Publication in Science Translational Medicine shows local striatal delivery of microRNA-gene therapy results in widespread brain huntingtin protein lowering in Huntington’s disease minipigs
LEXINGTON, Mass. and AMSTERDAM, April 08, 2021 (GLOBE NEWSWIRE) — uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, today announced that three manuscripts on preclinical data from its gene therapy candidate AMT-130 in Huntington’s disease have been accepted for publication, in the journals Science Translational Medicine, Brain Science, and Brain Communications. The publications show the safety and efficacy of AMT-130 in the deep brain structures of a large animal model and outline a promising novel efficacy biomarker for AMT-130.
“Taken together, these publications demonstrate widespread biodistribution and strong, durable efficiency of AMT-130 in disease-relevant regions in a large brain,” stated Ricardo Dolmetsch, Ph.D., president of research and development at uniQure. “The data provide further support for the potential therapeutic value of AMT-130, and we remain enthusiastic about our Phase I/II clinical trial of AMT-130 in patients with Huntington’s disease.”
Widespread and Sustained Target Engagement in Huntington Disease Minipigs
The paper published this week in Science Translational Medicine examines the translatability and long-term durability of AMT-130 in transgenic Huntington’s disease minipigs, which were used to assess the biodistribution and target engagement in a larger brain. The minipig model is the largest diseased animal model available, generally weighing up to 300 pounds.
AMT-130 was administered by MRI-guided convention-enhanced delivery (CED) at a single dose, bilaterally in the caudate and putamen. Vector DNA distribution and transgene expression in minipig brains demonstrated extensive brain coverage comparable at the interim sacrifice timepoints of 6- and 12-months post administration, leading to significant lowering of mutant huntingtin (mHTT) protein in the brain.
At 12 months, the most pronounced mHTT protein lowering was observed in the putamen (85%), caudate (80%) and amygdala (78%), followed by thalamus (56%) and cerebral cortex (44%).
The publication, “Widespread and Sustained Target Engagement in Huntington Disease Minipigs upon Intrastriatal MicroRNA-based Gene Therapy,” is available online in the journal Science Translational Medicine (DOI: 10.1126/scitranslmed.abb8920).
Well-tolerated in non-human primates and rats
In addition, a GLP toxicity study of AMT-130 in non-human primates and rats was published in January 2021 in the journal Brain Science. The study demonstrated an excellent safety profile and biodistribution after MRI-guided CED of AMT-130 in the treated animals. One-time bilateral administration in the caudate and putamen resulted in widespread vector DNA and miHTT transgene distribution in the brain, particularly in areas associated with HD pathology. Intrastriatal administration of AAV5-miHTT was well tolerated, with no clinically relevant changes in either species.
The publication, “Intrastriatal Administration of AAV5-miHTT in Non-Human Primates and Rats Is Well Tolerated and Results in miHTT Transgene Expression in Key Areas of Huntington Disease Pathology,” is available online in the journal Brain Science (DOI: 10.3390/brainsci11020129).
Monitoring Durability of MicroRNA-based Therapies
A third manuscript was published last week in the journal Brain Communications, examining the potential use of measuring therapeutic HTT microRNA (miHTT) in extracellular vesicles in CSF as sources to monitor the expression and durability of gene therapies in the brain. After AAV treatment in non-human primates, the secretion of mature engineered microRNA molecules was confirmed, with extracellular microRNA levels correlating with viral dose and cellular microRNA expression in neurons. In investigating the detection of engineered microRNAs over time in the CSF of non-human primates after a single intrastriatal injection of AAV5-miHTT, quantifiable engineered microRNA levels enriched in extracellular vesicles were detected in the CSF up to two years after brain infusion.
The results confirm the long-term expression (up to two years) of AAV5-delivered microRNAs in non-human primates and provide further support for the potential use of extracellular vesicle-associated microRNAs as novel biomarkers in ongoing clinical trials of gene therapies for neurodegenerative diseases, including AMT-130.
The publication, “Secreted therapeutics: Monitoring durability of microRNA-based gene therapies in the central nervous system,” is available online in the journal Brain Communications (DOI: 10.1093/braincomms/fcab054).