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\u2019s miQURE\u2122 technology, a proprietary, next-generation gene-silencing platform.<\/p>\n\n\n\n
Both\nstudies are published in the scientific journal, Molecular Therapy Nucleic\nAcids. The first manuscript entitled \u201cArtificial microRNAs targeting C9orf72\ncan reduce accumulation of the intra-nuclear transcripts in ALS and FTD\npatients\u201d describes the design and in vitro characterization of artificial\nmicro-RNA (miC) that silence the mutated C9orf72 gene. The second manuscript\nentitled \u201cTargeting RNA-mediated toxicity in C9orf72 ALS\/FTD by RNAi based gene\ntherapy\u201d reports that an AAV vector carrying a DNA cassette encoding miC\nsilences the mutated C9orf72 gene in iPSC-neurons derived from an FTD patient\nand in an ALS mouse model that carries the human gene with the C9orf72\nmutation. The studies show significant silencing of C9orf72 in human-derived\niPSC neurons, and the mutated C9orf72 was also reduced in the cell nucleus.\nAAV5-miC injected into the striatum of ALS mice reduced mutated C9orf72 in the\ntransduced areas.<\/p>\n\n\n\n
\u201cThese\nfindings are potentially significant for the treatment of ALS and FTD patients,\nand the ability to silence C9orf72 transcripts in the nucleus may prove to be\ncritical for therapeutic efficacy of gene therapies for these diseases,\u201d stated\nSander van Deventer, M.D., Ph.D., chief scientific officer of uniQure. \u201cIn ALS,\nmutated C9orf72 transcipts are confined to the cell nucleus causing so-called\nRNA foci, which are toxic clumps of mutated C9orf72 RNA that sequester critical\nproteins, resulting in cellular dysfunction and death. Whereas most miRNA\nconstructs exclusively target cytoplasmic mRNA, AAV5-miC significantly reduced\nformation of RNA foci in the nuclei of neurons from C9orf72 mice.\u201d<\/p>\n\n\n\n
\u201cTaken 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,\u201d he added. \u201cThese 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.\u201d<\/p>\n\n\n\n