Gene therapy for blindness is a matter of dose

A fluorescent green study with monkeys shows that virus vectors can safely and effectively deliver therapeutic genes to the rods and cones at clinical doses.
Written by Janet Fang, Contributor

A new dosage study sets the stage for gene therapy to treat blindness. In particular, eye diseases caused by the malfunction or loss of our light sensitive neurons – called photoreceptor cells, our rods and cones.

Gene therapy – which specifically targets single genes – has always had its eye on, well, eyes. They’re small and self-contained, which means that even the tiniest doses of gene-carrying vectors can be potent.

Eyes are also one of the few things endowed with the ability to tolerate foreign substances without inciting an inflammatory response.

Previously, a handful of clinical trials have reported some success in using gene therapy to restore (at least partially) vision in patients with eye diseases. However, most of these only involve defects in the retina’s pigmented layer, which is outside of the neurosensory area:

During a human trial conducted at the Children's Hospital of Philadelphia, researchers packaged a normal version of a gene missing in Leber's congenital amaurosis inside a genetically engineered vector. This delivered the gene to retinal cells, where the gene produced an enzyme that restored light receptors.

Yet, many other retinal diseases are caused by the loss of our rod and cone photoreceptor cells, such as with retinitis pigmentosa. These have proved to be more difficult to target with vectors carrying therapeutic genes.

To use gene therapy for targeting photoreceptors, University of Pennsylvania researchers experimented with two viruses in monkeys: adeno-associated virus vectors AAV2 and AAV8.

  1. They injected both eyes of 14 monkeys with varying doses of AAV2 and AAV8.
  2. The vectors carried genetic material that encodes for a green fluorescent protein – which they used as a marker to visualize the dose that vectors could effectively deliver working genes into retinal cells. (Top image: green protein, blue cells, red cone photoreceptors. Bottom image: a montage of monkey retinas.)
  3. Then they compared doses of the two virus vectors.

Both delivered the gene safely, but as it turns out, AAV8 was able to deliver genes into photoreceptors at normal doses, while AAV2 could only do so at the highest dose.

So using AAV8 at an intermediate dose – the kind used in experimental clinical protocols – may be the best approach for gene therapy to treat photoreceptor diseases.

The study was published in Science Translational Medicine today.

Images: Luk Vandenberghe

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