Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model

Marie Reine Haddad, Eun Young Choi, Patricia M. Zerfas, Ling Yi, Diego Martinelli, Patricia Sullivan, David S. Goldstein, Jose A. Centeno, Lauren R. Brinster, Martina Ralle, Stephen G. Kaler

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Menkes disease is a lethal neurodegenerative disorder of copper metabolism caused by mutations in an evolutionarily conserved copper transporter, ATP7A. Based on our prior clinical and animal studies, we seek to develop a therapeutic approach suitable for application in affected human subjects, using the mottled-brindled (mo-br) mouse model that closely mimics the Menkes disease biochemical and clinical phenotypes. Here, we evaluate the efficacy of low-, intermediate-, and high-dose recombinant adeno-associated virus serotype 9 (rAAV9)-ATP7A delivered to the cerebrospinal fluid (CSF), in combination with subcutaneous administration of clinical-grade copper histidinate (sc CuHis, IND #34,166). Mutant mice that received high-dose (1.6 × 1010 vg) cerebrospinal fluid-directed rAAV9-rsATP7A plus sc copper histidinate showed 53.3% long-term (≥300-day) survival compared to 0% without treatment or with either treatment alone. The high-dose rAAV9-rsATP7A plus sc copper histidinate-treated mutant mice showed increased brain copper levels, normalized brain neurochemical levels, improvement of brain mitochondrial abnormalities, and normal growth and neurobehavioral outcomes. This synergistic treatment effect represents the most successful rescue to date of the mo-br mouse model. Based on these findings, and the absence of a large animal model, we propose cerebrospinal fluid-directed rAAV9-rsATP7A gene therapy plus subcutaneous copper histidinate as a potential therapeutic approach to cure or ameliorate Menkes disease.

Original languageEnglish (US)
Pages (from-to)165-178
Number of pages14
JournalMolecular Therapy - Methods and Clinical Development
Volume10
DOIs
StatePublished - Sep 21 2018

Fingerprint

Menkes Kinky Hair Syndrome
Dependovirus
Cerebrospinal Fluid
Copper
Survival
Brain
Therapeutics
Serogroup
Neurodegenerative Diseases
Genetic Therapy
Animal Models
Phenotype
Mutation
Growth

Keywords

  • adeno-associated virus
  • ATP7A
  • choroid plexus epithelia
  • copper
  • dopamine-beta-hydroxylase
  • Menkes disease

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. / Haddad, Marie Reine; Choi, Eun Young; Zerfas, Patricia M.; Yi, Ling; Martinelli, Diego; Sullivan, Patricia; Goldstein, David S.; Centeno, Jose A.; Brinster, Lauren R.; Ralle, Martina; Kaler, Stephen G.

In: Molecular Therapy - Methods and Clinical Development, Vol. 10, 21.09.2018, p. 165-178.

Research output: Contribution to journalArticle

Haddad, Marie Reine ; Choi, Eun Young ; Zerfas, Patricia M. ; Yi, Ling ; Martinelli, Diego ; Sullivan, Patricia ; Goldstein, David S. ; Centeno, Jose A. ; Brinster, Lauren R. ; Ralle, Martina ; Kaler, Stephen G. / Cerebrospinal Fluid-Directed rAAV9-rsATP7A Plus Subcutaneous Copper Histidinate Advance Survival and Outcomes in a Menkes Disease Mouse Model. In: Molecular Therapy - Methods and Clinical Development. 2018 ; Vol. 10. pp. 165-178.
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abstract = "Menkes disease is a lethal neurodegenerative disorder of copper metabolism caused by mutations in an evolutionarily conserved copper transporter, ATP7A. Based on our prior clinical and animal studies, we seek to develop a therapeutic approach suitable for application in affected human subjects, using the mottled-brindled (mo-br) mouse model that closely mimics the Menkes disease biochemical and clinical phenotypes. Here, we evaluate the efficacy of low-, intermediate-, and high-dose recombinant adeno-associated virus serotype 9 (rAAV9)-ATP7A delivered to the cerebrospinal fluid (CSF), in combination with subcutaneous administration of clinical-grade copper histidinate (sc CuHis, IND #34,166). Mutant mice that received high-dose (1.6 × 1010 vg) cerebrospinal fluid-directed rAAV9-rsATP7A plus sc copper histidinate showed 53.3{\%} long-term (≥300-day) survival compared to 0{\%} without treatment or with either treatment alone. The high-dose rAAV9-rsATP7A plus sc copper histidinate-treated mutant mice showed increased brain copper levels, normalized brain neurochemical levels, improvement of brain mitochondrial abnormalities, and normal growth and neurobehavioral outcomes. This synergistic treatment effect represents the most successful rescue to date of the mo-br mouse model. Based on these findings, and the absence of a large animal model, we propose cerebrospinal fluid-directed rAAV9-rsATP7A gene therapy plus subcutaneous copper histidinate as a potential therapeutic approach to cure or ameliorate Menkes disease.",
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AU - Yi, Ling

AU - Martinelli, Diego

AU - Sullivan, Patricia

AU - Goldstein, David S.

AU - Centeno, Jose A.

AU - Brinster, Lauren R.

AU - Ralle, Martina

AU - Kaler, Stephen G.

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AB - Menkes disease is a lethal neurodegenerative disorder of copper metabolism caused by mutations in an evolutionarily conserved copper transporter, ATP7A. Based on our prior clinical and animal studies, we seek to develop a therapeutic approach suitable for application in affected human subjects, using the mottled-brindled (mo-br) mouse model that closely mimics the Menkes disease biochemical and clinical phenotypes. Here, we evaluate the efficacy of low-, intermediate-, and high-dose recombinant adeno-associated virus serotype 9 (rAAV9)-ATP7A delivered to the cerebrospinal fluid (CSF), in combination with subcutaneous administration of clinical-grade copper histidinate (sc CuHis, IND #34,166). Mutant mice that received high-dose (1.6 × 1010 vg) cerebrospinal fluid-directed rAAV9-rsATP7A plus sc copper histidinate showed 53.3% long-term (≥300-day) survival compared to 0% without treatment or with either treatment alone. The high-dose rAAV9-rsATP7A plus sc copper histidinate-treated mutant mice showed increased brain copper levels, normalized brain neurochemical levels, improvement of brain mitochondrial abnormalities, and normal growth and neurobehavioral outcomes. This synergistic treatment effect represents the most successful rescue to date of the mo-br mouse model. Based on these findings, and the absence of a large animal model, we propose cerebrospinal fluid-directed rAAV9-rsATP7A gene therapy plus subcutaneous copper histidinate as a potential therapeutic approach to cure or ameliorate Menkes disease.

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