Canavan disease (CD) is a rare neurological disease resulting from genetic defects that manifest as a progressive neurodegenerative disease leading to paralysis and death, usually between 3 and 10 years of age. There is no effective treatment at the present time. CD is caused by mutations in the gene for the enzyme aspartoacylase (ASPA), which produces free acetate from the concentrated brain metabolite N-acetylaspartate (NAA). NAA is synthesized in neurons, but ASPA is expressed in oligodendrocytes, and evidence indicates that neurons transfer NAA to oligodendrocytes for acetyl CoA synthesis. Because acetyl CoA is a key building block for myelin lipid synthesis, and other critical developmental functions such as gene regulation through histone acetylation, we postulated that the inability to enzymatically catabolize NAA leads to an acetate deficiency in oligodendrocytes during postnatal CNS myelination, resulting in oligodendrocyte death and defective myelin lipid synthesis. We tested the hypothesis that dietary acetate supplementation during postnatal myelination would ameliorate the severe phenotype associated with ASPA deficiency using the tremor rat model of CD. Glyceryl-triacetate (GTA), a hydrophobic acetate source, was administered to tremor rats starting 7 days after birth, and administration was continued in food and water after weaning. Significant improvements were observed in motor performance. Further, the characteristic brain vacuolation associated with CD was modestly reduced by the treatment. The improvements in motor performance were positively correlated with the decreased vacuolation. Our central hypothesis continues to be that the inability to catabolize NAA leads to a brain acetate (acetyl CoA) deficiency during a critical period of CNS development, impairing myelination and other aspects of brain development. Currently, our acetate supplementation therapy has proved only partially effective in animal models of CD. We plan to test additional acetate/acetyl CoA sources alone and in combination to improve outcomes further. We have already identified five such test compounds. These compounds increase acetyl CoA by different biochemical mechanisms. Therefore, we are likely to achieve additive or synergetic effects in combination studies.
Specific Aim 1 is to determine the time course and dose response of the test compounds to increase acetyl CoA in brain and subsequently determine efficacy of the test compounds and their combinations in our in vivo model of CD using optimal dose and dosing schedules.
Specific Aim 2 is to determine the long term safety of the treatment with chronic administration in order to proceed as quickly as possible to prepare the method for clinical trials. Importance of the proposed studies lies in the fact that CD has no current treatment and remains a fatal disease which is devastating to the affected families. Acetate replacement therapy is a simple biochemical approach, which is safe, inexpensive and convenient for use in CD infants. Preclinical studies have shown that GTA is safe to use in infants, but the treatment still requires further improvements and optimization.
Canavan disease (CD) is a rare neurological disease resulting from genetic defects that manifest as a progressive neurodegenerative disease leading to paralysis and death, usually between 3 and 10 years of age. The goal of the present project is to build on our recent success in developing a treatment for CD using acetate supplementation and bring this therapeutic strategy for this devastating and fatal disease to the clinical trial stage. This therapeutic strategy is a simple biochemical approach, which is safe, inexpensive and convenient for use in CD infants.