Preclinical evaluation of ADVM-062, a novel intravitreal gene therapy vector for the treatment of blue cone monochromacy

Mol Ther. 2023 Jul 5;31(7):2014-2027. doi: 10.1016/j.ymthe.2023.03.011. Epub 2023 Mar 16.

Abstract

Blue cone monochromacy (BCM) is a rare X-linked retinal disease characterized by the absence of L- and M-opsin in cone photoreceptors, considered a potential gene therapy candidate. However, most experimental ocular gene therapies utilize subretinal vector injection which would pose a risk to the fragile central retinal structure of BCM patients. Here we describe the use of ADVM-062, a vector optimized for cone-specific expression of human L-opsin and administered using a single intravitreal (IVT) injection. Pharmacological activity of ADVM-062 was established in gerbils, whose cone-rich retina naturally lacks L-opsin. A single IVT administration dose of ADVM-062 effectively transduced gerbil cone photoreceptors and produced a de novo response to long-wavelength stimuli. To identify potential first-in-human doses we evaluated ADVM-062 in non-human primates. Cone-specific expression of ADVM-062 in primates was confirmed using ADVM-062.myc, a vector engineered with the same regulatory elements as ADVM-062. Enumeration of human OPN1LW.myc-positive cones demonstrated that doses ≥3 × 1010 vg/eye resulted in transduction of 18%-85% of foveal cones. A Good Laboratory Practice (GLP) toxicology study established that IVT administration of ADVM-062 was well tolerated at doses that could potentially achieve clinically meaningful effect, thus supporting the potential of ADVM-062 as a one-time IVT gene therapy for BCM.

Keywords: AAV; OPN1LW; animal models; blue cone monochromatism; cone photoreceptors; fovea; gene therapy; inherited retinal disorder; intravitreal; non-human primate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Genetic Therapy / methods
  • Humans
  • Opsins* / genetics
  • Primates / genetics
  • Primates / metabolism
  • Retinal Cone Photoreceptor Cells* / metabolism
  • Rod Opsins / genetics
  • Rod Opsins / metabolism

Substances

  • Opsins
  • Rod Opsins

Supplementary concepts

  • Blue cone monochromatism