Mir-142-3p target sequences reduce transgene directed immunogenicity following intramuscular AAV vector-mediated gene delivery
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1
uniQure B.V., Netherlands
Appearance of immune responses against the transgene product after adeno-associated virus (AAV) vector-based gene therapy is one of the concerns that limit efficacy of the treatment. Use of microRNAs (miRNAs) that are specifically expressed in antigen-presenting cells (APCs) is a promising approach to avoid those immune responses. Cellular mir-142-3p, which is APC-specific, is able to repress translation of its target cellular transcripts by binding to a specific target sequences.
We explored the potential of mir-142-3p specific target sequences to reduce or abolish immune responses directed against the immunogenic protein ovalbumin delivered intramuscularly by AAV vector.
The occurrence of humoral and cellular immune responses against OVA transgene following intramuscular delivery by AAV have been previously described and resulted in loss of OVA protein expression. In our study we demonstrate that OVA protein expression was maintained when mir-142-3pT sequences were incorporated in the expression cassette. The sustained expression of OVA protein over time correlated with a reduced increase in anti-OVA antibody level. Furthermore, no cellular infiltrates were observed in the muscle tissue when AAV1 vectors containing 4 or 8 repeats of mir-142-3p target sequences after OVA sequence were used.
Our data provides the evidence that humoral and cellular immune responses against OVA protein after intramuscular delivery can be efficiently reduced by use of mir-142-3p target sequences. Overall, this study identifies a promising approach for gene therapy applications targeting the muscle as it could be applied as a “safety lock” for any intramuscular AAV vector based therapeutic gene delivery.
Keywords:
adeno-associated virus (AAV),
mir-142-3p,
immune response against transgene,
gene tharapy,
intramuscular gene delivery
Conference:
15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013.
Presentation Type:
Abstract
Topic:
Translational immunology and immune intervention
Citation:
Majowicz
A,
Maczuga
P,
Kwikkers
KL,
Van Der Marel
S,
Van Logtenstein
R,
Petry
H,
Van Deventer
SJ,
Konstantinova
P and
Ferreira
V
(2013). Mir-142-3p target sequences reduce transgene directed immunogenicity following intramuscular AAV vector-mediated gene delivery.
Front. Immunol.
Conference Abstract:
15th International Congress of Immunology (ICI).
doi: 10.3389/conf.fimmu.2013.02.00244
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Received:
12 Mar 2013;
Published Online:
22 Aug 2013.
*
Correspondence:
Ms. Anna Majowicz, uniQure B.V., Amsterdam, Netherlands, a.majowicz@uniqure.com