Correction of neurological disease of Mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain-barrier gene delivery

Fu, Huiling; DiRosario, Julianne; Killedar, Smruti; Zaraspe, Kimberly; McCarty, Douglas M.

doi:10.1016/j.ymgme.2010.11.063

Cited by 16 publications

(32 citation statements)

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“…Similar to our previously published data, 29,37 rAAV9-treated MPS IIIB mice exhibited significant improvement in latency to find a hidden platform and swimming ability in the water maze ( Figure 5C), indicating the functional correction of neurological disorders. Seven rAAV9-treated animals were observed for longevity, showing significantly improved survival with a lifespan of 6-24 months, of which the majority lived within the lifespan of WT mice ( Figure 5D, p > 0.05).…”

Section: Molecular Therapysupporting

confidence: 90%

“…Serotype 9 rAAV vectors cross the BBB, and a systemic rAAV9-CMV-hNAGLU delivery previously was shown to result in both CNS and somatic correction of pathology in MPS IIIB mice. 29,37 Mass Spectrometry Provides Decisive MPS IIIB Metabolomic Profiles Global metabolomic profiling by mass spectrometry was performed on the serum samples from MPS IIIB and WT mice at ages 2 and 7 months to assess metabolic abnormalities during the disease progression. Principal-component analyses (PCAs) ( Figure 1A) and heatmap analyses ( Figure 1B) of the 361 metabolites showed clear separation of serum metabolomic profiles in 7-month-old MPS IIIB mice from those of age-matched WT mice and the rest of the experimental groups, with the exception of one WT mouse that appeared to be an outlier.…”

Section: Resultsmentioning

confidence: 99%

“…Most importantly, we demonstrate here that the serum metabolomic profiles in MPS IIIB mice responded well to a single systemic delivery of the rAAV9-hNAGLU, a previously established effective gene therapy approach targeting the root cause of the disease. 29 Notably, this systemic rAAV9-hNAGLU gene delivery approach recently has been approved by the U.S. Food and Drug Administration (FDA) for a phase 1/2 clinical trial in MPS IIIB patients (IND 16671, to be initiated). As demonstrated previously and again in this study, a single i.v.…”

Section: Discussionmentioning

confidence: 99%

“…27,28 The recent finding of trans-BBB neurotropism of AAV9 offers an effective solution for CNS gene therapy, showing great potential for the treatment of LSDs and other neurological diseases. [29][30][31][32][33] A single systemic delivery of rAAV9 vectors can lead to global CNS and widespread somatic restoration of enzyme activity, correction of lysosomal storage pathology, and functional neurological benefits in mice with MPS IIIB or IIIA. 29,30 As therapeutic development advances and more therapies for MPS become available, the lack of accessible biomarkers will be a critical challenge for therapeutic assessment.…”

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

“…[29][30][31][32][33] A single systemic delivery of rAAV9 vectors can lead to global CNS and widespread somatic restoration of enzyme activity, correction of lysosomal storage pathology, and functional neurological benefits in mice with MPS IIIB or IIIA. 29,30 As therapeutic development advances and more therapies for MPS become available, the lack of accessible biomarkers will be a critical challenge for therapeutic assessment. Urinary GAGs and specific lysosomal enzymes have been the only biomarkers for MPS, although recent studies identified serum heparin cofactor II-thrombin (HCII-T) as a biomarker for MPS I, II, and III; 34 dipeptidyl peptidase IV (DPP-IV) for MPS I, II, III, IVA, and VI; 35 and recently the potential of disease-specific non-reducing end carbohydrate biomarkers for MPS.…”

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

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Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Meadows

