The Christiana Care Health System’s Gene Editing Institute, based in Wilmington, Del., is pulling together a preliminary investigational new drug application (IND) for the U.S. Food and Drug Administration (FDA). The plan is to use CRISPR gene editing to improve the effectiveness of chemotherapy for treating KRAS-positive non-small-cell lung cancer (NSCLC). Patients with this subtype of lung cancer are strongly resistant to chemotherapy.
In December 2018, researchers with the Gene Editing Institute published a proof-of-concept study in the journal Molecular Therapy Oncolytics. The technique focuses on using CRISPR to edit the Nuclear Factor Erythroid 2-Related Factor (NRF2), which is a master regulator of 100 to 200 target genes involved in cellular responses to oxidative and/or electrophilic stress. They use CRISPR/Cas9 gene-editing to disable the NRF2 gene in lung cancer cells, which makes it incapable of producing a functional protein. This should make them more sensitive to chemotherapy, such as cisplatin, carboplatin, and vinorelbine.
“While we all hope for cures, the pioneering work of our gene editing team is making it a priority to improve the lives of today’s patients who are suffering with cancer and other diseases,” stated Janice E. Nevin, president and chief executive officer of Christiana Care Health System. “Our work in this promising frontier of medicine is guided strongly by our values of love and excellence.”
The Gene Editing Institute plans to work closely with the Certara regulatory science division, Synchrogenix, to get the IND submitted and approved.
“Certara brings expertise for this process and we are delighted to have them on board,” stated Eric Kmiec, director of the Gene Editing Institute.
Kmiec went on to say, “We are confident that the results of our animal studies now enable us to take the next step in the FDA approval process for a cancer clinical trial using CRISPR. It is an exciting journey. Our effort positions the Christiana Care’s Gene Editing Institute as a leader in bringing this heralded technology to people who need it most. Lots of translational scientists are providing advice on this genetic target. Once we get to a clinical trial, our results could have a major impact on our patients, and patients around the country and world.”
It’s pretty early in the game for human-based clinical trials using CRISPR gene editing, although it’s progressing steadily. The biggest controversy to date has been He Jiankui, a researcher at the Southern University of Science and Technology of China in Shenzhen, who used CRISPR gene editing in the context of in vitro fertilization to modify the CCR5 gene in human embryos. He performed this for seven couples, where the men had under-control HIV infections. In November 2018, He Jiankui announced a set of twins had been born and there was another pregnancy.
The announcement was met with widespread global condemnation.
He Jiankui’s research is dramatically different than what the Gene Editing Institute is proposing. First, there is an obvious unmet medical need to treat resistant strains of NSCLC. Second, the gene edits will target cancer cells, not germline cells, so any changes made will presumably not change the germline. One of the particularly concerning aspects of the Chinese story is that whatever changes were made to the babies’ genes can be passed on to any offspring.
In the U.S., CRISPR has only recently been used in human clinical trials. Physicians at the University of Pennsylvania are conducting clinical trials on cancer patients. In that trial, one patient has multiple myeloma, the other sarcoma. In that trial, they remove immune cells from the patient, then use CRISPR to modify them, then infuse them back into the patient’s body.
The patients are at the Abramson Cancer Center. The clinical trial is funded by the Parker Institute for Cancer Immunotherapy in San Francisco and Tmunity, a biotech company in Philadelphia.
Kmiec told Delaware Public Media, “What they did in China was to modify a fertilized egg so that the child itself was born with the modification. We’re just attacking, in our case, lung cancer cells, and at Penn they’re making cells that already exist in the body to fight the cancer.”
Very few clinical trials have been performed on human beings, although most have been in China. There are a few in Europe and even less in the U.S. CRISPR Therapeutics of Cambridge, Mass. is running one in beta thalassemia in Germany and another on sickle cell disease, which is expected to begin in the U.S.
Another Cambridge company, Editas Medicine, is working toward a clinical trial in Leber Congenital Amaurosis, an inherited form of blindness. NPR notes that this is “noteworthy because it would be the first time scientists try using CRISPR to edit genes while they are inside the human body. The other studies involve removing cells from patients, editing the DNA in those cells in the lab and then infusing the modified cells back into patients’ bodies.”
These are typically Phase I clinical trials. For the most part, the primary goal of a Phase I trial is to test the safety of a drug or therapeutic in a small population group. Although efficacy data is also collected and important, the biggest focus is on whether the procedure or drug is safe.
Kmiec told Delaware Public Media, “As these things move through the FDA, get approved and get out into the public, a lot of the mystique around CRISPR will begin to abate and we could see some really good results.”
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