In vivo targeting of a variant causing vanishing white matter using CRISPR/Cas9

Hillen, Anne E J; Hruzova, Martina; Rothgangl, Tanja; Breur, Marjolein; Bugiani, Marianna; Knaap, Marjo S. van der; Schwank, Gerald; Heine, Vivi M.

doi:10.1016/j.omtm.2022.02.006

Cited by 7 publications

(2 citation statements)

References 41 publications

(48 reference statements)

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“…As an example, this approach has been used to develop a therapy for VWM. However, induction of indels resulted in a more severe phenotype [146]. Ex vivo approaches are generally more amenable to effectively incur HDR, because target cells can be enriched in small volumes, and subsequently genetically altered.…”

Section: Raav Vectors In Leukodystrophiesmentioning

confidence: 99%

Gene and Cellular Therapies for Leukodystrophies

Aerts-Kaya,

van Til

2023

Pharmaceutics

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Leukodystrophies are a heterogenous group of inherited, degenerative encephalopathies, that if left untreated, are often lethal at an early age. Although some of the leukodystrophies can be treated with allogeneic hematopoietic stem cell transplantation, not all patients have suitable donors, and new treatment strategies, such as gene therapy, are rapidly being developed. Recent developments in the field of gene therapy for severe combined immune deficiencies, Leber’s amaurosis, epidermolysis bullosa, Duchenne’s muscular dystrophy and spinal muscular atrophy, have paved the way for the treatment of leukodystrophies, revealing some of the pitfalls, but overall showing promising results. Gene therapy offers the possibility for overexpression of secretable enzymes that can be released and through uptake, allow cross-correction of affected cells. Here, we discuss some of the leukodystrophies that have demonstrated strong potential for gene therapy interventions, such as X-linked adrenoleukodystrophy (X-ALD), and metachromatic leukodystrophy (MLD), which have reached clinical application. We further discuss the advantages and disadvantages of ex vivo lentiviral hematopoietic stem cell gene therapy, an approach for targeting microglia-like cells or rendering cross-correction. In addition, we summarize ongoing developments in the field of in vivo administration of recombinant adeno-associated viral (rAAV) vectors, which can be used for direct targeting of affected cells, and other recently developed molecular technologies that may be applicable to treating leukodystrophies in the future.

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Section: Raav Vectors In Leukodystrophiesmentioning

confidence: 99%

Gene and Cellular Therapies for Leukodystrophies

Aerts-Kaya,

van Til

2023

Pharmaceutics

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“…We used astrocyte-selective AAV expressing iAChSnFR 42 to measure the dynamics of acetylcholine in astrocytes of the nucleus accumbens during reinforcement learning. This collection of tools opens up new opportunities for selective labeling and functional interrogation of glial cell types across species and disease states, and could have translational applications via AAV-based therapeutics [43][44][45] .…”

Section: Introductionmentioning

confidence: 99%

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Mich,

Sunil,

Johansen

et al. 2023

Preprint

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Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and our astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

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Vanishing white matter

van der Knaap,

Abbink

2025

Rosenberg's Molecular and Genetic Basis of Neurological and Psychiatric Disease

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In vivo targeting of a variant causing vanishing white matter using CRISPR/Cas9

Cited by 7 publications

References 41 publications

Gene and Cellular Therapies for Leukodystrophies

Gene and Cellular Therapies for Leukodystrophies

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Vanishing white matter

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