AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease

Johnson, Tyler B.; White, Katherine A.; Brudvig, Jon; Cain, Jacob T.; Langin, Logan M.; Pratt, Melissa A.; Booth, Clarissa D.; Timm, Derek; Davis, Samantha; Meyerink, Brandon; Likhite, Shibi; Meyer, Kathrin; Weimer, Jill M.

doi:10.1016/j.ymthe.2020.09.033

Cited by 28 publications

(43 citation statements)

References 44 publications

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“…This is a condition caused by biallelic mutations in the gene CLN8 which encodes an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis (di Ronza et al, 2018). A single neonatal ICV injection of a scAAV-9 vector encoding human CLN8 has recently shown a successful degree of rescue in a mouse CLN8 model, as revealed by reduced histopathology, substantial behavioral improvement, and increased lifespan (Johnson et al, 2021). These data clearly encourage the testing of gene therapy for this disorder.…”

Section: Cln8 Diseasementioning

confidence: 90%

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

Jensen

Gøtzsche

Woldbye

2021

Front. Mol. Neurosci.

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In recent years, gene therapy has been raising hopes toward viable treatment strategies for rare genetic diseases for which there has been almost exclusively supportive treatment. We here review this progress at the pre-clinical and clinical trial levels as well as market approvals within diseases that specifically affect the brain and spinal cord, including degenerative, developmental, lysosomal storage, and metabolic disorders. The field reached an unprecedented milestone when Zolgensma® (onasemnogene abeparvovec) was approved by the FDA and EMA for in vivo adeno-associated virus-mediated gene replacement therapy for spinal muscular atrophy. Shortly after EMA approved Libmeldy®, an ex vivo gene therapy with lentivirus vector-transduced autologous CD34-positive stem cells, for treatment of metachromatic leukodystrophy. These successes could be the first of many more new gene therapies in development that mostly target loss-of-function mutation diseases with gene replacement (e.g., Batten disease, mucopolysaccharidoses, gangliosidoses) or, less frequently, gain-of-toxic-function mutation diseases by gene therapeutic silencing of pathologic genes (e.g., amyotrophic lateral sclerosis, Huntington's disease). In addition, the use of genome editing as a gene therapy is being explored for some diseases, but this has so far only reached clinical testing in the treatment of mucopolysaccharidoses. Based on the large number of planned, ongoing, and completed clinical trials for rare genetic central nervous system diseases, it can be expected that several novel gene therapies will be approved and become available within the near future. Essential for this to happen is the in depth characterization of short- and long-term effects, safety aspects, and pharmacodynamics of the applied gene therapy platforms.

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Section: Cln8 Diseasementioning

confidence: 90%

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

Jensen

Gøtzsche

Woldbye

2021

Front. Mol. Neurosci.

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“…An scAAV9 vector carrying human CLN8 protein injected ICV in neonatal CLN8-deficient mice was well tolerated and produced robust CLN8 expression throughout the CNS from 4 to 24 months. At the same time, histopathological and behavioral hallmarks of the CLN disease were reduced, and the life span was increased from 10 months in untreated CLN8-deficient mice to beyond 24 months in treated animals ( Johnson et al, 2020 ).…”

Section: Nbts In Orphan Neurological Disordersmentioning

confidence: 99%

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

Khorkova

Hsiao

Wahlestedt

2021

Front. Mol. Biosci.

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The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid–based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood–brain barrier, neurological diseases are significantly represented among the first targets for NBTs. As orphan disease NBTs are now entering the clinical stage, substantial efforts are required to develop the scientific background and infrastructure for NBT design and mechanistic studies, genetic testing, understanding natural history of orphan disorders, data sharing, NBT manufacturing, and regulatory support. The outcomes of these efforts will also benefit patients with “common” diseases by improving diagnostics, developing the widely applicable NBT technology platforms, and promoting deeper understanding of biological mechanisms that underlie disease pathogenesis. Furthermore, with successes in genetic research, a growing proportion of “common” disease cases can now be attributed to mutations in particular genes, essentially extending the orphan disease field. Together, the developments occurring in orphan diseases are building the foundation for the future of personalized medicine. In this review, we will focus on recent achievements in developing therapies for orphan neurological disorders.

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“…One gene (Cxcl10) was upregulated in the Epm2b -/mice, and corrected. The above ~17% disruption was achieved by ICV injection in neonatal mice, of all known situations the most permissive given the yet immature nature of intercompartmental barriers at this age [42][43][44]. Treatments at older ages through any route (ICV, intrathecal, intra-cisterna magna, or intravenous) are expected to be less widespread and effective, and will require enhanced viral or other delivery systems.…”

Section: Effects On Pb-associated Immune Activationmentioning

confidence: 99%

Targeting Gys1 with AAV‐SaCas9 decreases pathogenic polyglucosan bodies and neuroinflammation in Adult Polyglucosan Body and Lafora disease mouse models

Gumusgoz

Guisso

Kasiri

et al. 2021

Preprint

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Many adult and most childhood neurological diseases have a genetic basis. CRISPR/Cas9 biotechnology holds great promise in neurological therapy, pending the clearance of major delivery, efficiency and specificity hurdles. We apply CRISPR/Cas9 genome editing in its simplest modality, namely inducing gene sequence disruption, to one adult and one pediatric disease. Adult polyglucosan body disease is a neurodegenerative disease resembling amyotrophic lateral sclerosis. Lafora disease is a severe late childhood onset progressive myoclonus epilepsy. The pathogenic insult in both is formation in the brain of glycogen with overlong branches, which precipitates and accumulates into polyglucosan bodies that drive neuroinflammation and neurodegeneration. We packaged Staphylococcus aureus Cas9 and a guide RNA targeting the glycogen synthase gene Gys1 responsible for brain glycogen branch elongation in AAV9 virus, which we delivered by neonatal intracerebroventricular injection to one mouse model of adult polyglucosan body disease and two mouse models of Lafora disease. This resulted, in all three models, in editing of approximately 17% of Gys1 alleles and a similar extent of reduction of Gys1 mRNA across the brain. The latter led to approximately 50% reductions of GYS1 protein, of abnormal glycogen accumulation and of polyglucosan bodies, as well as corrections of neuroinflammatory markers in all three models. Our work represents proof of principle for virally-delivered CRISPR/Cas9 neurotherapeutics in an adult-onset (adult polyglucosan body) and a childhood-onset (Lafora) neurological diseases.

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AAV9 Gene Therapy Increases Lifespan and Treats Pathological and Behavioral Abnormalities in a Mouse Model of CLN8-Batten Disease

Cited by 28 publications

References 44 publications

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

Current and Future Prospects for Gene Therapy for Rare Genetic Diseases Affecting the Brain and Spinal Cord

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

Targeting Gys1 with AAV‐SaCas9 decreases pathogenic polyglucosan bodies and neuroinflammation in Adult Polyglucosan Body and Lafora disease mouse models

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