Non-genetic therapeutic approaches to Canavan disease

Abstract

ABSTRACT:Canavan disease (CD) is a rare leukodystrophy characterized by diffuse spongiform white matter degeneration, dysmyelination and intramyelinic oedema with consequent impairment of psychomotor development and early death. The molecular cause of CD has been identified as being mutations of the gene encoding the enzyme aspartoacylase

Antisense Oligonucleotide Reverses Leukodystrophy in Canavan Disease Mice

“…Canavan disease (CD) is a vacuolar leukodystrophy caused by Aspa gene mutations that block expression of functional aspartoacylase, an enzyme required for catabolism of the abundant brain amino acid N‐acetyl‐L‐aspartate (NAA) . Current therapies for CD, including dietary manipulations, lithium citrate administration, stem cell transplants, and brain intraparenchymal adeno‐associated viral (AAV)‐ Aspa vector administration, have not been successful in reversing or preventing progression of CD . The brain concentration of NAA ([NAA B ]) is markedly elevated in CD, and also in aspartoacylase‐deficient CD mice .…”

“…[1][2][3] Current therapies for CD, including dietary manipulations, lithium citrate administration, stem cell transplants, and brain intraparenchymal adenoassociated viral (AAV)-Aspa vector administration, have not been successful in reversing or preventing progression of CD. 4,5 The brain concentration of NAA ([NAA B ]) is markedly elevated in CD, 2,4 and also in aspartoacylasedeficient CD mice. [6][7][8][9] We now report that lowering [NAA B ] in young-adult CD mice by administration into cisterna magna of a locked nucleic acid antisense oligonucleotide (LNA-ASO, or gapmer) 10 to knockdown expression of the neuronal NAA-synthesizing enzyme N-acetyltransferase 8-like (Nat8l) 11 reverses ataxia, Purkinje cell dendritic atrophy, and cerebellar/thalamic vacuolation.…”

Microbial Neuraminidase Induces a Moderate and Transient Myelin Vacuolation Independent of Complement System Activation

“…Furthermore, temporal factors should also be considered, as they might contribute to those differences: in Mag-null and B4galnt1-null mutants, the MAG-ganglioside interaction is permanently disrupted, while in NA-induced vacuolation, the disruption is transient. Similar intramyelinic vacuolation has been found in mitochondrial encephalopathies as Kearns-Sayre syndrome (60), in Canavan's disease (61), in vitamin B12-deficient animals (62), in toxin-induced injuries (63), and in retroviral infections (64). Although in some of these myelinopathies the authors have placed the oligodendrocytes in the center of the disease (60,65,66), the mechanisms of vacuolation remain speculative in most of them.…”

Cytotoxic edema and diffusion restriction as an early pathoradiologic marker in canavan disease: case report and review of the literature

“…Our results support the notion of an acute phase in disease progression. Together with evidence that NAA levels are related to myelin degeneration [2, 3], that NAA levels rise during the first year of life in Canavan disease [25], and the possibility for potential treatments [20, 22, 23], these findings suggest that there is a window available for therapeutic intervention and support the need for early identification of patients with Canavan disease.…”

“…Interest in improved understanding of the pathology and the early diagnosis of Canavan disease has arisen in part because of the potential for new treatments [20]. Gene therapy replacement of ASPA has been used successfully in a rodent Canavan model and appears safe in humans [21, 22].…”