Rescuing Canavan disease: engineering the wrong cell at the right time
| Autor: | Morris H. Baslow |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Aspartic Acid Pathology medicine.medical_specialty Canavan Disease business.industry Cell Audiology medicine.disease Canavan disease Human genetics Amidohydrolases Aspartoacylase 03 medical and health sciences 030104 developmental biology medicine.anatomical_structure Myelin sheath Genetics medicine Humans business Myelin Sheath Genetics (clinical) Research Article |
| Zdroj: | Journal of Inherited Metabolic Disease. 40:627-628 |
| ISSN: | 1573-2665 0141-8955 |
| DOI: | 10.1007/s10545-017-0038-2 |
| Popis: | Canavan disease (CD) is a debilitating and lethal leukodystrophy caused by mutations in the aspartoacylase (ASPA) gene and the resulting defect in N-acetylaspartate (NAA) metabolism in the CNS and peripheral tissues. Recombinant adeno-associated virus (rAAV) has the ability to cross the blood-brain barrier and widely transduce the CNS. We developed a rAAV-based and optimized gene replacement therapy, which achieves early, complete, and sustained rescue of the lethal disease phenotype in CD mice. Our treatment results in a super-mouse phenotype, increasing motor performance of treated CD mice beyond that of WT control mice. We demonstrate that this rescue is oligodendrocyte independent, and that gene correction in astrocytes is sufficient, suggesting that the establishment of an astrocyte-based alternative metabolic sink for NAA is a key mechanism for efficacious disease rescue and the super-mouse phenotype. Importantly, the use of clinically translatable high-field imaging tools enables the noninvasive monitoring and prediction of therapeutic outcomes for CD and might enable further investigation of NAA-related cognitive function. |
| Databáze: | OpenAIRE |
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