Widespread and sustained target engagement in Huntington's disease minipigs upon intrastriatal microRNA-based gene therapy.

Autor:	Vallès A; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands. a.vallessanchez@uniqure.com m.evers@uniqure.com., Evers MM; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands. a.vallessanchez@uniqure.com m.evers@uniqure.com., Stam A; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Sogorb-Gonzalez M; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Brouwers C; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Vendrell-Tornero C; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Acar-Broekmans S; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Paerels L; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Klima J; Institute of Animal Physiology and Genetics, Rumburská 89, 277 21 Libechov, Czech Republic., Bohuslavova B; Institute of Animal Physiology and Genetics, Rumburská 89, 277 21 Libechov, Czech Republic., Pintauro R; Department of Translational Biology, IRBM Science Park S.p.A., Via Pontina km 30,600, 00071 Pomezia, Italy., Fodale V; Department of Translational Biology, IRBM Science Park S.p.A., Via Pontina km 30,600, 00071 Pomezia, Italy., Bresciani A; Department of Translational Biology, IRBM Science Park S.p.A., Via Pontina km 30,600, 00071 Pomezia, Italy., Liscak R; Department of Stereotactic Radioneurosurgery, Na Homolce Hospital, Roentgenova 37/2, 150 30, Prague 5, Czech Republic., Urgosik D; Department of Stereotactic Radioneurosurgery, Na Homolce Hospital, Roentgenova 37/2, 150 30, Prague 5, Czech Republic., Starek Z; Interventional Cardiac Electrophysiology, St. Anne's University Hospital, Pekařská 53, 656 91 Brno, Czech Republic., Crha M; Small Animal Clinic, Veterinary and Pharmaceutical University, Palackého třída 1946/1, 612 42 Brno, Czech Republic., Blits B; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Petry H; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Ellederova Z; Institute of Animal Physiology and Genetics, Rumburská 89, 277 21 Libechov, Czech Republic., Motlik J; Institute of Animal Physiology and Genetics, Rumburská 89, 277 21 Libechov, Czech Republic., van Deventer S; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands., Konstantinova P; Department of Research and Development, uniQure biopharma B.V., Paasheuvelweg 25a, 1105 BP Amsterdam, Netherlands.
Jazyk:	angličtina
Zdroj:	Science translational medicine [Sci Transl Med] 2021 Apr 07; Vol. 13 (588).
DOI:	10.1126/scitranslmed.abb8920
Abstrakt:	Huntingtin (HTT)-lowering therapies hold promise to slow down neurodegeneration in Huntington's disease (HD). Here, we assessed the translatability and long-term durability of recombinant adeno-associated viral vector serotype 5 expressing a microRNA targeting human HTT (rAAV5-miHTT) administered by magnetic resonance imaging-guided convention-enhanced delivery in transgenic HD minipigs. rAAV5-miHTT (1.2 × 10 13 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. (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
Databáze:	MEDLINE
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