More Effective Gene Therapy May Be On The Horizon

Degenerative diseases of the retina arise from pathogenic mutations in mRNA transcripts expressed in the eye’s photoreceptor cells or retinal pigment epithelium (RPE), leading to cell death and structural deterioration over time.

A photoreceptor cell is a specialized type of neuron found in the retina, capable of phototransduction – converting visible electromagnetic radiation into signals.

There are two types of photoreceptors present in the eye – rods and cones.

Cones are responsible for detecting and visualizing color while rods absorb light. Interestingly, rods are extremely sensitive, and can be triggered by as few as six photons.

At very low light levels, visual acuity is based solely on the rod signal. This explains why colors cannot be seen at low light levels, as only one type of photoreceptor cell is active.

Retinal pigment epithelium (RPE) is the pigmented cell layer just outside the neurosensory retina that nourishes retinal visual cells, and is firmly attached to both the underlying choroid and overlying retinal visual cells.

Adeno-associated virus (AAV) is a small respiratory virus which infects humans and some primate species. Gene therapy vectors using AAV can infect both dividing and quiescent cells, and persist in an extra-chromosomal state without integrating into the genome of the host cell.

These features make AAV a very attractive candidate for creating viral vectors for gene therapy. Recent trials using AAV for gene therapy in the retina have shown promise.

Inherited retinal degenerative diseases are a clinically promising focus of AAV mediated gene therapy, reports Science, as current treatments require a delivery method of sub-retinal injections in order to reach the photoreceptors and RPE.


But this technique – requiring hospitalization and general anesthetic – has the potential for injury and is only suitable for extremely rare cases so long as the retinal structures are still intact.

Directed evolution of a gene therapy virus vector improves penetration of the treatment into the retina. To test this, researchers, using a mouse models, implemented in-vivo directed evolution, engineered AAV variants capable of delivering the designer gene cargo into the outer retina after intravitreally injecting it into the eye’s vitreous humor – a much easier, less invasive approach over traditional methods.

David Schaffer – a professor of chemical and biomolecular engineering, bioengineering, and neuroscience at the University of California, Berkeley – led the research. The AAV variant mediated widespread delivery to the outer retina and rescued the disease phenotypes of X-linked retinoschisis and Leber’s congenital amaurosis in the models.

However, AAV vectors are still problematic as the vectors themselves are currently incapable of penetrating deeper into the retina where a disease is typically located.

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