinol acetate (ALK-001, Alkeus Pharmaceuticals), designed to reduce the dimerization of vitamin A, is showing promise as an oral therapy for patients with Stargardt disease caused by a mutation in ABCA4. Preliminary data from TEASE-3 (NCT02402660) demonstrated that treated patients showed no progression and remained asymptomatic during therapy (between 2 and 6 years).²⁸

USHER SYNDROME

Usher syndrome, an autosomal-recessive condition, leads to deafness and retinal degeneration. USH2A is the most common cause of syndromic and non-syndromic RP, and two mutations in exon 13, c.2299delG and c.2276G>T, constitute approximately 35% of pathogenic allele-causing disease.²⁹ One clinical trial is investigating the efficacy of an intravitreal antisense oligonucleotide (QR-421a, ProQR Therapeutics) to induce in-frame skipping of exon 13.³⁰ A phase 1b/2 study of 14 treated patients showed improvements in BCVA, perimetry, and ellipsoid zone architecture.³¹ The phase 2/3 study is evaluating two different loading doses, followed by maintenance dosing at 3 months and every 6 months thereafter. Although further development is on pause,¹² Théa recently acquired this program.³²

CHOROIDEREMIA

Choroideremia is an X-linked recessive chorioretinal degenerative disease caused by mutations in CHM, which encodes the REP1 protein. It has a prevalence of one in 50,000 to 100,000 and presents with nyctalopia in childhood or early adolescence.³³ Despite early-onset severe chorioretinal degeneration, small irregular islands of relatively preserved retina remain throughout the disease process.

The phase 1/2 trial of subretinal rAAV2.REP1 (University of Oxford) revealed surgical complications of foveal damage, which led to the use of an automated injection system, intraoperative OCT, and the subretinal saline pre-bleb technique to limit retinal stretch and reflux into the vitreous space.^34-36 To decrease the risk of retinal damage from surgical intervention, 4D Molecular Therapeutics is exploring an intravitreal delivery of REP1 (4D-110) in a phase 1 dose-escalation study (NCT04483440) using the same AAV R100 capsid variant technology employed in targeting RPGR.³⁷

ACHROMATOPSIA

Achromatopsia is an autosomal recessive disease with an estimated 70% to 80% of cases associated with CNGA3 or CNGB3, encoding for the subunits of cone cyclic nucleotide-gated channels.³⁸ The 3-year outcomes of gene replacement of CNGA3 in the STZ Eyetrial (NCT02610582) reported no serious adverse events, although no statistical significance was reached between treated and untreated eyes, given improvements also observed in the untreated eye.³⁹

Treatment of CNGA3 with AGTC-402 (AGTC) in the phase 1/2 clinical trial (NCT02935517) was halted due to lack of consistent biological improvement and three cases of severe inflammation.⁴⁰ The phase 1/2 trial targeting CNGB3 (NCT02599922) showed promising results, although the program has since stopped due to a sponsorship change.

CHALLENGES AHEAD

While the IRD clinical trial landscape expands, challenges remain in adequate timing of intervention and expectations in meeting outcome measures, which may differ in each disease. With developments in intravitreal antisense oligonucleotides, further research is needed to evaluate treatment durability and balance potential adverse effects. Lastly, novel gene-agnostic strategies are emerging, which may better encompass treatment for these rare diseases.