A 3D representation of the huntingtin protein. Overproduced by a mutated HTT gene, it causes Huntington’s disease. Image courtesy of Cambridge Independent.
Yeo and his team, along with colleagues at UC Irvine and Johns Hopkins University, investigated whether the recently described RNA-targeting CRISPR technique could be used to influence HD-associated RNA (the chemistry between DNA instructions and protein production). intermediates) accumulate.
Using a viral vector to deliver the therapy to neuronal cultures developed from stem cells from HD patients, they found that the approach not only targeted and destroyed the mutated RNA molecule, but also cleared the toxic protein. accumulation. They also demonstrated that the expression of other human genes is not normally disrupted by the therapy.
“Our goal is to design a treatment that targets only the toxic RNA that causes HD and leaves the rest of the human genome and transcriptome intact,” said co-first author Kathryn Morelli, Ph.D., a researcher in Yeo’s lab. “We specifically screened the top therapeutic constructs in HD patient cell lines to ensure this.”
Developing effective HD therapies has proven challenging. For example, in 2021, two clinical trials of promising gene therapies were halted after disappointing performance results. Both potential drugs are being touted as game-changers for HD. Currently, there are no treatments that alter the course of the disease, although medications can reduce some symptoms.
“The Huntington’s disease community has been hit hard by the failure of clinical trials, mainly due to target specificity and toxic effects,” Yeo said. “But their termination will only re-energize the scientific community to find alternative strategies.”
Yeo’s lab worked with Wenzhen Duan, MD, PhD, professor of psychiatry and behavioral sciences at the Johns Hopkins School of Medicine, to conduct preclinical testing in mice. Duan and co-first author Qian Wu, Ph.D., found that the treatment improved motor coordination, attenuated striatal degeneration and reduced levels of toxic proteins in a mouse model of HD. These improvements persisted for at least 8 months, with no side effects and 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, UC San Diego; Hongshuai Liu, Minmin Yao, and Chuang Chuang Zhang, Johns Hopkins University; Beijing Chen Jiaxu, University of Traditional Chinese Medicine; Charlene Smith-Geater and Leslie M. Thompson, University of California, Irvine.
This research was funded in part by the National Institutes of Health (grants EY029166, NS103172, MH107367, AI132122, HG004659, HG009889, NS099397, NS124084, T32GM008666) Bev Hartig Huntington’s Disease Foundation, NIH NS1123 Postdoctoral Fellowship UC Chancellor’s Postdoctoral Fellowship , Paul G. Allen Foundation, China Scholarship Council and National Natural Science Foundation of China (82174278 and 81973748), Genetic Disease Foundation, NIH Predoctoral Fellowship (NS111859), National Science Foundation Graduate Research Fellowship (DGE-2038238) , Myotonic Dystrophy Foundation Doctoral Research Fellowship, Society for Women in Science Fellowship and Triton Research and Experiential Learning Fellowship from Eureka! Research Scholarships.
Disclosure: Gene Yeo is a member of the Scientific Advisory Board of Jumpcode Genomics and a co-founder, board member, scientific advisory board member, equity holder and paid advisor of Locanabio and Eclipse BioInnovations. He is also a Distinguished Visiting Professor at the National University of Singapore.