Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood.

Journal Article (Journal Article)

Alternating Hemiplegia of Childhood (AHC) is a devastating autosomal dominant disorder caused by ATP1A3 mutations, resulting in severe hemiplegia and dystonia spells, ataxia, debilitating disabilities, and premature death. Here, we determine the effects of delivering an extra copy of the normal gene in a mouse model carrying the most common mutation causing AHC in humans, the D801N mutation. We used an adeno-associated virus serotype 9 (AAV9) vector expressing the human ATP1A3 gene under the control of a human Synapsin promoter. We first demonstrated that intracerebroventricular (ICV) injection of this vector in wild-type mice on postnatal day 10 (P10) results in increases in ouabain-sensitive ATPase activity and in expression of reporter genes in targeted brain regions. We then tested this vector in mutant mice. Simultaneous intracisterna magna and bilateral ICV injections of this vector at P10 resulted, at P40, in reduction of inducible hemiplegia spells, improvement in balance beam test performance, and prolonged survival of treated mutant mice up to P70. Our study demonstrates, as a proof of concept, that gene therapy can induce favorable effects in a disease caused by a mutation of the gene of a protein that is, at the same time, an ATPase enzyme, a pump, and a signal transduction factor.

Full Text

Duke Authors

Cited Authors

  • Hunanyan, AS; Kantor, B; Puranam, RS; Elliott, C; McCall, A; Dhindsa, J; Pagadala, P; Wallace, K; Poe, J; Gunduz, T; Asokan, A; Koeberl, DD; ElMallah, MK; Mikati, MA

Published Date

  • April 2021

Published In

Volume / Issue

  • 32 / 7-8

Start / End Page

  • 405 - 419

PubMed ID

  • 33577387

Pubmed Central ID

  • PMC8182483

Electronic International Standard Serial Number (EISSN)

  • 1557-7422

Digital Object Identifier (DOI)

  • 10.1089/hum.2020.191


  • eng

Conference Location

  • United States