Dataset Information

Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.

ABSTRACT: We report a global adeno-associated virus (AAV)9-based gene therapy protocol to deliver therapeutic galactosylceramidase (GALC), a lysosomal enzyme that is deficient in Krabbe's disease. When globally administered via intrathecal, intracranial, and intravenous injections to newborn mice affected with GALC deficiency (twitcher mice), this approach largely surpassed prior published benchmarks of survival and metabolic correction, showing long-term protection of demyelination, neuroinflammation, and motor function. Bone marrow transplantation, performed in this protocol without immunosuppressive preconditioning, added minimal benefits to the AAV9 gene therapy. Contrasting with other proposed pre-clinical therapies, these results demonstrate that achieving nearly complete correction of GALC's metabolic deficiencies across the entire nervous system via gene therapy can have a significant improvement to behavioral deficits, pathophysiological changes, and survival. These results are an important consideration for determining the safest and most effective manner for adapting gene therapy to treat this leukodystrophy in the clinic.

SUBMITTER: Marshall MS

PROVIDER: S-EPMC5910889 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Publications

Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.

Marshall Michael S MS Issa Yazan Y Jakubauskas Benas B Stoskute Monika M Elackattu Vince V Marshall Jeffrey N JN Bogue Wil W Nguyen Duc D Hauck Zane Z Rue Emily E Karumuthil-Melethil Subha S Zaric Violeta V Bosland Maarten M van Breemen Richard B RB Givogri Maria I MI Gray Steven J SJ Crocker Stephen J SJ Bongarzone Ernesto R ER

Molecular therapy : the journal of the American Society of Gene Therapy 20180117 3

We report a global adeno-associated virus (AAV)9-based gene therapy protocol to deliver therapeutic galactosylceramidase (GALC), a lysosomal enzyme that is deficient in Krabbe's disease. When globally administered via intrathecal, intracranial, and intravenous injections to newborn mice affected with GALC deficiency (twitcher mice), this approach largely surpassed prior published benchmarks of survival and metabolic correction, showing long-term protection of demyelination, neuroinflammation, an ...[more]

PMID: 29433937

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Project description:BackgroundAcute benzodiazepine withdrawal has been described, but literature regarding the benzodiazepine-induced neurological injury that may result in enduring symptoms and life consequences is scant.ObjectiveWe conducted an internet survey of current and former benzodiazepine users and asked about their symptoms and adverse life events attributed to benzodiazepine use.MethodsThis is a secondary analysis of the largest survey ever conducted with 1,207 benzodiazepine users from benzodiazepine support groups and health/wellness sites who completed the survey. Respondents included those still taking benzodiazepines (n = 136), tapering (n = 294), or fully discontinued (n = 763).ResultsThe survey asked about 23 specific symptoms and more than half of the respondents who experienced low energy, distractedness, memory loss, nervousness, anxiety, and other symptoms stated that these symptoms lasted a year or longer. These symptoms were often reported as de novo and distinct from the symptoms for which the benzodiazepines were originally prescribed. A subset of respondents stated that symptoms persisted even after benzodiazepines had been discontinued for a year or more. Adverse life consequences were reported by many respondents as well.LimitationsThis was a self-selected internet survey with no control group. No independent psychiatric diagnoses could be made in participants.ConclusionsMany prolonged symptoms subsequent to benzodiazepine use and discontinuation (benzodiazepine-induced neurological dysfunction) have been shown in a large survey of benzodiazepine users. Benzodiazepine-induced neurological dysfunction (BIND) has been proposed as a term to describe symptoms and associated adverse life consequences that may emerge during benzodiazepine use, tapering, and continue after benzodiazepine discontinuation. Not all people who take benzodiazepines will develop BIND and risk factors for BIND remain to be elucidated. Further pathogenic and clinical study of BIND is needed.

Dataset Information

Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.

Publications

Long-Term Improvement of Neurological Signs and Metabolic Dysfunction in a Mouse Model of Krabbe's Disease after Global Gene Therapy.

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