Targeting gene therapy for achromatopsia

Reviewed by Mark E. Pennesi, MD, PhD

Preliminary results of 2 ongoing phase 1/2 clinical trials evaluating the effects of subretinal gene therapies for achromatopsia (ACHM) indicate that both drugs, AGTC-401 and AGTC-402 (Applied Genetic Technologies Corporation), seem safe and well tolerated in patients with ACHM.

It is noteworthy that data from both studies are showing encouraging signs of biologic activity, according to Mark E. Pennesi, MD, PhD, an associate professor of ophthalmology, molecular and medical genetics; Kenneth C. Swan Endowed Professor; and division chief of ophthalmic genetics at Oregon Health and Science University’s Casey Eye Institute in Portland.

Related: Investigators start pivotal subretinal gene therapy trial

ACHM is an autosomal recessive disease that causes a cone dysfunction syndrome, with the bulk of the mutations found in 2 genes, CNGA3 and CNGB3.

Two clinical trials of the affected genes are underway. One is a long-term follow-up gene therapy study for achromatopsia CNGB3 and CNGA3, at Moorfields Eye Hospital in London, England, and Kellogg Eye Center in Ann Arbor, Michigan.

The other is a natural history study of achromatopsia CNGB3 and CNGA3, at Moorfields Eye Hospital.

Patients with ACHM have central vision in the range of 20/100 to 20/200, nystagmus, color vision defects, photophobia, and high myopia.

Electroretinography (ERG) shows severely decreased cone function but normal rod function, Pennesi explained. Both trials are phase 1/2, open-label, dose-escalation studies.

Related: The increasing potential of electroretinography in ophthalmic diagnostics

The enrolled patients were treated with 1 subretinal injection of either AGTC-401 (rAAV2tYF-PR1.7-hCNGB3; 26 patients) or AGTC-402 (rAAV2tYF-PR1.7-hCNGA3; 19 patients) into the macular region on 1 eye (study eye). All patients were 14 years or older.

Participants were sequentially assigned to 1 of 4 dosing groups in both studies.

The primary end points were changes in the best-corrected visual acuity, light discomfort testing by ocular photosensitivity analyzer, ERG and multifocal ERG, retinal sensitivity by static perimetry and microperimetry, color vision testing using the Farnsworth D15 and color assessment and diagnosis tests, and patient-reported outcomes using the quality-of-life Visual Light Sensitivity Questionnaire-8.

Most ocular adverse events were mild to moderate in nature. Of those that occurred in more than 20% of eyes, the most common was conjunctival hemorrhage, which likely was related to the surgical procedure.

Vitreous and anterior chamber cells were seen more frequently in the ACHM-CNGB3 group.

Related: The first steps in gene therapy for achromatopsia

In the CNGA3 group, 2 patients had a serious adverse event. One was a macular hole related to the study surgery, and the other was ocular hypertension related to the steroids prescribed. It was controlled with modification of the steroids.

One patient in the CNGB3 group had steroid-related increased intraocular pressure that was controlled with modification of the steroids.

The preliminary results also showed improvements in photosensitivity and 2-color dark light-adapted perimetry in 3 of the 16 patients in the CNGA3 study and 7 of the 16 patients in the CNGB3 study in the higher-dose groups.

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Mark E. Pennesi, MD, PhD
e:pennesim@oshu.edu
This article is adapted from Pennesi’s presentation at the Association for Research in Vision and Ophthalmology’s 2021 virtual annual meeting. He is a consultant to Applied Genetic Therapies Corporation.