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uniQure Publications on AAV Gene Therapy Approach to ALS and Dementia

uniQure, a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today announced two recent online publications of preclinical studies showing significant silencing, or knockdown, of the mutated gene most commonly known to lead to onset of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), two devastating neurodegenerative diseases. The proof-of-concept studies were conducted by uniQure scientists and utilized the Company’s miQURE™ technology, a proprietary, next-generation gene-silencing platform.

Both studies are published in the scientific journal, Molecular Therapy Nucleic Acids. The first manuscript entitled “Artificial microRNAs targeting C9orf72 can reduce accumulation of the intra-nuclear transcripts in ALS and FTD patients” describes the design and in vitro characterization of artificial micro-RNA (miC) that silence the mutated C9orf72 gene. The second manuscript entitled “Targeting RNA-mediated toxicity in C9orf72 ALS/FTD by RNAi based gene therapy” reports that an AAV vector carrying a DNA cassette encoding miC silences the mutated C9orf72 gene in iPSC-neurons derived from an FTD patient and in an ALS mouse model that carries the human gene with the C9orf72 mutation. The studies show significant silencing of C9orf72 in human-derived iPSC neurons, and the mutated C9orf72 was also reduced in the cell nucleus. AAV5-miC injected into the striatum of ALS mice reduced mutated C9orf72 in the transduced areas.

“These findings are potentially significant for the treatment of ALS and FTD patients, and the ability to silence C9orf72 transcripts in the nucleus may prove to be critical for therapeutic efficacy of gene therapies for these diseases,” stated Sander van Deventer, M.D., Ph.D., chief scientific officer of uniQure. “In ALS, mutated C9orf72 transcipts are confined to the cell nucleus causing so-called RNA foci, which are toxic clumps of mutated C9orf72 RNA that sequester critical proteins, resulting in cellular dysfunction and death. Whereas most miRNA constructs exclusively target cytoplasmic mRNA, AAV5-miC significantly reduced formation of RNA foci in the nuclei of neurons from C9orf72 mice.”

“Taken together, these preclinical findings further support the feasibility of advancing this program through research and potentially into development of a promising gene therapy with the potential to alleviate the toxicity caused by the mutated C9orf72 in ALS and FTD,” he added. “These data illustrate the potential of our miQURE platform to degrade disease-causing genes, without off-target toxicity. We are very pleased to have these data published in a highly relevant journal for the field and look forward to further exploring this opportunity.”

Source: uniQure