Detail
Article
Online article
FT
Medvik - BMC
  • Something wrong with this record ?

Development of an AAV-Based MicroRNA Gene Therapy to Treat Machado-Joseph Disease

R. Martier, M. Sogorb-Gonzalez, J. Stricker-Shaver, J. Hübener-Schmid, S. Keskin, J. Klima, LJ. Toonen, S. Juhas, J. Juhasova, Z. Ellederova, J. Motlik, E. Haas, S. van Deventer, P. Konstantinova, HP. Nguyen, MM. Evers,

. 2019 ; 15 (-) : 343-358. [pub] 20191028

Language English Country United States

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc19043914

Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is a progressive neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene. The expanded CAG repeat is translated into a prolonged polyglutamine repeat in the ataxin-3 protein and accumulates within inclusions, acquiring toxic properties, which results in degeneration of the cerebellum and brain stem. In the current study, a non-allele-specific ATXN3 silencing approach was investigated using artificial microRNAs engineered to target various regions of the ATXN3 gene (miATXN3). The miATXN3 candidates were screened in vitro based on their silencing efficacy on a luciferase (Luc) reporter co-expressing ATXN3. The three best miATXN3 candidates were further tested for target engagement and potential off-target activity in induced pluripotent stem cells (iPSCs) differentiated into frontal brain-like neurons and in a SCA3 knockin mouse model. Besides a strong reduction of ATXN3 mRNA and protein, small RNA sequencing revealed efficient guide strand processing without passenger strands being produced. We used different methods to predict alteration of off-target genes upon AAV5-miATXN3 treatment and found no evidence for unwanted effects. Furthermore, we demonstrated in a large animal model, the minipig, that intrathecal delivery of AAV5 can transduce the main areas affected in SCA3 patients. These results proved a strong basis to move forward to investigate distribution, efficacy, and safety of AAV5-miATXN3 in large animals.

References provided by Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc19043914
003      
CZ-PrNML
005      
20230414110708.0
007      
ta
008      
200107s2019 xxu f 000 0|eng||
009      
AR
024    7_
$a 10.1016/j.omtm.2019.10.008 $2 doi
035    __
$a (PubMed)31828177
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxu
100    1_
$a Martier, Raygene $u Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
245    10
$a Development of an AAV-Based MicroRNA Gene Therapy to Treat Machado-Joseph Disease / $c R. Martier, M. Sogorb-Gonzalez, J. Stricker-Shaver, J. Hübener-Schmid, S. Keskin, J. Klima, LJ. Toonen, S. Juhas, J. Juhasova, Z. Ellederova, J. Motlik, E. Haas, S. van Deventer, P. Konstantinova, HP. Nguyen, MM. Evers,
520    9_
$a Spinocerebellar ataxia type 3 (SCA3), or Machado-Joseph disease (MJD), is a progressive neurodegenerative disorder caused by a CAG expansion in the ATXN3 gene. The expanded CAG repeat is translated into a prolonged polyglutamine repeat in the ataxin-3 protein and accumulates within inclusions, acquiring toxic properties, which results in degeneration of the cerebellum and brain stem. In the current study, a non-allele-specific ATXN3 silencing approach was investigated using artificial microRNAs engineered to target various regions of the ATXN3 gene (miATXN3). The miATXN3 candidates were screened in vitro based on their silencing efficacy on a luciferase (Luc) reporter co-expressing ATXN3. The three best miATXN3 candidates were further tested for target engagement and potential off-target activity in induced pluripotent stem cells (iPSCs) differentiated into frontal brain-like neurons and in a SCA3 knockin mouse model. Besides a strong reduction of ATXN3 mRNA and protein, small RNA sequencing revealed efficient guide strand processing without passenger strands being produced. We used different methods to predict alteration of off-target genes upon AAV5-miATXN3 treatment and found no evidence for unwanted effects. Furthermore, we demonstrated in a large animal model, the minipig, that intrathecal delivery of AAV5 can transduce the main areas affected in SCA3 patients. These results proved a strong basis to move forward to investigate distribution, efficacy, and safety of AAV5-miATXN3 in large animals.
655    _2
$a časopisecké články $7 D016428
700    1_
$a Sogorb-Gonzalez, Marina $u Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
700    1_
$a Stricker-Shaver, Janice $u Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
700    1_
$a Hübener-Schmid, Jeannette $u Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
700    1_
$a Keskin, Sonay $u Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands.
700    1_
$a Klima, Jiri $u Institute of Animal Physiology and Genetics, Libechov, Czech Republic.
700    1_
$a Toonen, Lodewijk J $u Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands.
700    1_
$a Juhas, Stefan $u Institute of Animal Physiology and Genetics, Libechov, Czech Republic.
700    1_
$a Juhasova, Jana $u Institute of Animal Physiology and Genetics, Libechov, Czech Republic.
700    1_
$a Ellederova, Zdenka $u Institute of Animal Physiology and Genetics, Libechov, Czech Republic.
700    1_
$a Motlik, Jan $u Institute of Animal Physiology and Genetics, Libechov, Czech Republic.
700    1_
$a Haas, Eva $u Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany.
700    1_
$a van Deventer, Sander $u Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands. Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, the Netherlands.
700    1_
$a Konstantinova, Pavlina $u Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands.
700    1_
$a Nguyen, Huu Phuc $u Department of Human Genetics, Medical Faculty, Ruhr University Bochum, Bochum, Germany.
700    1_
$a Evers, Melvin M $u Department of Research & Development, uniQure Biopharma B.V., Amsterdam, the Netherlands.
773    0_
$w MED00190078 $t Molecular therapy. Methods & clinical development $x 2329-0501 $g Roč. 15, č. - (2019), s. 343-358
856    41
$u https://pubmed.ncbi.nlm.nih.gov/31828177 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y a $z 0
990    __
$a 20200107 $b ABA008
991    __
$a 20230414110701 $b ABA008
999    __
$a ind $b bmc $g 1480503 $s 1082584
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2019 $b 15 $c - $d 343-358 $e 20191028 $i 2329-0501 $m Molecular therapy. Methods & clinical development $n Mol Ther Methods Clin Dev $x MED00190078
LZP    __
$a Pubmed-20200107

Find record

Citation metrics

Archiving options