An Improved Adeno-Associated Virus Vector for Neurological Correction of the Mouse Model of Mucopolysaccharidosis IIIA

Gray, Anna L.; O’Leary, Claire; Liao, Aiyin; Agúndez, Leticia; Youshani, Amir Saam; Gleitz, Hélène; Parker, Helen; Taylor, Jessica; Danos, Olivier; Hocquemiller, Michaël; Palomar, Nuria; Henckaerts, Els; Holley, Rebecca; Bigger, Brian

doi:10.1089/hum.2018.189

Cited by 15 publications

(20 citation statements)

References 34 publications

(37 reference statements)

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“…The ability of LYS-SAF302 to significantly reduce microgliosis in the brain of MPS IIIA mice is of particular relevance, as neuroinflammation mediated by activated microglia is thought to play a key role in MPS pathogenesis and disease progression 18 . Consistent with the present findings, 4-week treatment with LYS-SAF302 reduced inflammatory chemokines and cytokines in the brain of MPS IIIA mice 15 . The ability of LYS-SAF302 to cause a long-lasting reversal of the neuroinflammatory phenotype of microglia, which is thought to lead to and exacerbate neuronal damage in MPS IIIA, 18 could have profound implications for its therapeutic potential.…”

Section: Discussionsupporting

confidence: 88%

“…LYS-SAF302 was shown to be about 3-fold more potent than LYS-SAF301 in directing the expression of SGSH in the brain of MPS IIIA mice. In parallel, LYS-SAF302 was more efficacious in correcting lysosomal storage defects and inflammatory pathology at 4 weeks following intrastriatal dosing at 4E+09 vg/animal in this mouse model 15 . The results of the present study confirm and extend these observations, by demonstrating dose-dependent and long-term effects of LYS-SAF302 in MPS IIIA mice.…”

Section: Discussionsupporting

confidence: 84%

“…Quantitative measures of transduction identified both AAV9 and AAVrh.10 as significantly more efficient than either AAV1 or AAV5 at transducing cerebral cortex, caudate nucleus, thalamus, and internal capsule after brain injection. Fluorescence co-labeling with cell-type-specific antibodies demonstrated that both AAV9 and AAVrh.10 primarily transduce neurons, although glial transduction was also identified 15 , 21 . AAVrh.10 vectors have been used in clinical trials for MPS IIIA 22 , neuronal ceroid lipofuscinosis, 23 and metachromatic leukodystrophy, 24 and they are being explored for several other neurological indications 11 …”

Section: Discussionmentioning

confidence: 99%

“…LYS-SAF302 is an AAVrh.10 vector containing a stronger gene promoter (CAG versus murine phosphoglycerate kinase [mPGK] in LYS-SAF301), and it carries SGSH as a single transgene. In short-term (4-week) studies, LYS-SAF302 was shown to be about 3-fold more potent in directing brain expression of SGSH following intrastriatal administration in MPS IIIA mice 15 . The objective of the present work was to study the long-term effects of this vector on lysosomal pathology in MPS IIIA mice.…”

Section: Introductionmentioning

confidence: 96%

“…In short-term (4-week) studies, LYS-SAF302 was shown to be about 3-fold more potent in directing brain expression of SGSH following intrastriatal administration in MPS IIIA mice. 15 The objective of the present work was to study the long-term effects of this vector on lysosomal pathology in MPS IIIA mice. In addition, we asked the question whether LYS-SAF302, administered by an improved delivery technique into white matter fiber tracts, was able to achieve therapeutically relevant SGSH expression and broad enzyme distribution in the brain of two large animal species, dogs and cynomolgus monkeys.…”

Section: Introductionmentioning

confidence: 99%

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AAVrh10 Vector Corrects Disease Pathology in MPS IIIA Mice and Achieves Widespread Distribution of SGSH in Large Animal Brains

