New Editing Tools for Gene Therapy in Inherited Retinal Dystrophies

Abstract

Inherited retinal dystrophies (IRDs) are a heterogeneous group of diseases that affect more than 2 million people worldwide. Gene therapy (GT) has emerged as an exciting treatment modality with the potential to provide long-term benefit to patients. Today, gene addition is the most straightforward GT for autosomal recessive IRDs. However, there are three scenarios where this approach falls short. First, in autosomal dominant diseases caused by gain-of-function or dominant-negative mutations, the toxic mutated protein needs to be silenced. Second, a number of IRD genes exceed the limited carrying capacity of adeno-associated virus vectors. Third, there are still about 30% of patients with unknown mutations. In the first two contexts, precise editing tools, such as CRISPR-Cas9, base editors, or prime editors, are emerging as potential GT solutions for the treatment of IRDs. Here, we review gene editing tools based on CRISPR-Cas9 technology that have been used in vivo and the recent first-in-human application of CRISPR-Cas9 in an IRD.

FIG. 1.

Characteristics and mechanism of several CRISPR-Cas9 gene editing tools. Adeno-associated virus capacity is limited to maximum of 3.9 kb for the carried gene. However, the sizes of the cDNA and proteins are increasing with the improvements and changes in the different gene editing tools. ABE8E cDNA size from Ritcher et al. CP-CBEE cDNA size from Huang et al. PE cDNA size from Anzalone et al.

FIG. 2.

Schematic figure of the eye, demonstrating the possible routes of delivery to introduce a gene editing system into the eye to target the retina (highlight in yellow) for gene therapy to treat IRDs.