Targeting Huntingtin Expression in Patients with Huntington’s Disease

Tabrizi, Sarah J.; Leavitt, Blair R.; Landwehrmeyer, G. Bernhard; Wild, Edward J.; Saft, Carsten; Barker, Roger A.; Blair, Nick F; Craufurd, David; Priller, Josef; Rickards, Hugh; Rosser, Anne Elizabeth; Kordasiewicz, Holly; Czech, Christian; Swayze, Eric E.; Norris, Daniel A.; Baumann, Tiffany L.; Gerlach, Irene; Schobel, Scott; Paz, Erika; Smith, Anne; Bennett, C. Frank; Lane, Roger

doi:10.1056/nejmoa1900907

Cited by 567 publications

(513 citation statements)

References 26 publications

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“…The present study may have important implications for future clinical research. The intrathecal injection of ASOs has been shown to be safe in a first‐in‐man clinical trial . However, little information is available about the role of astrocytes in ASO therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Although intrathecal administration of ASO is safe and has been well tolerated in phase I/IIa clinical trial, a major challenge of ASO therapy is delivery to brain deep structures such as the striatum, the brain region that it first and most severely affected in HD . Based on a predictive preclinical model, it is estimated that a 40% HTT reduction in cerebrospinal fluid (CSF) is equal to a 70% HTT reduction in cortical tissue and 35% HTT reduction in striatal tissue . The glymphatic system is a newly discovered pathway in the brain for the clearance of extracellular soluble proteins and metabolites .…”

Section: Introductionmentioning

confidence: 99%

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Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice

Feng

et al. 2019

Stem Cells

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Huntington's disease (HD) is a neurodegenerative disorder caused by a mutation in the huntingtin (HTT) gene that results in the production of neurotoxic mutant HTT (mHTT) protein. Suppressing HTT production with antisense oligonucleotides (ASOs) is a promising treatment strategy for HD; however, the difficulty of delivering ASOs to deep brain structures is a major barrier for its clinical application. The glymphatic system of astrocytes involving aquaporin 4 (AQP-4) controls the entry of macromolecules from the cerebrospinal fluid into the brain. Mesenchymal stem cells (MSCs) target astrocytes to inhibit neuroinflammation. Here we examined the glymphatic distribution of ASO in the brain and the therapeutic potential of combining intravenously injection of mesenchymal stem cells (IV-MSC) and ASOs for the treatment of HD. Our results show that Cy3-labeled ASOs entered the brain parenchyma via the perivascular space following cisternal injection, but the brain distribution was significantly lower in AQP-4 −/− as compared with wild-type mice. Downregulation of the AQP-4 M23 isoform was accompanied by decreased brain levels of ASOs in BACHD mice as well as an increase in astrogliosis and phosphorylation of nuclear factor κB (NF-κB) p65. IV-MSC treatment restored AQP-4 M23 expression, attenuated astrogliosis, and decreased NF-κB p65 phosphorylation; it also increased the brain distribution of ASOs and enhanced the suppression of mHTT in BACHD mice.These results suggest that modulating glymphatic activity using IV-MSC is a novel strategy for improving the potency of ASO in the treatment of HD.Teng-teng Wu and Feng-juan Su have contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Mesenchymal stem cells alleviate AQP-4-dependent glymphatic dysfunction and improve brain distribution of antisense oligonucleotides in BACHD mice

Feng

et al. 2019

Stem Cells

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“…The recently published full results report that all participants completed the entire trial, and no severe adverse events related to the drug were encountered. In a post hoc analysis, several clinical measures and a predefined compound measure showed favorable relationships with the degree of huntingtin lowering . These intriguing results are cause for optimism but make no difference to the need for a full‐scale pivotal trial to test whether huntingtin lowering by this drug will slow the progression of HD.…”

Section: The Third Age Of Huntington's Disease?mentioning

confidence: 99%

One decade ago, one decade ahead in huntington's disease

Wild

Tabrizi

2019

Movement Disorders

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“…The recent phase 1‐2a randomized, placebo‐controlled trial in early‐stage HD patients of antisense oligonucleotide (ASO) IONIS‐HTTRx (HTT RX ) shows great promise in the development of a novel disease‐modifying intervention for HD. HTT RX is a nonspecific ASO that binds to both wild‐type and mutant mRNA coding the protein Huntingtin (HTT).…”

mentioning

confidence: 99%