Sma Therapies I

Mendell, J. R.; Al-Zaidy, Samiah; Shell, Richard; Arnold, W.; Rodino‐Klapac, Louise R.; Prior, TW; Lowes, Linda; Alfano, L.; Berry, Katherine; Church, Kathleen; Kissel, John T.; Nagendran, Sukumar; Italien, J.L.; Sproule, D.M.; Wells, Courtney; Burghes, Arthur H.M.; Foust, K.; Meyer, Kathrin; Likhite, Shibi; Kaspar, B.

doi:10.1016/j.nmd.2018.06.205

Cited by 11 publications

(14 citation statements)

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“…Recent successes in AAV gene therapy in the clinic (4,36) highlight the potential for in vivo gene therapy to treat multiple types of disorders. However, as the field moves beyond the most devastating diseases, there is a pressing need to address host immune responses (2)(3)(4)(5)(6)(7)(8).…”

Section: Discussionmentioning

confidence: 99%

“…Gene therapy holds exciting promise for treating many genetic disorders, but host immune responses pose a major challenge for in vivo gene transfer (1). Whereas adeno-associated viral (AAV) vectors are known to be less immunogenic than other viral vectors such as adenoviruses, preclinical and clinical studies have demonstrated dose-dependent inflammation, which can reduce efficacy and lead to dose-limiting toxicity (2)(3)(4)(5)(6)(7)(8). Examples include ocular AAV therapies leading to a permanent reduction in visual acuity following intraocular inflammation (9)(10)(11) and liver-directed therapies resulting in liver transaminase elevation, which coincides with decreased factor IX (FIX) transgene expression, likely due to AAV capsid-specific cytotoxic T cells destroying transduced hepatocytes (12,13).…”

Section: Introductionmentioning

confidence: 99%

“…The p values are calculated based on a two-tailed Mann-Whitney test comparing fold expression. All qPCR reactions were run on a realplex4 MasterCycler (Eppendorf).For histology, liver samples were processed at Beth Israel Deaconess Medical Center histology core facility. The immunohistochemistry staining was performed on paraffin embedded mouse liver tissue sections that were cut, deparaffinized and hydrated before use.…”

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confidence: 99%

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Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses

et al. 2021

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Nucleic acids are used in many therapeutic modalities, including gene therapy, but their ability to trigger host immune responses in vivo can lead to decreased safety and efficacy. In the case of adeno-associated viral (AAV) vectors, studies have shown that the genome of the vector activates Toll-like receptor 9 (TLR9), a pattern recognition receptor that senses foreign DNA. Here, we engineered AAV vectors to be intrinsically less immunogenic by incorporating short DNA oligonucleotides that antagonize TLR9 activation directly into the vector genome. The engineered vectors elicited markedly reduced innate immune and T cell responses and enhanced gene expression in clinically relevant mouse and pig models across different tissues, including liver, muscle, and retina. Subretinal administration of higher-dose AAV in pigs resulted in photoreceptor pathology with microglia and T cell infiltration. These adverse findings were avoided in the contralateral eyes of the same animals that were injected with the engineered vectors. However, intravitreal injection of higher-dose AAV in macaques, a more immunogenic route of administration, showed that the engineered vector delayed but did not prevent clinical uveitis, suggesting that other immune factors in addition to TLR9 may contribute to intraocular inflammation in this model. Our results demonstrate that linking specific immunomodulatory noncoding sequences to much longer therapeutic nucleic acids can “cloak” the vector from inducing unwanted immune responses in multiple, but not all, models. This “coupled immunomodulation” strategy may widen the therapeutic window for AAV therapies as well as other DNA-based gene transfer methods.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses

et al. 2021

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“…67,68 Gene-replacement therapy via an adenovirus vector has also shown promise in this disorder. 69 Given the rarity of DRPLA it is more likely that therapeutic advancements will arise through the understanding of other neurodegenerative and CAG repeat expansion disorders. At present, optimized clinical management includes a timely diagnosis and access to the multidisciplinary team, as well as the resources needed for ongoing care.…”

