Widespread and sustained target engagement in Huntington’s disease minipigs upon intrastriatal microRNA-based gene therapy
Astrid Vallès, Melvin M. Evers, Anouk Stam, Marina Sogorb-González, Cynthia Brouwers, Carlos Vendrell‐Tornero, Seyda Acar-Broekmans, Lieke Paerels, Jiřı́ Klı́ma, Božena Bohuslavová, Roberta Pintauro, Valentina Fodale, Alberto Bresciani, Roman Liščák, Dušan Urgošík, Zdeněk Stárek, Michal Crha, Bas Blits, Harald Petry, Zdeňka Ellederová, Jan Motlík, Sander van Deventer, Pavlina Konstantinova
Abstract
vector genome (VG) copies per brain) was successfully administered into the striatum (bilaterally in caudate and putamen), using age-matched untreated animals as controls. Widespread brain biodistribution of vector DNA was observed, with the highest concentration in target (striatal) regions, thalamus, and cortical regions. Vector DNA presence and transgene expression were similar at 6 and 12 months after administration. Expression of miHTT strongly correlated with vector DNA, with a corresponding reduction of mutant HTT (mHTT) protein of more than 75% in injected areas, and 30 to 50% lowering in distal regions. Translational pharmacokinetic and pharmacodynamic measures in cerebrospinal fluid (CSF) were largely in line with the effects observed in the brain. CSF miHTT expression was detected up to 12 months, with CSF mHTT protein lowering of 25 to 30% at 6 and 12 months after dosing. This study demonstrates widespread biodistribution, strong and durable efficiency of rAAV5-miHTT in disease-relevant regions in a large brain, and the potential of using CSF analysis to determine vector expression and efficacy in the clinic.