Ware

et al. 2017

Molecular Therapy

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Mucopolysaccharidosis (MPS) IIIB is a lysosomal storage disease with complex CNS and somatic pathology due to a deficiency in a-N-acetylglucosaminidase (NAGLU). Using global metabolic profiling by mass spectrometry targeting 361 metabolites, this study detected significant decreases in 225 and increases in six metabolites in serum samples from 7-monthold MPS IIIB mice, compared to wild-type (WT) mice. The metabolic disturbances involve virtually all major pathways of amino acid, peptide (58/102), carbohydrate (18/28), lipid (111/139), nucleotide (12/24), energy (2/9), vitamin and cofactor (11/16), and xenobiotic (11/28) metabolism. Notably, the reduced metabolites included eight essential amino acids, vitamins (C, E, B2, and B6), and neurotransmitters (serotonin, glutamate, aspartate, tryptophan, and N-acetyltyrosine). The metabolic impairments appear to emerge early during disease progression before the age of 2 months. Importantly, the restoration of NAGLU activity with an intravenous (i.v.) injection of rAAV9-hNAGLU vector led to near-complete correction of all serum metabolite abnormalities, with 201 (87%) metabolites normalized and 30 (13%) over-corrected. While the mechanisms are unclear, our data demonstrate that the lack of NAGLU activity triggers profound functional metabolic disturbances in MPS IIIB. These metabolic impairments respond well to a systemic rAAV9-hNAGLU gene delivery, supporting the surrogate biomarker potential of serum metabolomic profiles for MPS IIIB therapies.

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Section: Molecular Therapysupporting

confidence: 90%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

Section: Mucopolysaccharidosis (Mps) Iiib (Online Mendelian Inheritanmentioning

confidence: 99%

See 3 more Smart Citations

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Meadows

Ware

et al. 2017

Molecular Therapy

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New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

Spratley

Deane

2016

J of Neuroscience Research

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Missense mutations in the lysosomal hydrolase β‐galactocerebrosidase (GALC) account for at least 40% of known cases of Krabbe disease (KD). Most of these missense mutations are predicted to disrupt the fold of the enzyme, preventing GALC in sufficient amounts from reaching its site of action in the lysosome. The predominant central nervous system (CNS) pathology and the absence of accumulated primary substrate within the lysosome mean that strategies used to treat other lysosomal storage disorders (LSDs) are insufficient in KD, highlighting the still unmet clinical requirement for successful KD therapeutics. Pharmacological chaperone therapy (PCT) is one strategy being explored to overcome defects in GALC caused by missense mutations. In recent studies, several small‐molecule inhibitors have been identified as promising chaperone candidates for GALC. This Review discusses new insights gained from these studies and highlights the importance of characterizing both the chaperone interaction and the underlying mutation to define properly a responsive population and to improve the translation of existing lead molecules into successful KD therapeutics. We also highlight the importance of using multiple complementary methods to monitor PCT effectiveness. Finally, we explore the exciting potential of using combination therapy to ameliorate disease through the use of PCT with existing therapies or with more generalized therapeutics, such as proteasomal inhibition, that have been shown to have synergistic effects in other LSDs. This, alongside advances in CNS delivery of recombinant enzyme and targeted rational drug design, provides a promising outlook for the development of KD therapeutics. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.

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Gene Therapy for the Nervous System: Challenges and New Strategies

et al. 2014

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Current clinical treatments for central nervous system (CNS) diseases, such as Parkinson's disease and glioblastoma do not halt disease progression and have significant treatment morbidities. Gene therapy has the potential to "permanently" correct disease by bringing in a normal gene to correct a mutant gene deficiency, knocking down mRNA of mutant alleles, and inducing cell-death in cancer cells using transgenes encoding apoptosis-inducing proteins. Promising results in clinical trials of eye disease (Leber's congenital aumorosis) and Parkinson's disease have shown that genebased neurotherapeutics have great potential. The recent development of genome editing technology, such as zinc finger nucleases, TALENS, and CRISPR, has made the ultimate goal of gene correction a step closer. This review summarizes the challenges faced by gene-based neurotherapeutics and the current and recent strategies designed to overcome these barriers. We have chosen the following challenges to focus on in this review: (1) delivery vehicles (both virus and nonviral), (2) use of promoters for vector-mediated gene expression in CNS, and (3) delivery across the blood-brain barrier. The final section (4) focuses on promising pre-clinical/clinical studies of neurotherapeutics.

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Correction of neurological disease of Mucopolysaccharidosis IIIB in adult mice by rAAV9 trans-blood-brain-barrier gene delivery

Cited by 16 publications

References 0 publications

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

Near-Complete Correction of Profound Metabolomic Impairments Corresponding to Functional Benefit in MPS IIIB Mice after IV rAAV9-hNAGLU Gene Delivery

New therapeutic approaches for Krabbe disease: The potential of pharmacological chaperones

Gene Therapy for the Nervous System: Challenges and New Strategies

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