Section: Future Directionsmentioning

confidence: 99%

Dentatorubral-pallidoluysian Atrophy: An Update

Carroll

Massey

Wardle

et al. 2018

Tremor and Other Hyperkinetic Movements

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Background: Dentatorubral-pallidoluysian atrophy (DRPLA) is a rare, autosomal dominantly inherited disorder characterized by myoclonus, epilepsy, ataxia, and dementia. Diagnosis is challenging due to the heterogeneous presentation and symptomatic overlap with other spinocerebellar ataxias. Symptoms vary according to age of onset, with a mean age at onset of 31 years. A CAG repeat expansion in the ATN1 gene results in neuronal intranuclear inclusions, variable neuronal loss, and astrocytosis in the globus pallidus, dentate and red nuclei. No disease-modifying or curative treatments are currently available Methods: We performed an online literature search using PubMed for all articles published in an English Language format on the topics of DRPLA or ATN1 over the last 10 years. Where these articles cited other research as support for findings, or statements, these articles were also reviewed. Contemporary articles from related research fields (e.g., Huntington's Disease) were also included to support statements.Results: Forty-seven articles were identified, 10 were unobtainable and 10 provided no relevant information. The remaining 27 articles were then used for the review template: seven case reports, seven case series, six model system articles (one review article), four population clinical and genetic studies (one review article), two general review articles, and one human gene expression study. Other cited articles or research from related fields gave a further 42 articles, producing a total of 69 articles cited: 15 case series (including eight family studies), 14 model systems (one review article), 14 population clinical and genetic studies (two review articles), 10 case reports, eight clinical trials/guidelines, four genetic methodology articles, three general review articles, and one human gene expression study.Discussion: DRPLA remains an intractable, progressive, neurodegenerative disorder without effective treatment. Early recognition of the disorder may improve patient understanding, and access to services and treatments. Large-scale studies are lacking, but are required to characterize the full allelic architecture of the disorder in all populations and the heterogeneous phenotypic spectrum, including neuroimaging findings, possible biomarkers, and responses to treatment.

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“…Recombinant adeno-associated viral vectors (rAAVs) can overcome many of the above issues. They can be made relatively quickly, generally do not insert into the genome or replicate, and can be used in a variety of species (Watakabe et al, 2015) including humans and therefore have clinical potential as well (Bouard et al, 2009;Dias et al, 2018;Kotterman and Schaffer, 2014;Mendell et al, 2017). However, efforts to generate cellspecific viral vectors by capsid modifications (Koerber et al, 2008 or using promoters (Delzor et al, 2012;Kugler et al, 2003;Shevtsova et al, 2005) have been largely unsuccessful to date to address a particular cell type, with a few notable exceptions (Dimidschstein et al, 2016;Hartl et al, 2017), and even those are likely to have multiple subclasses.…”

Section: Introductionmentioning

confidence: 99%

Enhancer-Driven Gene Expression (EDGE) Enables the Generation of Viral Vectors Specific to Neuronal Subtypes

Nair¹,

Blankvoort²,

Lagartos³

et al. 2020

iScience

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Although a variety of remarkable molecular tools for studying neural circuits have recently been developed, the ability to deploy them in particular neuronal subtypes is limited by the fact that native promoters are almost never specific enough. We recently showed that one can generate transgenic mice with anatomical specificity surpassing that of native promoters by combining enhancers uniquely active in particular brain regions with a heterologous minimal promoter, an approach we call EDGE (Enhancer-Driven Gene Expression). Here we extend this strategy to the generation of viral (rAAV) vectors, showing that some EDGE rAAVs can recapitulate the specificity of the corresponding transgenic lines in wild-type animals, even of another species. This approach thus holds the promise of enabling circuit-specific manipulations in wild-type animals, not only enhancing our understanding of brain function, but perhaps one day even providing novel therapeutic avenues to approach disorders of the brain.

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Sma Therapies I

Cited by 11 publications

References 0 publications

Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses

Engineering adeno-associated viral vectors to evade innate immune and inflammatory responses

Dentatorubral-pallidoluysian Atrophy: An Update

Enhancer-Driven Gene Expression (EDGE) Enables the Generation of Viral Vectors Specific to Neuronal Subtypes

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