UW researchers to test gene-editing therapy to cure blindness

Three side-by-side microscope images of retinal cells stained green, red, and blue.

Microscopic images showing the process of correcting inherited mutations within human cells through genome editing. Red and green mark channel proteins within cells, and blue marks each cell’s nucleus, which houses the cell’s genetic code. Research led by UWMadison will test gene-editing drug therapies to trample blindness in humans.

With new support from the National Institutes of Health, a team of researchers from the Wisconsin Institute of Discovery will conduct therapeutic drug trials for two diseases known to cause blindness.

Over the next five years, the collaborative project will use the $29 million NIH grant to combine new drug delivery systems with advanced CRISPR genome technology, innovating new treatments for Leber’s disease (BD) and congenital amaurosis (LCA), both currently incurable hereditary diseases.

“Genetic mutations can cause some of the rarest and most devastating nervous system disorders,” said Walter Koroshetz, co-chair of the Somatic Cell Genome Editing Program and director of the National Institute of Neurological Disorders and Stroke. Thanks to large-scale efforts like the SCGP, we are starting to bring tools into the clinic to modify these genetic mutations. While there are still challenges to overcome, the level of hope for effective treatments is high.

The researchers decided to focus on the eye as a starting point because it is autonomous and isolated from other organs, as well as because of its accessibility, ease of monitoring and reduced likelihood of adverse immune reactions.

David Gamm

David Gamm

Our focus is on two different diseases: LCA, a severe and rare group that affects children and their entire vision, and BD, which affects older individuals’ central vision and has a slower onset, says David Gamm, a professor of ophthalmology at UWMadison and director of the McPherson Eye Research Institute. By targeting these two diseases, we can gain a broader perspective on the effectiveness of our gene-editing therapies.

Krishanu Saha, a professor of biomedical engineering at WID and a member of the NIH’s Somatic Cell Genome Editing Consortium, sees this grant as a crucial step toward advancing gene editing therapy and drug development on campus.

The genome editing piece is a game changer, Saha says. The opportunity to do this in a safe and meaningful way for patients, especially Wisconsin patients currently diagnosed with one of these diseases, would be a nice accompaniment to why we do the work and why it’s publicly funded.

Krishnanu Saha

Krishnanu Saha

Genome editing involves splicing or cutting DNA at a specific point or inserting a DNA template that replaces the cut site. This corrects disease-causing mutations by deleting or replacing the mutated sequence. Despite significant advances in CRISPR gene-editing technology, it has thus far resulted in few useful drug therapies. This is mainly because although CRISPR can modify the DNA of a single cell, the treatment of billions of cells is required for effective treatment.

First, to ensure that a therapy is safe and effective for patients, a model system is needed to mimic what would happen to a patient, without jeopardizing their safety.

This can be done through animal models or systems based on cells grown in the lab, says Gamm. Our role is to develop, grow and maintain the cell-based system for testing.

Additionally, most CRISPR technology uses a virus delivery system that is currently hampered by unintended off-target effects, such as shortened lifetimes, unwanted immune reactions, and supply chain difficulties. To overcome these limitations, the project aims to exploit nanotechnology to develop new methods for efficient drug delivery of the CRISPR gene editor.

Shaoqin Sarah Gong

Shaoqin Sarah Gong

One delivery approach will be led by Shaoqin Sarah Gong, professor of ophthalmology and visual sciences and biomedical engineering at UWMadison.

Developing a safe and efficient delivery system for the CRISPR genome editor is essential for clinical translation, Gong says.

His work focuses on a new family of nanoscale capsules that can deliver genome-editing tools to target organs or cells throughout the body and then harmlessly dissolve.

In the past, there have been biosafety concerns resulting from sustained expression of gene editors via viral delivery. However, the Gong lab has engineered biodegradable nanocapsules that can deliver genome editors to reduce off-target editing effects.

Early studies showed no adverse events in human cell cultures or mouse models. With support from the U19 grant, the team aims to optimize nanocapsule formulations for increased modification efficiency, develop a manufacturing process, and evaluate biosafety and efficiency in nonhuman primates. This will lead to safer and more efficient nanoparticle-based ocular gene editing therapy.

Another approach to improve the delivery of genome editing therapies involves a partnership with start-up biotech company Spotlight Therapeutics Incorporated. The California-based company will use a multi-pronged approach to solve delivery challenges using proteins and peptides. They will also focus on streamlining the industrial side of drug therapy development, from conceptualization to implementation.

This project could have a potentially lasting impact, Saha points out. Just trying is a big deal. It’s a long way from the pencil-and-paper design stage to formulating effective therapies with lifetime impact. It takes a lot of investment. The fact that we’re pooling resources and people here in Madison makes it really exciting and meaningful.

Another challenge is the economic one. Rare diseases and disorders do not appeal to the pharmaceutical industry because the market cannot support the millions of dollars and time needed to invest in the resources needed to demonstrate that genome-editing therapies are safe and effective.

This grant gives us the resources to improve processes, develop a safe and effective model patient care system, and improve vision function. While they may not completely eliminate the disease, the goal is to create a significant improvement, says Gamm.

The fellowship began in May and is one of five multidisciplinary fellowships the NIH will award in 2023.

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