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Intracisternal AAV9-MAG-hABCD1 Vector Reverses Motor Deficits in Adult Adrenomyeloneuropathy Mice
Yasemin Özgür Günes1,2,3, Catherine Le Stunff1,2,4, Pierre Bougnères1,2,5,6
1Laboratoire des Maladies Neurodégénératives, MIRCen Institute, Fontenay-aux-Roses, France.
Human Gene Therapy
|December 26, 2024
Summary
Gene therapy using AAV9-MAG-hABCD1 shows promise for adrenomyeloneuropathy (AMN). Intracisternal injection in symptomatic mice improved motor function and spinal cord health, offering a new treatment avenue.
Area of Science:
- Neurology
- Gene Therapy
- Molecular Biology
Background:
- Adrenomyeloneuropathy (AMN) is a debilitating spinal cord axonopathy affecting thousands of males with ATP Binding Cassette Subfamily D Member 1 (ABCD1) mutations.
- Current treatment options for AMN are limited, with AAV gene therapy emerging as a promising therapeutic strategy for this orphan disease.
Purpose of the Study:
- To evaluate the efficacy of intracisternal AAV9-MAG-hABCD1 vector delivery in a mouse model of AMN at an early symptomatic stage.
- To assess the impact of gene therapy on motor function and spinal cord pathology in Abcd1-/- mice.
Main Methods:
- Intracisternal injection of AAV9-MAG-hABCD1 vector into 18-month-old Abcd1-/- mice, an established model for AMN.
- Longitudinal assessment of motor performance using standardized tests.
- Histological analysis of spinal cord white matter, including gene expression in oligodendrocytes and astrocytes.
Main Results:
- Treated mice (n=24) exhibited near-normal motor performances six months post-injection, contrasting with significant deterioration in untreated controls (n=34).
- Expression of human ABCD1 (hABCD1) was detected in 22% of oligodendrocytes and 22% of astrocytes in cervical spinal cord white matter.
- hABCD1 expression was also observed in the cerebellum, brainstem, and lower spinal cord, primarily in oligodendrocytes and astrocytes.
Conclusions:
- Intracisternal AAV9-MAG-hABCD1 gene therapy is effective in ameliorating motor deficits and improving neurological status in a symptomatic AMN mouse model.
- The vector targets oligodendrocytes and astrocytes in key central nervous system regions, suggesting a targeted oligotropic therapeutic approach for AMN.
