Bridging from Intramuscular to Limb Perfusion Delivery of rAAV: Optimization in a Non-human Primate Study
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Authors
Gruntman, AlishaGernoux, Gwladys
Tang, Qiushi
Ye, Guo-Jie
Knop, Dave R.
Wang, Gensheng
Benson, Janet
Coleman, Kristen E.
Keeler, Allison M.
Mueller, Christian
Chicoine, Louis G.
Chulay, Jeffrey D.
Flotte, Terence R.
UMass Chan Affiliations
Department of Pediatrics, Division of Pediatric PulmonologyGene Therapy Center
Document Type
Journal ArticlePublication Date
2019-02-02Keywords
gene therapyrecombinant adeno-associated virus serotype 1
rAAV1
serum alpha-1 antitrypsin (AAT) deficiency
Genetics and Genomics
Molecular Biology
Therapeutics
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Show full item recordAbstract
Phase 1 and phase 2 gene therapy trials using intramuscular (IM) administration of a recombinant adeno-associated virus serotype 1 (rAAV1) for replacement of serum alpha-1 antitrypsin (AAT) deficiency have shown long-term (5-year) stable transgene expression at approximately 2% to 3% of therapeutic levels, arguing for the long-term viability of this approach to gene replacement of secreted serum protein deficiencies. However, achieving these levels required 100 IM injections to deliver 135 mL of vector, and further dose escalation is limited by the scalability of direct IM injection. To further advance the dose escalation, we sought to bridge the rAAV-AAT clinical development program to regional limb perfusion, comparing two methods previously established for gene therapy, peripheral venous limb perfusion (VLP) and an intra-arterial push and dwell (IAPD) using rAAV1 and rAAV8 in a non-human primate (rhesus macaque) study. The rhesus AAT transgene was used with a c-myc tag to enable quantification of transgene expression. 5 cohorts of animals were treated with rAAV1-IM, rAAV1-VLP, rAAV1-IAPD, rAAV8-VLP, and rAAV8-IAPD (n = 2-3), with a dose of 6 x 10(12) vg/kg. All methods were well tolerated clinically. Potency, as determined by serum levels of AAT, of rAAV1 by the VLP method was twice that observed with direct IM injection; 90 mug/mL with VLP versus 38 mug/mL with direct IM injection. There was an approximately 25-fold advantage in estimated vector genomes retained within the muscle tissue with VLP and a 5-fold improvement in the ratio of total vector genomes retained within muscle as compared with liver. The other methods were intermediate in the potency and retention of vector genomes. Examination of muscle enzyme (CK) levels indicated rAAV1-VLP to be equally safe as compared with IM injection, while the IAPD method showed significant CK elevation. Overall, rAAV1-VLP demonstrates higher potency per vector genome injected and a greater total vector retention within the muscle, as compared to IM injection, while enabling a much greater total dose to be delivered, with equivalent safety. These data provide the basis for continuation of the dose escalation of the rAAV1-AAT program in patients and bode well for rAAV-VLP as a platform for replacement of secreted proteins.Source
Mol Ther Methods Clin Dev. 2019 Feb 2;13:233-242. doi: 10.1016/j.omtm.2019.01.013. eCollection 2019 Jun 14. Link to article on publisher's site
DOI
10.1016/j.omtm.2019.01.013Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40957PubMed ID
30828586Related Resources
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Copyright 2019. The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Distribution License
http://creativecommons.org/licenses/by/4.0/ae974a485f413a2113503eed53cd6c53
10.1016/j.omtm.2019.01.013
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Except where otherwise noted, this item's license is described as Copyright 2019. The Authors. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).