Efficient Rescue of Retinal Degeneration in Pde6a Mice by Engineered Base Editing and Prime Editing

Area of Science:

• Genetics
• Ophthalmology
• Molecular Biology

Background:

• Retinitis pigmentosa (RP) encompasses inherited retinal diseases causing photoreceptor degeneration and blindness.
• Autosomal recessive RP (RP43) linked to PDE6A mutations currently lacks effective treatments.
• Genome editing technologies like base editing (BE) and prime editing (PE) offer potential therapeutic strategies.

Purpose of the Study:

• To evaluate the efficacy of engineered base editing (BE) and prime editing (PE) systems for treating a specific Pde6a mutation causing RP.
• To assess the efficiency and specificity of these gene editing tools in preclinical models.

Main Methods:

• Optimized BE and PE systems were screened in N2a cells.
• Gene editing efficiency was assessed in electroporated mouse retinas.
• The optimal prime editing system was delivered via dual adeno-associated virus (AAV) vectors in a Pde6a mouse model.

Main Results:

• Prime editing demonstrated high efficiency (average 9.4%) in correcting the Pde6a (c.2009A > G, p.D670G) mutation with no detectable bystander editing.
• Correction of the mutation restored PDE6A protein expression.
• Photoreceptor preservation and rescue of retinal function were observed in treated Pde6a mice.

Conclusions:

• Engineered prime editing systems show high efficiency and specificity for correcting the Pde6a mutation in vivo.
• This study provides a proof-of-concept for using base and prime editing as potential gene therapies for Pde6a-related retinal degeneration.