uniQure – gene therapy SCA3 mousemodel

Spinocerebellar Ataxia Type 3, also known as Machado-Joseph disease, is caused by a CAG-repeat expansion in the ATXN3 gene that results in an abnormal form of the toxic protein ataxin-3, leading to brain degeneration that results in movement disorders, rigidity, muscular atrophy and paralysis.

The company has engineered an artificial microRNA candidate, AMT-150, to target the ataxin-3 gene in a SCA3 knock-in mouse model. 

An inactivated virus vector is used to deliver AMT-150 to the nerve cells. The virus containing AMT-150 is injected close to the cerebellum. 

The 6-week proof-of-concept study demonstrated that a single AMT-150 injection in the cerebrospinal fluid resulted in significant mutant ataxin-3 lowering at each of the primary sites of disease neuropathology, namely the cerebellum (up to 53%) and brainstem (up to 65%).

These results were corroborated by preclinical studies in human induced Pluripotent Stem Cell (iPSC)-derived neurons showing a dose-dependent lowering of ataxin-3 mRNA of up to 55%.

These studies further demonstrate the potential utility and safety profile of the miQURE™ technology, the Company’s proprietary gene-silencing platform.

“We believe that the data from these preclinical studies in the knock-in mouse model and in iPSC-derived neurons show the potential of AMT-150 to alter the course of this devastating disease after a single administration,” stated Sander van Deventer, M.D., Ph.D., chief scientific officer at uniQure.

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Press release, 7 May 2019