Skip to Content
Merck
  • Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.

Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.

Molecular therapy : the journal of the American Society of Gene Therapy (2018-02-13)
Michael S Marshall, Yazan Issa, Benas Jakubauskas, Monika Stoskute, Vince Elackattu, Jeffrey N Marshall, Wil Bogue, Duc Nguyen, Zane Hauck, Emily Rue, Subha Karumuthil-Melethil, Violeta Zaric, Maarten Bosland, Richard B van Breemen, Maria I Givogri, Steven J Gray, Stephen J Crocker, Ernesto R Bongarzone
ABSTRACT

We report a global adeno-associated virus (AAV)9-based gene therapy protocol to deliver therapeutic galactosylceramidase (GALC), a lysosomal enzyme that is deficient in Krabbe's disease. When globally administered via intrathecal, intracranial, and intravenous injections to newborn mice affected with GALC deficiency (twitcher mice), this approach largely surpassed prior published benchmarks of survival and metabolic correction, showing long-term protection of demyelination, neuroinflammation, and motor function. Bone marrow transplantation, performed in this protocol without immunosuppressive preconditioning, added minimal benefits to the AAV9 gene therapy. Contrasting with other proposed pre-clinical therapies, these results demonstrate that achieving nearly complete correction of GALC's metabolic deficiencies across the entire nervous system via gene therapy can have a significant improvement to behavioral deficits, pathophysiological changes, and survival. These results are an important consideration for determining the safest and most effective manner for adapting gene therapy to treat this leukodystrophy in the clinic.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal Anti-Ceramide antibody produced in mouse, clone MID 15B4, purified immunoglobulin, buffered aqueous solution
Sigma-Aldrich
Anti-Actin antibody produced in rabbit, affinity isolated antibody, buffered aqueous solution
Avanti
N-C12-desoxymethylsphingosine, Avanti Research - A Croda Brand 860466P, powder
Avanti
Lactosyl(β) Sphingosine (d18:1), Avanti Research - A Croda Brand 860542P, powder