Gene Therapy for the Treatment of Neurological Disorders: Metabolic Disorders

Gessler, Dominic J.; Gao, Guangping

doi:10.1007/978-1-4939-3271-9_30

Cited by 25 publications

(23 citation statements)

References 173 publications

(231 reference statements)

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“…Pools of these osmolytes are primarily located in glia and are directly involved in the regulation of water homeostasis, membrane stability, pH and survival [ 8 , 14 , 16 , 21 , 23 , 34 ]. NAA distribution is dynamically regulated during osmotic fluctuations, but the role of NAA as osmolyte remains controversial [ 6 , 8 , 18 , 30 , 64 , 72 , 74 , 76 ]. Importantly, our findings indicate that increased NAA concentrations are uncoupled from CNS pathology and neurological dysfunction.…”

Section: Discussionmentioning

confidence: 99%

“…CD is a bona fide target for gene therapy as it is a devastating, fatal childhood disorder and there is no treatment available. In the mouse, a naturally short-lived mammalian species, systemic AAV-mediated ASPA delivery has recently shown great therapeutic success [ 2 , 30 ]. Nevertheless, immunogenicity and limitations in production continue to impede systemic AAV delivery for treatment of CNS disorders in humans [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Gene therapy for NDDs represents a rapidly developing novel therapeutic approach with a potential capability of restoring normal neuronal functions [37] by intracellular delivery of exogenous genetic material, carrying a disease correcting/therapeutic information in the form of recombinant deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) molecules engineered into a delivery vehicle, known as vector. Once inside a recipient (host) cell, the transferred genetic material utilizes cellular machinery to biosynthesize (translate the encoded information into) therapeutic proteins aimed at replacing their defective counterparts, produced in neurons by mutated endogenous gene, inactivating the mutated gene's product or inserting a foreign transgene with therapeutic properties to battle the disease.…”

Section: Choosing An Ideal Vectormentioning

confidence: 99%

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

Mijanović

Branković

Borovjagin

et al. 2020

Viruses

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Neurodegenerative diseases (NDDs) are most commonly found in adults and remain essentially incurable. Gene therapy using AAV vectors is a rapidly-growing field of experimental medicine that holds promise for the treatment of NDDs. To date, effective delivery of a therapeutic gene into target cells via AAV has been a major obstacle in the field. Ideally, transgenes should be delivered into the target cells specifically and efficiently, while promiscuous or off-target gene delivery should be minimized to avoid toxicity. In the pursuit of an ideal vehicle for NDD gene therapy, a broad variety of vector systems have been explored. Here we specifically outline the advantages of adeno-associated virus (AAV)-based vector systems for NDD therapy application. In contrast to many reviews on NDDs that can be found in the literature, this review is rather focused on AAV vector selection and their testing in experimental and preclinical NDD models. Preclinical and in vitro data reveal the strong potential of AAV for NDD-related diagnostics and therapeutic strategies.

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“…Although most gene therapies involve local administration or ex vivo gene transfer ( Table 1 ), the advent of Zolgensma confirmed that in vivo targeted gene therapy is a clear possibility and is expected to further accelerate the development of DDS technology in anticipation of gene therapy. In addition, gene therapy has emerged as having potential for the treatment of CNS diseases in the past decade [ 11 , 12 , 13 , 14 , 15 ]. Gene therapy strategies and therapeutic effects for CNS diseases that have been demonstrated are summarized in Table 2 .…”

Section: Introductionmentioning

confidence: 99%

Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

Kimura

Harashima

2020

Pharmaceutics

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The era of the aging society has arrived, and this is accompanied by an increase in the absolute numbers of patients with neurological disorders, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). Such neurological disorders are serious costly diseases that have a significant impact on society, both globally and socially. Gene therapy has great promise for the treatment of neurological disorders, but only a few gene therapy drugs are currently available. Delivery to the brain is the biggest hurdle in developing new drugs for the central nervous system (CNS) diseases and this is especially true in the case of gene delivery. Nanotechnologies such as viral and non-viral vectors allow efficient brain-targeted gene delivery systems to be created. The purpose of this review is to provide a comprehensive review of the current status of the development of successful drug delivery to the CNS for the treatment of CNS-related disorders especially by gene therapy. We mainly address three aspects of this situation: (1) blood-brain barrier (BBB) functions; (2) adeno-associated viral (AAV) vectors, currently the most advanced gene delivery vector; (3) non-viral brain targeting by non-invasive methods.

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Gene Therapy for the Treatment of Neurological Disorders: Metabolic Disorders

Cited by 25 publications

References 173 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

Battling Neurodegenerative Diseases with Adeno-Associated Virus-Based Approaches

Current Status and Challenges Associated with CNS-Targeted Gene Delivery across the BBB

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