Widespread and sustained target engagement in Huntington's disease minipigs upon intrastriatal microRNA-based gene therapy
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F67985904%3A_____%2F21%3A00542472" target="_blank" >RIV/67985904:_____/21:00542472 - isvavai.cz</a>
Alternative codes found
RIV/00159816:_____/21:00074716 RIV/00023884:_____/21:00009041 RIV/62157124:16170/21:43879263
Result on the web
<a href="https://asep.lib.cas.cz/arl-cav/cs/csg/?repo=crepo1&key=99302825624" target="_blank" >https://asep.lib.cas.cz/arl-cav/cs/csg/?repo=crepo1&key=99302825624</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1126/scitranslmed.abb8920" target="_blank" >10.1126/scitranslmed.abb8920</a>
Alternative languages
Result language
angličtina
Original language name
Widespread and sustained target engagement in Huntington's disease minipigs upon intrastriatal microRNA-based gene therapy
Original language description
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 x 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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10603 - Genetics and heredity (medical genetics to be 3)
Result continuities
Project
<a href="/en/project/LO1609" target="_blank" >LO1609: Models of the Serious Human Diseases: Traumatic Spinal Cord Injury, Huntington’s Disease, Melanoma and Infertility</a><br>
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Science Translational Medicine
ISSN
1946-6234
e-ISSN
1946-6242
Volume of the periodical
13
Issue of the periodical within the volume
588
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
eabb8920
UT code for WoS article
000637774400004
EID of the result in the Scopus database
2-s2.0-85104098942