A5089853347- Muscle Physiology and Disorders
- Virus-based gene therapy research
- Lysosomal Storage Disorders Research
- Viral Infectious Diseases and Gene Expression in Insects
- Neurogenetic and Muscular Disorders Research
- Alzheimer's disease research and treatments
- Autism Spectrum Disorder Research
- Muscle metabolism and nutrition
- Viral Infections and Immunology Research
- Machine Learning in Bioinformatics
- Trypanosoma species research and implications
- Genetic Neurodegenerative Diseases
- Adipose Tissue and Metabolism
- Cytomegalovirus and herpesvirus research
- Macrophage Migration Inhibitory Factor
- Cardiomyopathy and Myosin Studies
- RNA Interference and Gene Delivery
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Skin and Cellular Biology Research
- Neonatal and fetal brain pathology
- Glycogen Storage Diseases and Myoclonus
- Retinal Development and Disorders
- Sarcoma Diagnosis and Treatment
- Immunotherapy and Immune Responses
- Neuroinflammation and Neurodegeneration Mechanisms
Nationwide Children's Hospital
2007-2017
The Ohio State University
2009
A mouse model for Duchenne muscular dystrophy engineered to produce human-like glycosylation mimics the human disease better than existing models.
The cytotoxic T cell (CT) GalNAc transferase, or Galgt2, is a UDP-GalNAc:beta1,4-N-acetylgalactosaminyltransferase that localized to the neuromuscular synapse in adult skeletal muscle, where it creates synaptic CT carbohydrate antigen {GalNAcbeta1,4[NeuAc(orGc)alpha2, 3]Galbeta1,4GlcNAcbeta-}. Overexpression of Galgt2 muscles transgenic mice inhibits development muscular dystrophy mdx mice, model for Duchenne dystrophy. Here, we provide physiological evidence as how may inhibit muscle...
Overexpression of GALGT2 in skeletal muscle can stimulate the glycosylation α dystroglycan and upregulation normally synaptic dystroglycan-binding proteins, some which are dystrophin laminin α2 surrogates known to be therapeutic for several forms muscular dystrophy. This article describes vascular delivery gene therapy a large animal model, rhesus macaque. Recombinant adeno-associated virus, serotype 74 (rAAVrh74), was used deliver via femoral artery gastrocnemius using an isolated focal...
Pre-existing antibodies (Abs) to AAV pose a critical challenge for the translation of gene therapies. No effective approach is available overcome pre-existing Abs. Given complexity Ab production, overcoming Abs will require broad immune targeting. We generated mouse model AAV9 test multiple immunosuppressants, including bortezomib, rapamycin, and prednisolone, individually or in combination. identified an combining rapamycin reducing serum by 70%-80% at 4 weeks 85%-93% 8 treatment. The plus...
We have previously reported that mice with muscular dystrophy, including mdx mice, develop embryonal rhabdomyosarcoma (eRMS) a low incidence after 1 year of age and almost all such tumours contain cancer-associated p53 mutations. To further demonstrate the relevance inactivation, we created p53-deficient mice. Here loss one or both (Trp53) alleles accelerates eRMS in background, Trp53(-/-) animals by 5 months age. ascertain whether increased tumour was due to regenerative microenvironment...
The expression of N-glycolylneuraminic acid (Neu5Gc) and the cytotoxic T cell (CT) carbohydrate can impact severity muscular dystrophy arising from loss dystrophin in mdx mice. Here, we describe these two glycans skeletal muscles dogs humans with or without dystrophin-deficiency. Neu5Gc was highly reduced (>95%) muscle normal golden retriever crosses (GR, n = 3) (GRMD, 5) at multiple ages (3, 6 13 months) when compared to mouse muscle, however, overall sialic GR GRMD remained high all ages....
No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to defect in α-N-acetylglucosaminidase (NAGLU). In preparation clinical trial, we performed an IND-enabling GLP-toxicology study assess systemic rAAV9-CMV-hNAGLU gene delivery WT C57BL/6 mice at 1 × 1014 vg/kg and 2 (n = 30/group, M:F 1:1), non-GLP testing MPS IIIB vg/kg. Importantly, no adverse signs or chronic toxicity were observed through the 6 month duration. The...
Roughly 3 million years ago, an inactivating deletion occurred in CMAH, the human gene encoding CMP-Neu5Ac (cytidine-5′-monophospho-N-acetylneuraminic acid) hydroxylase (Chou HH, Takematsu H, Diaz S, Iber J, Nickerson E, Wright KL, Muchmore EA, Nelson DL, Warren ST, Varki A. 1998. A mutation CMP-sialic acid after Homo-Pan divergence. Proc Natl Acad Sci USA. 95:11751–11756). This is now homozygous all humans, causing loss of N-glycolylneuraminic (Neu5Gc) biosynthesis cells and tissues. The...
Mucopolysaccharidosis (MPS) II is an X-linked recessive lysosomal storage disease caused by defect in iduronate-2-sulfatase (IDS), leading to the accumulation of glycosaminoglycans (GAGs) cells CNS and peripheral organs, profound multisystem disorders majority patients. No treatment available for neurological MPS II. In this study, we developed 2 self-complementary (sc) AAV9 vectors expressing human IDS tested them mice via systemic delivery. At a dose 5e12vg/kg, IV injection either...
No treatment is currently available for mucopolysaccharidosis (MPS) IIIB, a neuropathic lysosomal storage disease due to autosomal recessive defect in α-N-acetylglucosaminidase (NAGLU). In preparation clinical trial, we performed an IND-enabling GLP-toxicology study assess systemic rAAV9-CMV-hNAGLU administration wt C57BL/6 mice (6-8wk-old), at 1e14 vg/kg or 2e14 (n=30/group, M:F=1:1). These were 2 and 4-fold higher, respectively, than our proposed high dose. adverse signs observed during...
Mucopolysaccharidosis (MPS) I is a lysosomal storage disease caused by autosomal recessive defect in iduronidase (IDUA). The lack of IDUA activity results the accumulation GAGs cells virtually all organs, leading to profound somatic and neurological disorders. No treatment currently available for disorders MPS I. In this study, we have developed self-complementary (sc) AAV9 vector expressing human IDUA, targeting root cause. A single intravenous injection scAAV9-hIDUA at 5×1012vg/kg led...
Pre-existing antibodies (Abs) poses a critical challenge for the translation of gene therapy approaches using viral vectors, especially AAV, which is widespread in humans. It known that very complex anatomical niches, molecular signals and cellular components are required development, priming survival Ab producing plasma cells (PCs), maintenance production. We therefore hypothesize overcoming pre-existing Abs requires broad immune targeting. In preliminary studies, we generated mouse model...
Clinical and pre-clinical studies suggest that both active passive immunization strategies targeting beta-amyloid can have therapeutic benefit in Alzheimer's disease. We studied vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native beta-amyloid-specific binding peptide (Wang et al. 2010 Neurobiol Dis. 39:409–22), to understand if a targeted oligomer-specific vaccine could be developed based on peptide-mimotope strategy. SDPM1 mimotope antibodies including P4D6 specifically...