Several Gene Therapies on Horizon for Retinitis Pigmentosa


A wave of novel gene therapies is on the horizon as treatments for patients with retinitis pigmentosa.

Tad Seifert, MD

Guylene Le Meur, MD, Ophthalmology Clinic, University Hospital of Nantes

Guylene Le Meur, MD

A wave of novel gene therapies are under development as treatments for patients with retinitis pigmentosa (RP), following on the approval of voretigene neparvovec in late 2017. Each new therapy is being developed for a specific subpopulations of patients with RP, similar to the selection of those with RPE65 mutations for voretigene neparvovec.

A large number of these agents are still in preclinical studies; however, a handful of gene therapies are currently in phase 1/2 clinical trials, each geared at a highly selective subpopulation of patients. These agents include RST-001, which is geared toward channelrhodopsin, SAR-421869 (also called UshStat), aimed at the MYO7A gene, AAV-RPGR, targeting the RPGR gene, and recently HORA-PDE6B for patients with PDE6β-mutated RP.

An update on HORA-PDE6B was presented at the 2018 ARVO annual meeting. The poster presentation contained patient characteristics for the first 3 individuals enrolled in the study, which is hoping to include 12 total participants. The ages of patients ranged from 43 to 54 years and all had rod cone dystrophy related to the PDE6β gene mutation. Two of the three patients had photophobia and dyschromatopsia at baseline, and visual acuity was limited to hand movement for 1 patient.

"This clinical trial for PDE6β genes, or in other clinical trials for gene therapy for retinitis pigmentosa, I think for patients they want to be stable at first. If in gene therapy trials we can just delay blindness or if we have stop the decrease of the visual field it will be very great for patients," lead investigator of the HORA-PDE6B trial, Guylène Le Meur, MD, Ophthalmology Clinic, University Hospital of Nantes, Nantes, France, told MD Magazine at the conference.

The characteristics of the first 3 patients enrolled in the HORA-PDE6B trial emphasized the need for an effective treatment for RP, which is the leading cause of blindness in the Western world. Of these patients, 2 had a visual field that was restricted to a central island, and 1 had some peripheral islands.

"The first step in this trial is to ensure safety, then after we're going to look at secondary endpoints. For this we'll have to examine the effects of retinal injection of the product," said Le Meur. "The last patient was just injected last week, so we will have to wait."

In the two studies that led to the FDA approval of voretigene neparvovec, which was the first approved gene therapy for an inherited disorder, there was significant improvement in multi-luminance mobility testing (MLMT) scores with the gene therapy for patients with biallelic RPE65-mutated retinal dystrophy, which could include RP or Leber congenital amaurosis (LCA).

In the first trial exploring voretigene neparvovec there was a mean bilateral change in MLMT from baseline of 2 with voretigene neparvovec compared with 0 in the control group (P = .001). In the second trial, several patients had an MLMT score change of 2 to 4 (52%) with the gene therapy compared with just 10% having a change of 2 in the control arm. Ocular adverse events with voretigene neparvovec occurred in 57% of injected eyes, the most common being conjunctival hyperemia (11%), cataract (19%), and increased intraocular pressure (10%).

In the studies exploring subretinal injection of voretigene neparvovec there were no clinically significant cytotoxic T-cell responses to either RPE65 or AAV2, which is the viral vector used to deliver the non-mutated form of the gene. HORA-PDE6B, along with other gene therapies under exploration, also utilize the AAV2 vector and subretinal delivery; however, other non-AAV2 approaches are in the preclinical stage, including gene editing with CRISPR/Cas9.

In another poster at the ARVO meeting, researchers from the University of Southern California presented findings showing the effective delivery of CRISPR/Cas9 ribonucleoprotein (RNP) complex using a lipid nanoparticle. In this scenario, the researchers used gene editing to disrupt activity of the RHO gene, which is the primary culprit involved in autosomal dominant RP.

For this early research, the nanoparticle encapsulated CRISPR/Cas9 complex was injected into HEK293 cells. Using polymerase chain reaction testing, the investigators could confirm that the RHO gene was disrupted in the correct region, setting the stage for future research.

These findings join other results published earlier in the year showing the efficacy of using CRISPR/Cas9 to edit a single-base P23H mutation for RHO-associated dominant RP. These findings were from mouse studies.

The from both CRISPR studies serve as a proof of concept but have not yet been replicated in clinical trials. Human trials for CRISPR-based therapies have not yet gained widespread adoption and acceptance with the FDA. The company Editas Medicine, which is working toward bring CRISPR therapies to the market, plans to gain FDA permission to test their CRISPR-based therapy for patients with LCA later this year.

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