Therapeutic prime editing for gene therapy against ocular dystrophy

This technology is a collection of optimized therapeutic prime-editing strategies targeting four common splicing mutations in the peripherin‐2 gene (PRPH2) that are associated with various retinal degenerations.

Unmet Need: Targeted therapeutics against peripherin‐2 gene (PRPH2), which mediates retinal degeneration

The peripherin-2 gene (PRPH2) encodes a protein necessary in the formation, maintenance, and renewal of photoreceptors in the eye, and its disruption is associated with a variety of retinal degenerations, including macular dystrophy and cone‐rod dystrophy. While more than three hundred PRPH2 mutations have been documented, a number of these occur in the c.828 splice site, including c.828+3A.T, the second most reported disease-causing variant. As there are currently no therapeutics on the market to treat peripherin‐2 (PRPH2) mutations, there is a need for treatment approaches to ocular dystrophies.

The Technology: Gene augmentation methods and systems for PRPH2 retinal dystrophy therapeutics

This technology encompasses a series of methods and systems to correct +1, +2, and +3 c.828 splice site PRPH2 mutations. The method uses prime-editing to modify up to four c.828+ mutations in any combination in PRPH2 using a modified version of the Cas9 nickase-reverse transcriptase, optimized pegRNA, and nicking sgRNA. The technology is a targeted approach configured for delivery to retinal cells.

This technology was validated in vitro using patient-induced pluripotent stem cell (iPSC)-derived retinal organoids.

Applications:

  • Method for modifying a gene using prime-editing
  • Prime-editing therapeutic strategy consisting of a variety of the following: Cas protein, a reverse transcriptase, RNA spacer or extension sequence, and a nicking guide RNA (ngRNA)
  • Package to correct the +1, +2 and +3 c.828 PRPH2 patient mutations, which includes the second most reported variant
  • Treatment for retinal degeneration, retinitis pigmentosa, macular degeneration, macular dystrophy, fundus flavimaculatus-like dystrophy, central areolar choroidal dystrophy, and cone-rod dystrophy
  • Methods can be developed to similarly edit optical dystrophies in domestic animal and livestock breeding industries

Advantages:

  • Can correct several splice mutations with a single therapeutic design
  • Can be easily converted into a genome therapeutic product using AAV or lentiviruses
  • Enables precise base edits of patient-derived mutations
  • Research tool capable of studying complex base transitions and conversions
  • Can be developed into a clinical treatment or preventive for patients with PRPH2 mutations

Lead Inventor:

Stephen H. Tsang, M.D., Ph.D.

Patent Information:

Patent Pending (US20250090690)

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