Researchers to Conduct Gene Editing Therapy Trial to Treat Blindness

With recent backing from the National Institutes of Health (NIH), the Wisconsin Institute of Discovery's team of researchers will lead gene editing therapy for two diseases recognized for their association with blindness.

Over the course of the next five years, this joint endeavor will leverage the $29 million NIH grant to integrate novel drug delivery systems with state-of-the-art genome CRISPR technology, revolutionizing treatment options for Best Disease (BD) and Leber Congenital Amaurosis (LCA). These hereditary conditions currently lack effective therapeutic interventions.

“Genetic mutations can cause some of the most rare and devastating disorders of the nervous system,” 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 edit out these gene mutations. While there are still challenges to overcome, the level of hope for effective treatments is high.”

The researchers opted to begin their focus on the eye due to its self-contained nature and isolation from other organs. Additionally, they considered its accessibility, ease of monitoring, and reduced risk of adverse immune reactions as factors in their decision-making process.

“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, UW–Madison ophthalmology professor 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 therapeutics.”

Krishanu Saha, a professor of biomedical engineering at WID and an active member of the NIH's Somatic Cell Genome Editing Consortium, regards this grant as a pivotal stride towards progressing gene editing therapy and drug development within the campus.

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

Genome editing encompasses the process of precisely splicing or cutting DNA at a targeted location, or introducing a DNA template to substitute the cut site. By eliminating or replacing the mutated sequence, this technique addresses disease-causing mutations. Despite remarkable progress in CRISPR gene editing technology, its application in generating beneficial drug therapies has been limited thus far. The primary challenge lies in the fact that while CRISPR can modify the DNA of individual cells, treating billions of cells is imperative for achieving effective treatment outcomes.

Prior to implementing a therapeutic approach in patients, it is essential to establish a model system that replicates the conditions observed within a patient, while safeguarding their well-being. This model system serves as a crucial tool for assessing the safety and efficacy of the intended therapeutic intervention.

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

Nanotechnology Revolutionizes Drug Delivery for Gene Editing

Furthermore, the majority of CRISPR technology relies on a virus-based delivery system, which is currently impeded by unintended off-target effects, including reduced longevity, undesirable immune responses, and challenges in the supply chain. To address these limitations, the project's objective is to utilize nanotechnology in order to devise innovative approaches for effective drug delivery of the CRISPR gene editor.

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

Shaoqin "Sarah" Gong, a professor of ophthalmology and visual sciences and biomedical engineering at UW-Madison, will spearhead one of the delivery approaches.

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

Dr. Shaoqin "Sarah" Gong's research centers around a novel class of nanoparticles designed to transport genome-editing tools to specific organs or cells throughout the body, subsequently dissolving harmlessly.

Previously, extended expression of gene editors through viral delivery has raised biosafety concerns. However, the Gong lab has developed biodegradable nanoparticles that effectively deliver genome editors while minimizing off-target editing effects.

Preliminary investigations have demonstrated the absence of adverse events in human cell cultures and mouse models. With the support of the U19 grant, the team's objectives encompass refining the nanoparticle formulations to enhance editing efficiency, establishing a manufacturing process, and evaluating biosafety and efficacy in non-human primates. These endeavors will pave the way for a safer and more effective ocular gene editing therapy utilizing nanoparticles.

Furthermore, a collaborative effort has been initiated with Spotlight Therapeutics Incorporated, a biotechnology startup based in California, to address the challenges associated with genome editing therapeutic delivery. Spotlight Therapeutics will employ a multifaceted approach involving proteins and peptides. Their focus extends beyond delivery advancements and encompasses streamlining the drug therapeutic development process, encompassing all stages from conception to implementation.

“This project could have a potentially durable impact,” remarks Saha. “Just trying is a big deal. It’s a long road from the design stage of paper and pencil to formulating effective therapeutics with a lifetime impact. It takes lots of investment. The fact that we are piecing together the resources and the people here in Madison makes that really exciting and meaningful.”

Another obstacle in the field of genome editing therapeutics is of an economic nature. Pharmaceutical companies in the industry often find rare disorders and diseases unattractive due to the insufficient market size. The significant financial investment and time required to demonstrate the safety and efficacy of genome editing therapeutics make it challenging to justify such endeavors.

“This grant offers us the resources to improve processes, develop a safe and effective patient treatment model system and enhance visual function. Although they may not eliminate the disease entirely, the goal is to create meaningful improvement,” says Gamm.