Gene-Augmentation Therapy
Gene therapy typically refers to gene-augmentation therapy. In this approach, a healthy version of the mutated gene is packaged inside an engineered and nonpathogenic form of adeno-associated virus (AAV), with the virus serving as a vector to carry the gene. AAV does not cause disease in humans. The primary delivery method at this time is by the subretinal injection of a small volume of the gene-containing AAV during a vitrectomy. The virus is then in an optimal location to deliver its cargo—the healthy gene—to retinal cells, thus enabling synthesis of normal protein.
Gene-augmentation therapy is an appropriate strategy when genetic mutations result in absent or diminished protein function. In contrast, if a genetic mutation results in a protein that is toxic or damaging to the retina, then adding normal copies of the gene may not help. In addition, some genes are too large to package into viruses. Genome editing, or gene-editing, offers a solution in these scenarios.
Gene Editing
The discovery of the CRISPR/Cas9 system, which was adapted from a bacterial defense system in the early 2010s, paved the way for current genome-editing strategies. This system allows the targeting of specific sequences of DNA to correct errors in the genetic sequence, remove segments of a gene that result in dysfunctional protein, or selectively disable a mutated copy of a gene. Like gene-augmentation therapy, the components of the CRISPR/Cas9 system can be packaged into AAVs and delivered by a subretinal injection during vitrectomy. In contrast to gene augmentation therapy, CRISPR/Cas9 genome editing is specific not only to a particular gene, but also to certain mutations in that gene.
We hope that both of these DNA-targeting therapies will have durable effects over time.
A third category of therapy is antisense oligonucleotides. These drugs target RNA, which is the intermediary between DNA and protein. These drugs are injected into the vitreous and have the potential to address some of the same types of scenarios as genome editing, but repeated ongoing treatment will be required if this method is successful.