Suppression of proteolipid protein rescues Pelizaeus–Merzbacher disease

Elitt, Matthew S.; Barbar, Lilianne; Shick, H. Elizabeth; Powers, Berit; Maeno-Hikichi, Yuka; Madhavan, Mayur; Allan, Kevin; Nawash, Baraa S.; Gevorgyan, Artur S.; Hung, Stevephen; Nevin, Zachary S.; Olsen, Hannah; Hitomi, Midori; Schlatzer, Daniela; Zhao, Hien; Swayze, Adam; LePage, David F.; Jiang, Weihong; Conlon, Ronald A.; Rigo, Frank; Tesar, Paul J.

doi:10.1038/s41586-020-2494-3

Cited by 48 publications

(39 citation statements)

References 45 publications

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“…Recent studies have used ASO to specifically target neuronal and oligodendrocyte pathology in other degenerative disorders, including Huntington's and Pelizaeus-Merzbacher disease respectively (38,39). Here we demonstrate that targeting astrocyte specific Gfap rescues astrocyte function in AxD, allowing the recovery of other cell types in the CNS.…”

Section: Discussionmentioning

confidence: 60%

“…Treatment of R237H rats with Gfap-targeted ASO at weaning cleared molecular and cellular pathology preventing onset of clinical phenotypes, and R237H rats treated at this age were physically indistinguishable from wild-type animals (Movie S3). More importantly, treatment of severely affected young adult rats not only cleared pathology, but partially reversed white matter deficits and motor impairment.Recent studies have used ASO to specifically target neuronal and oligodendrocyte pathology in other degenerative disorders, including Huntington's and Pelizaeus-Merzbacher disease respectively(38,39). Here we demonstrate that targeting astrocyte specific Gfap rescues astrocyte function in AxD, allowing the recovery of other cell types in the CNS.…”

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confidence: 59%

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Antisense therapy in a new rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment

Hagemann

Powers

Lin

et al. 2021

Preprint

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Alexander disease (AxD) is a devastating leukodystrophy caused by gain of function mutations in GFAP, and the only available treatments are supportive. Recent advances in antisense oligonucleotide (ASO) therapy have demonstrated that transcript targeting can be a successful strategy for human neurodegenerative diseases amenable to this approach. We have previously used mouse models of AxD to show that Gfap-targeted ASO suppresses protein accumulation and reverses pathology; however, the mice have a mild phenotype with no apparent leukodystrophy or overt clinical features and are therefore limited for assessing functional outcomes. In this report we introduce a new rat model of AxD that exhibits hallmark pathology with GFAP aggregation in the form of Rosenthal fibers, widespread astrogliosis, and white matter deficits. These animals develop normally during the first postnatal weeks but fail to thrive after weaning and develop severe motor deficits as they mature, with approximately 15 % dying of unknown cause between 6 to 12 weeks of age. In this model, a single treatment with Gfap-targeted ASO provides long lasting suppression, reverses GFAP pathology, and depending on age of treatment, prevents or mitigates white matter deficits and motor impairment. This is the first report of an animal model of AxD with myelin pathology and motor impairment, recapitulating prominent features of the human disease. We use this model to show that ASO therapy has the potential to not only prevent but also reverse many aspects of disease.

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Section: Discussionmentioning

confidence: 60%

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confidence: 59%

Antisense therapy in a new rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment

Hagemann

Powers

Lin

et al. 2021

Preprint

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“…Recent studies in the jimpy mouse model of Pelizaeus-Merzbacher disease support the potential for blocking apoptosis to block disease progression, as blocking ferroptosis through iron chelation improved myelination (43). Similarly, intracerebral treatment of jimpy mice with antisense oligonucleotides that inhibit PLP1 expression rescued white matter degeneration (47) and blocking BAK and BAX expression with similar methods may treat diverse white matter-specific disorders.…”

Section: Discussionmentioning

confidence: 99%

Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration

Cleveland¹,

Romero-Morales

Azcona³

et al. 2020

Preprint

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SUMMARYDiverse mutations cause leukodystrophies through unresolved processes. Developing leukodystrophy therapies requires identifying mechanisms that operate downstream of causative mutations to produce white matter degeneration. We have identified the apoptosis regulator MCL-1 as required for white matter stability and depleted by leukodystrophy-causing mutations. Brain-specific deletion of Mcl-1 in mice recapitulates progressive leukodystrophy, with MRI changes, decreased oligodendrocytes, and astrocytic and microglial changes typical of Vanishing White Matter Disease (VWMD). Disabling apoptosis through co-deletion of Bax or Bak rescued white matter Mcl-1-dependence, broadly implicating the intrinsic apoptotic pathway in leukodystrophy pathogenesis. Bax and Bak co-deletions rescued different aspects of the Mcl-1-deleted phenotype, demonstrating their discrete roles in white matter stability. MCL-1 protein abundance was reduced in eif2b5-mutant mice that model VWMD, suggesting a mechanistic relationship between MCL-1 and VWMD. Our data show that oligodendrocytes require MCL-1 to suppress apoptosis, implicate MCL-1 loss in VWMD pathogenesis, and suggest inhibiting apoptosis for leukodystrophy therapy.

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“…Antisense oligonucleotides (ASOs), particularly when packaged into oligodendrogliotrophic exosomes that effectively cross the BBB are another developing technology that may hold promise in future. Indeed, therapeutic promise has recently been demonstrated in the ‘jimpy’ mouse model of PMD where single administration of a Plp1 – targeting ASO restored oligodendrocyte numbers, increased myelination, improved motor performance and extended lifespan ( Elitt et al, 2020 ).…”

Section: Leukodystrophies That May Benefit From Oligodendrocyte Targetingmentioning

confidence: 99%

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

Jonquières

Rae

Housley

2021

Front. Cell. Neurosci.

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Central Nervous System (CNS) homeostasis and function rely on intercellular synchronization of metabolic pathways. Developmental and neurochemical imbalances arising from mutations are frequently associated with devastating and often intractable neurological dysfunction. In the absence of pharmacological treatment options, but with knowledge of the genetic cause underlying the pathophysiology, gene therapy holds promise for disease control. Consideration of leukodystrophies provide a case in point; we review cell type – specific expression pattern of the disease – causing genes and reflect on genetic and cellular treatment approaches including ex vivo hematopoietic stem cell gene therapies and in vivo approaches using adeno-associated virus (AAV) vectors. We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future.

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Suppression of proteolipid protein rescues Pelizaeus–Merzbacher disease

Cited by 48 publications

References 45 publications

Antisense therapy in a new rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment

Antisense therapy in a new rat model of Alexander disease reverses GFAP pathology, white matter deficits, and motor impairment

Oligodendrocytes depend on MCL-1 to prevent spontaneous apoptosis and white matter degeneration

Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies

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