In:
Gene Regulation and Systems Biology, SAGE Publications, Vol. 3 ( 2009-01), p. GRSB.S2210-
Abstract:
Hereditary inclusion body myopathy-2 (HIBM2) is an adult-onset, muscular disease caused by mutations in the GNE gene. HIBM2-associated GNE mutations causing hyposialyation have been proposed to contribute to reduced muscle function in patients with HIBM2, though the exact cause of this disease is unknown. In the current studies we examined pre-clinical in vivo toxicity, and expression of the plasmid-based, CMV driven wild-type GNE plasmid vector. The plasmid vector was injected intramuscularly (IM) or systemically (IV) into BALB/c mice, following encapsulation in a cationic liposome (DOTAP: Cholesterol). Single IM injections of the GNE-lipoplex at 40 µg did not produce overt toxicity or deaths, indicating that the no observable adverse effect level (NOAEL) dose for IM injection was 〉 40 µg. Single intravenous (IV) infusion of GNE-lipoplex was lethal in 33% of animals at 100 µg dose, with a small proportion of animals in the 40 µg cohort demonstrating transient toxicity. Thus the NOAEL dose by the IV route was greater than 10 µg and less than or equal to 40 µg. Real-time RT-qPCR analysis demonstrated recombinant human GNE mRNA expression in 100% of muscle tissues that received IM injection of 40 µg GNE-lipoplex, at 2 weeks. These results indicate that GNE-lipoplex gene transfer is safe and can produce durable transgene expression in treated muscles. Our findings support future exploration of the clinical efficacy of GNE-lipoplex for experimental gene therapy of HIBM2.
Type of Medium:
Online Resource
ISSN:
1177-6250
,
1177-6250
Language:
English
Publisher:
SAGE Publications
Publication Date:
2009
detail.hit.zdb_id:
2383407-9
