AAV9-MCT8 delivery at juvenile stage ameliorates neurological and behavioral deficits in an AHDS mouse model

Allan-Herndon-Dudley syndrome (AHDS) is a severe X-linked intellectual and psychomotor disability disorder accompanied by abnormal thyroid hormone (TH) levels. AHDS is caused by inactivating mutations in the monocarboxylate transporter 8 (MCT8), a specific TH transporter widely expressed in the central nervous system. MCT8 gene mutations cause impaired transport of TH across brain barriers, leading to insufficient neural TH supply. There is currently no successful therapy for the neurological symptoms. AAV9-based gene therapy is a promising approach to treat monogenic neurological disorders. Here, the potential of this approach was tested in the well-established double knockout (dKO) Mct8-/y; Organic anion-transporting polypeptide 1c1 (Oatp1c1)-/- mouse model of AHDS, which displays disease-relevant neurological and TH phenotypes. Systemic intravenous delivery of adeno-associated virus serotype 9 (AAV9)-MCT8 at a juvenile stage led to improved locomotor and cognitive function, as well as rescue of T3-brain content and T3-related gene expression. This preclinical study indicates that this gene therapy may improve the neurological symptoms of AHDS patients.

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AAV-Mediated Gene Therapy in the Guanylate Cyclase (RetGC1/RetGC2) Double Knockout Mouse Model of Leber Congenital Amaurosis

Human Gene Therapy ◽

10.1089/hum.2012.193 ◽

2013 ◽

Vol 24 (2) ◽

pp. 189-202 ◽

Cited By ~ 40

Author(s):

Sanford L. Boye ◽

Igor V. Peshenko ◽

Wei Chieh Huang ◽

Seok Hong Min ◽

Issam McDoom ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Guanylate Cyclase ◽

Knockout Mouse ◽

Double Knockout ◽

Knockout Mouse Model ◽

Leber Congenital Amaurosis ◽

Double Knockout Mouse

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Faculty Opinions recommendation of CNS-targeted gene therapy improves survival and motor function in a mouse model of spinal muscular atrophy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725275418.793502456 ◽

2014 ◽

Author(s):

Chris Henderson

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Spinal Muscular Atrophy ◽

Motor Function ◽

Muscular Atrophy ◽

Targeted Gene Therapy

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Faculty Opinions recommendation of IL-17 sequestration via salivary gland gene therapy in a mouse model of Sjogren's syndrome suppresses disease-associated expression of the putative autoantigen Klk1b22.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.725703368.793512522 ◽

2015 ◽

Author(s):

Sarah Gaffen ◽

J Agustin Cruz

Keyword(s):

Gene Therapy ◽

Salivary Gland ◽

Mouse Model ◽

Sjögren’S Syndrome ◽

Sjögren's Syndrome ◽

Sjogren’S Syndrome ◽

Sjogren's Syndrome ◽

Sjögren‘S Syndrome

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Faculty Opinions recommendation of Efficacy of lentivirus-mediated gene therapy in an Omenn syndrome recombination-activating gene 2 mouse model is not hindered by inflammation and immune dysregulation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732304849.793555462 ◽

2019 ◽

Author(s):

Andrew Gennery

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Immune Dysregulation ◽

Omenn Syndrome ◽

Recombination Activating Gene

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Faculty Opinions recommendation of RNAi-Based Gene Therapy Rescues Developmental and Epileptic Encephalopathy in a Genetic Mouse Model.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.737854462.793574751 ◽

2020 ◽

Author(s):

Laurent Villard

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Epileptic Encephalopathy ◽

Genetic Mouse Model

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Vascular Endothelial Growth Factor Electro-Gene Therapy Improves Functional Outcome in a Mouse Model of ALS

Immunology Endocrine & Metabolic Agents - Medicinal Chemistry ◽

10.2174/1871522211313020004 ◽

2013 ◽

Vol 13 (2) ◽

pp. 107-111

Author(s):

Tatsufumi Murakami ◽

Yuki Shimada ◽

Yoshimi Imada ◽

Akihiro Nakamura ◽

Yoshihide Sunada

Keyword(s):

Gene Therapy ◽

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Mouse Model ◽

Functional Outcome ◽

Vascular Endothelial ◽

Endothelial Growth Factor

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Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice

Translational Neuroscience ◽

10.1515/tnsci-2020-0132 ◽

2020 ◽

Vol 11 (1) ◽

pp. 241-250

Author(s):

Zhenyu Li ◽

Guangqian Ding ◽

Yudi Wang ◽

Zelong Zheng ◽

Jianping Lv

Keyword(s):

Gene Therapy ◽

Transcription Factor ◽

Neurodegenerative Diseases ◽

Brain Tissue ◽

Inflammatory Responses ◽

Tissue Samples ◽

Protein Levels ◽

Virus Serotype ◽

Transcription Factor Eb ◽

The Brain

AbstractTranscription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.

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Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2

Nature Communications ◽

10.1038/s41467-020-20808-7 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Xuewen Wu ◽

Li Zhang ◽

Yihui Li ◽

Wenjuan Zhang ◽

Jianjun Wang ◽

...

Keyword(s):

Gene Therapy ◽

Mouse Model ◽

Inner Ear ◽

Viral Vectors ◽

Survival Rates ◽

Semicircular Canals ◽

Dependent Manner ◽

Syndrome Type ◽

Dose Dependent

AbstractMutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1−/− mice to treat both the hearing and vestibular symptoms. Results showed early treatment prevented collapse of the Reissner’s membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells. In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months. In the low-dosage group, a subgroup of mice (13/20) showed improvements only in the vestibular functions. Results supported that highly efficient transduction is one of the key factors for achieving the efficacy and maintaining the long-term therapeutic effect. Secondary outcomes of treatment included improved birth and litter survival rates. Our results demonstrated that gene therapy via the canalostomy approach, which has been considered to be one of the more feasible delivery methods for human inner ear gene therapy, preserved auditory and vestibular functions in a dose-dependent manner in a mouse model of JLNS2.

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