Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

Appu, Abhilash P.; Moffett, John R.; Arun, Peethambaran; Moran, Sean; Nambiar, Vikram; Krishnan, Jishnu K.S.; Puthillathu, Narayanan; Namboodiri, Aryan M.A.

doi:10.3389/fnmol.2017.00161

Cited by 18 publications

(14 citation statements)

References 83 publications

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“…Consequently, the increased overall NAA levels in ThyNAT brain extracts reflect increased extracellular or intra-neuronal concentrations that are not toxic per se and do not trigger a substantial alteration in principal osmolytes. This is supported by recent findings that extracellular elevation of NAA does not cause vacuolating histopathology [ 4 ]. While the aetiology is multifactorial, based on our data, we hypothesize that the CD pathology is triggered by oligodendroglial intolerance to supra-physiological NAA concentrations.…”

Section: Discussionsupporting

confidence: 83%

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

et al. 2017

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N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease—a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CNS pathology and lasting neurological benefits. This finding signifies the first successful post-symptomatic treatment of a white matter disorder using an adeno-associated virus vector tailored towards oligodendroglial-restricted transgene expression.Electronic supplementary materialThe online version of this article (10.1007/s00401-017-1784-9) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 83%

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

et al. 2017

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“…ASPA is broadly expressed in various tissues but plays an essential role in the degradation of N-acetylaspartate (NAA), one of the most abundant metabolites in the brain (Rigotti et al, 2011;Tallan, 1957). If deficient, NAA abnormally builds up in the CNS, leading to NAA acidemia and aciduria as well as a broad range of deleterious effects such as dysmyelination and spongiform degeneration in the CNS (Appu et al, 2017;Janson et al, 2006). During life, patients commonly present with head lag, macrocephaly, hypotonia, ataxia, inadequate visual tracking, epilepsy, and intellectual disabilities (Hoshino and Kubota, 2014), and many patients die before adolescence.…”

Section: Lysosomal Storage Diseasesmentioning

confidence: 99%

Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality

Hudry

Vandenberghe

2019

Neuron

282

204

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Gene transfer has long been a compelling yet elusive therapeutic modality. First mainly considered for rare inherited disorders, gene therapy may open treatment opportunities for more challenging and complex diseases such as Alzheimer's or Parkinson's disease. Today, examples of striking clinical proof of concept, the first gene therapy drugs coming onto the market, and the emergence of powerful new molecular tools have broadened the number of avenues to target neurological disorders but have also highlighted safety concerns and technology gaps. The vector of choice for many nervous system targets currently is the adeno-associated viral (AAV) vector due to its desirable safety profile and strong neuronal tropism. In aggregate, the clinical success, the preclinical potential, and the technological innovation have made therapeutic AAV drug development a reality, particularly for nervous system disorders. Here, we discuss the rationale, opportunities, limitations, and progress in clinical AAV gene therapy.

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“…Two recent studies found that elevating [NAA B ] in Aspa +/+ mice, either by oral administration of NAA-methyl ester 28 or by engineering neuronal transgenic overexpression of Nat8l, 26 was not sufficient to cause brain vacuolation. These results suggest that both aspartoacylase deficiency and elevated [NAA B ] are necessary to elicit spongiform leukodystrophy in Canavan disease.…”

Section: Discussionmentioning

confidence: 99%

Brain Nat8l Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model

et al. 2018

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Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis ("spongiform leukodystrophy"). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAA]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. We now report that brain Nat8l knockdown elicited by intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying a short hairpin Nat8l inhibitory RNA to neonatal aspartoacylase-deficient Aspa mice lowers [NAA] and suppresses development of spongiform leukodystrophy.

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Increasing N-acetylaspartate in the Brain during Postnatal Myelination Does Not Cause the CNS Pathologies of Canavan Disease

Cited by 18 publications

References 83 publications

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy

Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality

Brain Nat8l Knockdown Suppresses Spongiform Leukodystrophy in an Aspartoacylase-Deficient Canavan Disease Mouse Model

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