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Targeting KIT by frameshifting mRNA transcripts as a therapeutic strategy for aggressive mast cell neoplasm
NEW YORK, Aug. 11, 2021 /PRNewswire/ -- Hoth Therapeutics, Inc. (NASDAQ: HOTH), a patient-focused biopharmaceutical company, today highlights recent findings from North Carolina State University, that its new treatment for mast cell cancers, known as HT-KIT, reduces the number of mast cells by "mutating" the messenger RNA (mRNA) before it can deliver instructions for manufacturing the gene responsible for cell proliferation.
"Current treatments for mast cell cancers target signaling from the receptor encoded by the c-KIT gene, and the efficacy of current therapies can be negatively affected by c-KIT mutations associated with disease development," says Glenn Cruse, assistant professor of immunology at North Carolina State University and a Scientific Advisor to Hoth and corresponding author of the research. "We are targeting the gene itself, regardless of mutation. If we target the gene that drives progression, then we can target the disease."
"We are altering the message that makes the protein – flipping an 'on' switch to 'off,'" Cruse says. "If you get mRNA to produce a protein that is mutated and severely truncated, your cell will recognize that and degrade the message so that the protein isn't produced."
The researchers used their frameshifted c-KIT mRNA approach on mast cell leukemia cells in vitro and found that KIT protein expression, signaling and function were reduced. The cancer cells stopped proliferating and began dying within hours. In a mouse model, tumor growth and infiltration of other organs were reduced, and tumor cell death increased when the frameshifted c-KIT mRNA was induced.
"The other advantage to our technique is that it solves the problem of degradation evasion," Cruse says. "Occasionally faulty messages will evade degradation and their mutated proteins get produced anyway. But proteins produced by the frameshifted c-KIT mRNA are inert, or non-functional. So even if they get produced, they cannot cause more harm."
The research appears in Molecular Therapy and is supported by the National Institutes of Health. NC State postdoctoral researcher Douglas Snider is first author. The technology described in the paper has been exclusively licensed by Hoth Therapeutics and being developed as HT-KIT.
In an article written by NC State, it states that the novel process of frameshifting changes the pre-mRNA so that the mature mRNA is degraded, and any protein produced from its instructions is altered and inert. In a mouse model, frameshifting directed at the c-KIT gene reduced mast cell tumor size and prevented infiltration into other organs.
Earlier this year, Hoth announced that its novel HT-KIT exhibited highly positive results in humanized mast cell neoplasm models, representative in vitro and in vivo models for aggressive, mast cell-derived cancers such as mast cell leukemia and mast cell sarcoma. The anti-cancer therapeutic, which is currently in development, uses mRNA frame shifting that induces apoptosis of neoplastic mast cells.
About Hoth Therapeutics, Inc.
Hoth Therapeutics, Inc. is a clinical-stage biopharmaceutical company focused on developing new generation therapies for unmet medical needs. Hoth's pipeline development is focused to improve the quality of life for patients suffering from indications including atopic dermatitis, skin toxicities associated with cancer therapy, chronic wounds, psoriasis, asthma, acne, mast-cell derived cancers & anaphylaxis and pneumonia. Hoth has also entered into two different agreements to further the development of two therapeutic prospects to prevent or treat COVID-19. To learn more, please visit https://ir.hoththerapeutics.com/
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