Teaming Up for Gene Therapy

*This article originally appeared in the McPherson Eye Research Institute Summer 2021 InSights Newsletter

Millions of Americans currently battle inherited visual disorders, armed with very few therapeutic options. Recent advances in genome editing, which many believe is the life science breakthrough of our era (and which was awarded a Nobel Prize in 2020), now provide new hope for a life-long durable therapy from a “single shot” by editing the DNA sequence within the eye.

These advances have inspired a new $190M federal effort, the Somatic Cell Genome Editing (SCGE) Consortium. The SCGE is supported by the National Institutes for Health, with the aim of accelerating the development of safer and more effective methods to edit the genomes of diseased cells and tissues in patients. The initiative assembles a collection of multidisciplinary teams working on individual projects designed to develop new genome editors, delivery systems, and biological systems to measure the safety and efficacy of various genome-editing strategies. The end goal is a range of new therapies for inherited disorders.

The eye is the frontline for gene therapeutic development for many reasons, including ease of accessibility. The most common use of genome editors is to change the DNA base sequence directly within the genes in our cells. Genome editors could correct small “misspellings” in the genes that cause diseases such as retinitis pigmentosa, sickle cell disease, and others. Alternatively, genome editors might insert new synthetic genes to add functionality to a cell or tissue. Genome editing broadly encompasses diverse technologies that can make many different genomic alterations in different contexts, depending on the part of the gene or cell that needs to be fixed. In the eye, genome editors can target many cell types, including rod and cone photoreceptors, retinal pigmented epithelium (RPE) cells, and ganglion cells (whose axons comprise the optic nerve).

While a single shot cure holds much promise, new studies and tools are required to make this vision a reality. One team in the SCGE, led by Krishanu Saha, PhD, department of biomedical engineering, is using mini retinal tissues in a dish grown from stem cells. This effort builds on pioneering work by the David Gamm Lab on differentiating these retinal cells and tissues from human stem cells. New bioengineering techniques are being applied to monitor their health after gene editing, including a multiphotonic imaging process (image below) pioneered by Melissa Skala to measure the light sensitivity of the photoreceptors, and sequencing technology to measure all molecular perturbations in these cells. Machine learning, using novel methods developed by Sushmita Roy, is being applied to these datasets to identify signs of dysfunctional gene editing, which is essential for establishing safe dosing and formulation of a single shot therapeutic.

The second UW–Madison SCGE team, led by Shaoqin “Sarah” Gong, PhD, Vilas Distinguished Professor, biomedical engineering, is developing new non-viral materials to deliver these genome editors safely into the eye. These materials can be thought of as “shrink wrap”—they consist of a thin polymeric shell around the CRISPR-Cas9 protein complex (the actual gene editor). The chemistry of this shell has been tuned so that it protects the genome-editing machinery from degradation before it enters the target cell. Once this configuration, or nanoparticle, is engulfed within the targeted cells, the shell degrades to allow the CRISPR-Cas9 protein complex to edit the DNA. The same materials have already shown promise in delivering genome editors into the eye in collaborative projects with Bikash Pattnaik, PhD, assistant professor jointly appointed in pediatrics and ophthalmology and visual sciences. It is anticipated that the technologies, tools, and knowledge developed in one tissue system by SCGE investigators will be informative for studies in other tissues. The entire SCGE project, with key contributions from UW-Madison investigators, will share this information broadly to spur new therapies for the eye and other areas of the body.

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