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

Publication ,  Journal Article
Hunanyan, AS; Kantor, B; Puranam, RS; Elliott, C; McCall, A; Dhindsa, J; Pagadala, P; Wallace, K; Poe, J; Gunduz, T; Asokan, A; Koeberl, DD ...
Published in: Hum Gene Ther
April 2021

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.

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Published In

Hum Gene Ther

DOI

EISSN

1557-7422

Publication Date

April 2021

Volume

32

Issue

7-8

Start / End Page

405 / 419

Location

United States

Related Subject Headings

  • Sodium-Potassium-Exchanging ATPase
  • Mutation
  • Mice
  • Hemiplegia
  • Genetic Therapy
  • Dependovirus
  • Biotechnology
  • Animals
  • 3206 Medical biotechnology
  • 1103 Clinical Sciences
 

Citation

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Hunanyan, A. S., Kantor, B., Puranam, R. S., Elliott, C., McCall, A., Dhindsa, J., … Mikati, M. A. (2021). Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood. Hum Gene Ther, 32(7–8), 405–419. https://doi.org/10.1089/hum.2020.191
Hunanyan, Arsen S., Boris Kantor, Ram S. Puranam, Courtney Elliott, Angela McCall, Justin Dhindsa, Promila Pagadala, et al. “Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood.Hum Gene Ther 32, no. 7–8 (April 2021): 405–19. https://doi.org/10.1089/hum.2020.191.
Hunanyan AS, Kantor B, Puranam RS, Elliott C, McCall A, Dhindsa J, et al. Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood. Hum Gene Ther. 2021 Apr;32(7–8):405–19.
Hunanyan, Arsen S., et al. “Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood.Hum Gene Ther, vol. 32, no. 7–8, Apr. 2021, pp. 405–19. Pubmed, doi:10.1089/hum.2020.191.
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. Adeno-Associated Virus-Mediated Gene Therapy in the Mashlool, Atp1a3Mashl/+, Mouse Model of Alternating Hemiplegia of Childhood. Hum Gene Ther. 2021 Apr;32(7–8):405–419.
Journal cover image

Published In

Hum Gene Ther

DOI

EISSN

1557-7422

Publication Date

April 2021

Volume

32

Issue

7-8

Start / End Page

405 / 419

Location

United States

Related Subject Headings

  • Sodium-Potassium-Exchanging ATPase
  • Mutation
  • Mice
  • Hemiplegia
  • Genetic Therapy
  • Dependovirus
  • Biotechnology
  • Animals
  • 3206 Medical biotechnology
  • 1103 Clinical Sciences