Scientists at ChristianaCare gene editing institute use CRISPR tools to safely disable gene mutation linked to treatment-resistant melanoma

(Press-News.org) Scientists at ChristianaCare Gene Editing Institute Use CRISPR Tools to Safely Disable Gene Mutation Linked to Treatment-Resistant Melanoma
 
Study finds CRISPR restores the ability for cancer treatments to attack melanoma cancer cells with precision-guided gene edit that ignores healthy cells
 

Wilmington, DE, OCTOBER 15, 2024  -- In a potential advance for melanoma patients, researchers at ChristianaCare’s Gene Editing Institute have used CRISPR gene editing tools to disable a gene mutation often seen in aggressive forms of this dangerous skin cancer that renders promising treatments ineffective.
 
The study published in the CRISPR Journal focused on melanoma cells taken from a patient whose cancer had developed a mutation that causes drugs that can slow the progress of the disease to stop working. The scientists used CRISPR gene editing tools to disable the mutation and restore treatment sensitivity to the cancer cells in a way that appears to minimize risks of dangerous side effects. This approach is tumor-specific and will target melanoma tumor cells and leave healthy cells alone, restoring sensitivity to anticancer drugs only in the tumor cells.
 
“This study validates our previous research findings in lung cancer that CRISPR gene editing can disable genes involved in resistance to cancer treatments, and this now appears to extend to patients with melanoma,” said Eric Kmiec, Ph.D., executive director and chief scientific officer of ChristianaCare’s Gene Editing Institute, and senior author of the study. “This treatment could be delivered intravenously or by direct injection and represents a major step forward. This trend we are finding is extremely hopeful for people with cancer that is often resistant to current treatments like chemotherapy.”
 
The experiment with drug-resistant melanoma cells was inspired by the Gene Editing Institute’s success in using CRISPR to disable a gene that produces a protein linked to drug resistance in lung cancer. In both cases, the goal is to direct CRISPR to target genetic mutations that interfere with cancer treatment while mindful of a potential CRISPR risk: that an edit targeting a health problem can also disrupt gene functions that provide health benefits.
 
“We’re trying to advance CRISPR’s potential to safely address a major challenge that occurs with melanoma and a number of other cancers, which is the emergence of genetic mutations that help them develop resistance to proven treatments,” said Brett M. Sansbury, the principal author of the study.
 
Using CRISPR to address a dim prognosis for advanced melanoma
 
For the current study, researchers at the Gene Editing Institute focused on patients whose melanoma, which typically begins as skin lesions, has spread or “metastasized” to other parts of the body and is no longer treatable with surgery. About half of these patients have a type of melanoma that is initially responsive to a widely used drug regime. However, within a year, most of them develop resistance and face a poor prognosis.
 
The researchers focused on a mutation within the NRAS gene. In the human body, healthy NRAS genes control important, basic biological processes, like cell division. But mutated forms are implicated in driving a variety of cancers. Many patients with advanced melanoma eventually develop a type of NRAS mutation that causes treatments that had been keeping their cancer in check to stop working. Even worse, the study notes that there is evidence that the mutation can cause continued treatment to accelerate the cancer’s spread.
 
Kmiec said the challenge for his team—and for any team exploring CRISPR-related patient treatments—was to avoid a gene edit that causes “collateral damage.” He said that without proper guidance, a CRISPR edit may not be able to distinguish between a healthy and dangerously mutated form of the NRAS gene. It could end up altering both, he said, which could lead to significant risks for patients. 
 
The Gene Editing Institute team addressed this dilemma by focusing on a short sequence of DNA code that is unique to the harmful NRAS mutation seen in melanoma patients. They used the code as something of a homing beacon for implementing precision-guided CRISPR gene edits that ignored healthy NRAS genes and targeted only the NRAS gene linked to treatment-resistant melanoma.
 
About the ChristianaCare Gene Editing Institute
The Gene Editing Institute at ChristianaCare is a worldwide leader in CRISPR gene editing technology. As the only institute of its kind based within a community health care system, the Gene Editing Institute has a unique opportunity to take a patient-first approach in all its research by working side by side with oncologists and other medical experts to improve the lives of people with cancer and inherited diseases. Since 2015, its researchers have led several ground-breaking firsts in the field that will help bring treatments to patients quickly and safely. They recently discovered that disabling a lung cancer gene called NRF2 using CRISPR gene editing allows chemotherapy to work better to target cancer cells. The Gene Editing Institute, working with its spin out company CorriXR Therapeutics, is close to approval from the FDA to start clinical trials in humans. In addition to scientific breakthroughs, The Gene Editing Institute is preparing the next generation of gene editing scientists through its on-site Learning Lab and immersive CRISPR In A Box™ teaching toolkit reaching more than 1,000 students across multiple states.

 
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