Hocquemiller

Hemsley

Douglass

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Patients with mucopolysaccharidosis type IIIA (MPS IIIA) lack the lysosomal enzyme sulfamidase (SGSH), which is responsible for the degradation of heparan sulfate (HS). Build-up of undegraded HS results in severe progressive neurodegeneration for which there is currently no treatment. The ability of the vector adeno-associated virus (AAV)rh.10-CAG-SGSH (LYS-SAF302) to correct disease pathology was evaluated in a mouse model for MPS IIIA. LYS-SAF302 was administered to 5-week-old MPS IIIA mice at three different doses (8.6E+08, 4.1E+10, and 9.0E+10 vector genomes [vg]/animal) injected into the caudate putamen/striatum and thalamus. LYS-SAF302 was able to dose-dependently correct or significantly reduce HS storage, secondary accumulation of GM2 and GM3 gangliosides, ubiquitin-reactive axonal spheroid lesions, lysosomal expansion, and neuroinflammation at 12 weeks and 25 weeks post-dosing. To study SGSH distribution in the brain of large animals, LYS-SAF302 was injected into the subcortical white matter of dogs (1.0E+12 or 2.0E+12 vg/animal) and cynomolgus monkeys (7.2E+11 vg/animal). Increases of SGSH enzyme activity of at least 20% above endogenous levels were detected in 78% (dogs 4 weeks after injection) and 97% (monkeys 6 weeks after injection) of the total brain volume. Taken together, these data validate intraparenchymal AAV administration as a promising method to achieve widespread enzyme distribution and correction of disease pathology in MPS IIIA.

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Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

AAVrh10 Vector Corrects Disease Pathology in MPS IIIA Mice and Achieves Widespread Distribution of SGSH in Large Animal Brains

Hocquemiller

Hemsley

Douglass

et al. 2020

Molecular Therapy - Methods & Clinical Development

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Novel therapies for mucopolysaccharidosis type III

Yılmaz

Davison

Jones

et al. 2020

J of Inher Metab Disea

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Mucopolysaccharidosis type III (MPS III) or Sanfilippo disease is an orphan inherited lysosomal storage disease and one of the most common MPS subtypes. The classical presentation is an infantile‐onset neurodegenerative disease characterised by intellectual regression, behavioural and sleep disturbances, loss of ambulation, and early death. Unlike other MPS, no disease‐modifying therapy has yet been approved. Here, we review the numerous approaches of curative therapy developed for MPS III from historical ineffective haematopoietic stem cell transplantation and substrate reduction therapy to the promising ongoing clinical trials based on enzyme replacement therapy or adeno‐associated or lentiviral vectors mediated gene therapy. Preclinical studies are presented alongside the most recent translational first‐in‐man trials. In addition, we present experimental research with preclinical mRNA and gene editing strategies. Lessons from animal studies and clinical trials have highlighted the importance of an early therapy before extensive neuronal loss. A disease‐modifying therapy for MPS III will undoubtedly mandate development of new strategies for early diagnosis.

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Advances in therapies for neurological lysosomal storage disorders

Ellison

Parker

Bigger

2023

J of Inher Metab Disea

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Lysosomal Storage Disorders (LSDs) are a diverse group of inherited, monogenic diseases caused by functional defects in specific lysosomal proteins. The lysosome is a cellular organelle that plays a critical role in catabolism of waste products and recycling of macromolecules in the body. Disruption to the normal function of the lysosome can result in the toxic accumulation of storage products, often leading to irreparable cellular damage and organ dysfunction followed by premature death. The majority of LSDs have no curative treatment, with many clinical subtypes presenting in early infancy and childhood. Over two‐thirds of LSDs present with progressive neurodegeneration, often in combination with other debilitating peripheral symptoms. Consequently, there is a pressing unmet clinical need to develop new therapeutic interventions to treat these conditions. The blood–brain barrier is a crucial hurdle that needs to be overcome in order to effectively treat the central nervous system (CNS), adding considerable complexity to therapeutic design and delivery. Enzyme replacement therapy (ERT) treatments aimed at either direct injection into the brain, or using blood–brain barrier constructs are discussed, alongside more conventional substrate reduction and other drug‐related therapies. Other promising strategies developed in recent years, include gene therapy technologies specifically tailored for more effectively targeting treatment to the CNS. Here, we discuss the most recent advances in CNS‐targeted treatments for neurological LSDs with a particular emphasis on gene therapy‐based modalities, such as Adeno‐Associated Virus and haematopoietic stem cell gene therapy approaches that encouragingly, at the time of writing are being evaluated in LSD clinical trials in increasing numbers. If safety, efficacy and improved quality of life can be demonstrated, these therapies have the potential to be the new standard of care treatments for LSD patients.

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An Improved Adeno-Associated Virus Vector for Neurological Correction of the Mouse Model of Mucopolysaccharidosis IIIA

Abstract: Human Gene Therapy An improved AAV vector for neurological correction of the mouse model of Mucopolysaccharidosis IIIA

Cited by 15 publications

References 34 publications

AAVrh10 Vector Corrects Disease Pathology in MPS IIIA Mice and Achieves Widespread Distribution of SGSH in Large Animal Brains

AAVrh10 Vector Corrects Disease Pathology in MPS IIIA Mice and Achieves Widespread Distribution of SGSH in Large Animal Brains

Novel therapies for mucopolysaccharidosis type III

Advances in therapies for neurological lysosomal storage disorders

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