A 3-D illustration of the huntingtin protein. Produced in excess by the mutated HTT gene, it causes Huntington’s disease. Image courtesy of Cambridge Independent.
With colleagues from UC Irvine and Johns Hopkins University, Yeo and his team investigated whether the recently described RNA-targeting CRISPR technology could be used to affect the accumulation of RNA (a chemical intermediate between the instructions DNA and protein production) associated with HD.
They used viral vehicles to deliver therapy to neuronal cultures, which were grown from stem cells derived from HD patients, and found that the approach not only targeted and destroyed mutant RNA molecules, but also eliminates the accumulation of toxic proteins. They also demonstrated that the expression of other human genes was generally not disrupted by the therapy.
“Our goal was to design a type of therapy that would only target the toxic RNA that causes HD and could keep the rest of the human genome and transcriptome intact,” said co-first author Kathryn Morelli, PhD, researcher at the Yeo’s lab. . “We specifically screened our best therapeutic constructs in HD patient cell lines to make sure.”
Developing effective therapies for HD has proven difficult. In 2021, for example, two clinical trials of promising gene therapies were stopped following disappointing results. Both potential drugs had been touted as game changers for HD. Currently, no treatment can change the course of the disease, although medication can alleviate some symptoms.
“The Huntington community was devastated when clinical trials failed, primarily due to target specificity and toxic effects,” Yeo said. “But their shutdown only reinvigorated the scientific community to find alternative strategies.”
Yeo’s lab collaborated with Wenzhen Duan, MD, PhD, professor of psychiatry and behavioral sciences, at Johns Hopkins Medicine to perform preclinical tests on mice. Duan, along with co-first author Qian Wu, PhD, found that the therapy improved motor coordination, alleviated striatal breakdown, and reduced toxic protein levels in a mouse model of HD. Improvements lasted at least 8 months without adverse effects and with minimal off-target effects on other RNA molecules.
Co-authors include: Maya L. Gosztyla, Ryan J. Marina, Kari Lee, Krysten L. Jones, Megan Huang, and Allison Li, all at UC San Diego; Hongshuai Liu, Minmin Yao, and Chuangchuang Zhang, Johns Hopkins University; Jiaxu Chen, Beijing University of Chinese Medicine; and Charlene Smith-Geater and Leslie M. Thompson, UC Irvine.
Funding for this research came, in part, from the National Institutes of Health (Grants EY029166, NS103172, MH107367, AI132122, HG004659, HG009889, NS099397, NS124084, T32GM008666) the Bev Hartig Huntington’s Disease Foundation, a NIH-1 25 NS1 Postdoctoral Fellowship an University of California President’s Postdoctoral Fellowship, Paul G. Allen Foundation, China Scholarship Council and National Natural Science Foundation of China (82174278 and 81973748), Hereditary Disease Foundation, NIH Predoctoral Fellowship (NS111859), a National Science Foundation Graduate Fellowship (DGE-2038238), a Myotonic Dystrophy Foundation Doctoral Research Fellowship, an Association for Women in Science Fellowship, and a Triton Research and Experiential Learning Fellowship from ‘Eureka! Fellowship.
Disclosures: Gene Yeo is a member of the scientific advisory board of Jumpcode Genomics and co-founder, board member, member of the scientific advisory board, shareholder and paid consultant for Locanabio and Eclipse BioInnovations. He is also a Visiting Professor Emeritus at the National University of Singapore.