Early intervention to restore OL and myelin development in leukodystrophy model

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DESCRIPTION (provided by applicant): Abstract Project Summary: The objective of our research is to elucidate the role of myelin gene mutation on oligodendrocyte (OL) cell maturation and ensheathment of axons, failure of which results in hypomyelination that leads to leukodystrophy. Canavan disease (CD) is an example of such leukodystrophy which is caused by a metabolic mutation in aspartoacylase (ASPA) gene. Now recognized as a marker for OL cells, ASPA metabolizes N-acetyl aspartate (NAA) to release acetate and aspartic acid. The pathophysiology of this childhood disorder includes a spongy white matter morphology, mental retardation, megalencephaly, NAA aciduria, motor deficit, and early death. Because young children affected by Canavan disease display hypomyelination, the question arises whether this early event is indicative of OL dysfunction. An ASPA knockout (KO) mouse strain lacks expression of ASPA protein and enzyme activity, and closely resembles symptoms of human CD. Our preliminary work has shown that the ASPA knockout OLs exhibit lack of mature myelin basic proteins and lack of immunostaining of myelin proteins in cell processes in the CNS, even though presence of transcripts for myelin genes were identified. This suggests that expression of ASPA is critical during early stages of development for the maturation of OLs. In addition, a massive apoptotic cell death occurs in the CNS of ASPA knockout mice. Gene therapy was approved to another group of researchers, who administered an adenoviral-associated viral (AAV)-mediated ASPA gene therapy in a cohort of CD children, and in rodent models of CD after the peak period of myelination. No improvement in spongy white matter morphology was detected. During early development, OL progenitors arise embryonically, and yet another OL lineage is generated post- birth to populate the forebrain. Therefore, we propose to target these two early populations of OLs for delivery of ASPA gene to induce OL maturation and function in the KO brain. The findings will help understand the role of ASPA in prevention of leukodystrophy and will be useful for future development of therapies. Abstract Narrative: Objective of this proposal is to restore aspartoacylase activity during the embryonic and post-natal period of mouse model of Canavan Disease (CD). We will demonstrate that activity of this gene is critically necessary for the normal development of the myelin forming cells and the ensheathment of axons that is essential for normal CNS function. If successful, information from this study could be used to develop appropriate therapeutic interventions for the treatment of children affected by CD, the most devastating disease that causes mental retardation and death.