Krabbe disease successfully treated via monotherapy of intrathecal gene therapy

Bradbury, Allison M.; Bagel, Jessica H.; Nguyễn, Duy Anh; Lykken, Erik; Salvador, Jill Pesayco; Jiang, Xuntian; Swain, Gary P.; Assenmacher, Charles Antoine; Hendricks, Ian J.; Miyadera, Keiko; Hess, Rebecka S.; Ostrager, Arielle; O’Donnell, Patricia; Sands, Mark S.; Ory, Daniel S.; Shelton, G. Diane; Bongarzone, Ernesto R.; Gray, Steven J.; Vite, Charles H.

doi:10.1172/jci133953

Cited by 45 publications

(48 citation statements)

References 47 publications

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“…In particular, it might be useful to establish the adequate dose of gene therapy, able to completely correct KD impairments. In support of this, a recent study showed that low but not high-dose gene therapy-treated dogs had visual system deficits [ 44 ].…”

Section: Discussionmentioning

confidence: 92%

Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse

et al. 2020

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Krabbe disease (KD, or globoid cell leukodystrophy; OMIM #245200) is an inherited neurodegenerative condition belonging to the class of the lysosomal storage disorders. It is caused by genetic alterations in the gene encoding for the enzyme galactosylceramidase, which is responsible for cleaving the glycosydic linkage of galatosylsphingosine (psychosine or PSY), a highly cytotoxic molecule. Here, we describe morphological and functional alterations in the visual system of the Twitcher (TWI) mouse, the most used animal model of Krabbe disease. We report in vivo electrophysiological recordings showing defective basic functional properties of the TWI primary visual cortex. In particular, we demonstrate a reduced visual acuity and contrast sensitivity, and a delayed visual response. Specific neuropathological alterations are present in the TWI visual cortex, with reduced myelination, increased astrogliosis and microglia activation, and around the whole brain. Finally, we quantify PSY content in the brain and optic nerves by high-pressure liquid chromatography-mass spectrometry methods. An increasing PSY accumulation with time, the characteristic hallmark of KD, is found in both districts. These results represent the first complete characterization of the TWI visual system. Our data set a baseline for an easy testing of potential therapies for this district, which is also dramatically affected in KD patients.

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Section: Discussionmentioning

confidence: 92%

Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse

et al. 2020

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“…To address these limitations, preclinical studies have aimed at developing targeted protocols that can efficiently deliver the vector while still achieving satisfactory disease correction. An increasingly recognized effective strategy is the use of intrathecal administration of gene therapy in KD (Reddy et al, 2011 ; Qin et al, 2012 ; Karumuthil-Melethil et al, 2016 ; Marshall et al, 2018b ; Bradbury et al, 2020 ). Multiple studies have achieved significant improvements in lifespan and motor function with protocols that deliver a single intrathecal gene therapy dose (Karumuthil-Melethil et al, 2016 ; Bradbury et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

“…An increasingly recognized effective strategy is the use of intrathecal administration of gene therapy in KD (Reddy et al, 2011 ; Qin et al, 2012 ; Karumuthil-Melethil et al, 2016 ; Marshall et al, 2018b ; Bradbury et al, 2020 ). Multiple studies have achieved significant improvements in lifespan and motor function with protocols that deliver a single intrathecal gene therapy dose (Karumuthil-Melethil et al, 2016 ; Bradbury et al, 2020 ). This study is an important step toward characterizing the full extent of KD pathology in the spinal cord and supports the importance of intrathecal delivery for treating KD with gene therapy.…”

Section: Discussionmentioning

confidence: 99%

AAV-Mediated GALC Gene Therapy Rescues Alpha-Synucleinopathy in the Spinal Cord of a Leukodystrophic Lysosomal Storage Disease Mouse Model

Marshall

Issa

Heller

et al. 2020

Front. Cell. Neurosci.

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Krabbe's disease (KD) is primarily a demyelinating disorder, but recent studies have identified the presence of neuronal protein aggregates in the brain, at least partially composed by alpha-synuclein (α-syn). The role of this protein aggregation in the pathogenesis of KD is largely unknown, but it has added KD to a growing list of lysosomal storage diseases that can be also be considered as proteinopathies. While the presence of these protein aggregates within the KD brain is now appreciated, the remainder of the central nervous system (CNS) remains uncharacterized. This study is the first to report the presence of thioflavin-S reactive inclusions throughout the spinal cord of both murine and human spinal tissue. Stereological analysis revealed the temporal and spatial accumulation of these inclusions within the neurons of the ventral spinal cord vs. those located in the dorsal cord. This study also confirmed that these thio-S positive accumulations are present within neuronal populations and are made up at least in part by α-syn in both the twitcher mouse and cord autopsied material from affected human patients. Significantly, neonatal gene therapy for galactosylceramidase, a treatment that strongly improves the survival and health of KD mice, but not bone marrow transplantation prevents the formation of these inclusions in spinal neurons. These results expand the understanding of α-syn protein aggregation within the CNS of individuals afflicted with KD and underlines the tractability of this problem via early gene therapy, with potential impact to other synucleinopathies such as PD.

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“…AAV9 has also recently demonstrated effectiveness in a mouse model of Canavan disease (Gessler et al, 2017 ), which played a role in promoting the rAAV9- ASPA vector transitioning to a recent open-label clinical trial for Canavan disease ( CANaspire , ASPA Therapeutics). Finally, an exciting recent AAV9 finding is the success of AAV9- GALC in treating a canine model of globoid cell leukodystrophy or Krabbe disease, improving myelination and extending lifespan more than seven times beyond the typical life expectancy for model animals (Bradbury et al, 2020 ). However, AAV9 is not known to efficiently mediate significant transduction of oligodendrocyte lineage cells.…”

Section: Gene Transfer Therapy: Considerations In Leukodystrophiesmentioning

confidence: 99%

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

Perrier

Michell‐Robinson

Bernard

2021

Front. Cell. Neurosci.

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Leukodystrophies are a class of rare inherited central nervous system (CNS) disorders that affect the white matter of the brain, typically leading to progressive neurodegeneration and early death. Hypomyelinating leukodystrophies are characterized by the abnormal formation of the myelin sheath during development. POLR3-related or 4H (hypomyelination, hypodontia, and hypogonadotropic hypogonadism) leukodystrophy is one of the most common types of hypomyelinating leukodystrophy for which no curative treatment or disease-modifying therapy is available. This review aims to describe potential therapies that could be further studied for effectiveness in pre-clinical studies, for an eventual translation to the clinic to treat the neurological manifestations associated with POLR3-related leukodystrophy. Here, we discuss the therapeutic approaches that have shown promise in other leukodystrophies, as well as other genetic diseases, and consider their use in treating POLR3-related leukodystrophy. More specifically, we explore the approaches of using stem cell transplantation, gene replacement therapy, and gene editing as potential treatment options, and discuss their possible benefits and limitations as future therapeutic directions.

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Krabbe disease successfully treated via monotherapy of intrathecal gene therapy

Cited by 45 publications

References 47 publications

Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse

Visual System Impairment in a Mouse Model of Krabbe Disease: The Twitcher Mouse

AAV-Mediated GALC Gene Therapy Rescues Alpha-Synucleinopathy in the Spinal Cord of a Leukodystrophic Lysosomal Storage Disease Mouse Model

POLR3-Related Leukodystrophy: Exploring Potential Therapeutic Approaches

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