A5049971888- Neurogenetic and Muscular Disorders Research
- Virus-based gene therapy research
- Amyotrophic Lateral Sclerosis Research
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- Muscle Physiology and Disorders
- RNA Interference and Gene Delivery
- Neurogenesis and neuroplasticity mechanisms
- Pluripotent Stem Cells Research
- RNA Research and Splicing
- Genetics and Neurodevelopmental Disorders
- Nerve injury and regeneration
- Congenital Anomalies and Fetal Surgery
- Viral Infections and Immunology Research
- Neuroscience and Neuropharmacology Research
- Neuroinflammation and Neurodegeneration Mechanisms
- RNA regulation and disease
- Genetic Neurodegenerative Diseases
- Prion Diseases and Protein Misfolding
- Viral Infectious Diseases and Gene Expression in Insects
- Parkinson's Disease Mechanisms and Treatments
- Hereditary Neurological Disorders
- Thyroid Disorders and Treatments
- Alzheimer's disease research and treatments
- Muscle metabolism and nutrition
Multimeric Biotherapeutics (United States)
2024
The Ohio State University
2013-2023
Nationwide Children's Hospital
2014-2023
Baxalta (United States)
2017-2019
Columbus Oncology and Hematology Associates
2017
Pediatrics and Genetics
2013
Salk Institute for Biological Studies
1999-2010
Gene Therapy Laboratory
2010
Children’s Institute
2005
Johns Hopkins University
2003
Spinal muscular atrophy type 1 (SMA1) is a progressive, monogenic motor neuron disease with an onset during infancy that results in failure to achieve milestones and death or the need for mechanical ventilation by 2 years of age. We studied functional replacement mutated gene encoding survival (SMN1) this disease.Fifteen patients SMA1 received single dose intravenous adeno-associated virus serotype 9 carrying SMN complementary DNA missing protein. Three low (6.7×1013 vg per kilogram body...
Amyotrophic lateral sclerosis (ALS) is a progressive, lethal neuromuscular disease that associated with the degeneration of spinal and brainstem motor neurons, leading to atrophy limb, axial, respiratory muscles. The cause ALS unknown, there no effective therapy. Neurotrophic factors are candidates for therapeutic evaluation in ALS. Although chronic delivery molecules central nervous system has proven difficult, we recently discovered adeno-associated virus can be retrogradely transported...
In Parkinson9s disease, progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SN) leads to debilitating motor dysfunction. One current therapy aims at exogenous cellular replacement function by transplanting fetal midbrain cells into striatum, main projection area SN. However, results using this approach have shown variable success. It has been proposed that endogenous stem/progenitor may be useful for therapeutic interventions neurodegenerative diseases, including...
A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). encodes two protein isoforms unclear function. Reduced levels expression have been reported C9ALS/FTD patients, although haploinsufficiency has proposed to contribute C9ALS/FTD, its significance not yet clear. Here, we report that interacts with Rab1a Unc-51-like kinase 1 (ULK1) autophagy initiation complex. As a effector,...
Significance Direct conversion is a recently established method to generate neuronal progenitor cells (NPCs) from skin fibroblasts in fast and efficient manner. In this study, we show that can be used model neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Because the origin of ALS mainly sporadic with unknown cause, methods disease are urgently needed. The produced NPCs differentiated into astrocytes, which involved motor neuron death ALS. Strikingly, skin-derived...
Adeno-associated virus type 9 (AAV9) is a powerful tool for delivering genes throughout the central nervous system (CNS) following intravenous injection. Preclinical results in pediatric models of spinal muscular atrophy (SMA) and lysosomal storage disorders provide compelling case advancing AAV9 to clinic. An important translational step demonstrate efficient CNS targeting large animals at various ages. In present study, we tested systemically injected cynomolgus macaques, administered...
Widespread distribution of gene products at clinically relevant levels throughout the CNS has been challenging. Adeno-associated virus type 9 (AAV9) vector reported as a good candidate for intravascular delivery, but low preexisting antibody titers against AAV in blood abrogate cellular transduction within CNS. In present study we compared effectiveness vascular delivery and cerebrospinal fluid (CSF) AAV9 transducing tissue nonhuman primates. Both routes generated similar patterns, although...
Spinal muscular atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease caused by low abundance of survival motor neuron (SMN) protein leading to degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) self-complementary adeno-associated virus-9 carrying human SMN cDNA (scAAV9-SMN) resulted widespread transgene expression spinal cord neurons SMA mice as well nonhuman primates complete rescue...
Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype variable with loss ambulation in late teenage or mid-life years. There currently no treatment for this condition. In BMD proof-of-principle clinical trial, potent myostatin antagonist, follistatin (FS), was used to inhibit the pathway. Extensive preclinical studies, using adeno-associated virus (AAV) deliver follistatin, demonstrated an increase strength. For we alternatively...
De novo mutations in the X-linked gene encoding transcription factor methyl-CpG binding protein 2 (MECP2) are most frequent cause of neurological disorder Rett syndrome (RTT). Hemizygous males usually die neonatal encephalopathy. Heterozygous females survive into adulthood but exhibit severe symptoms including microcephaly, loss purposeful hand motions and speech, motor abnormalities, which appear after a period apparently normal development. Most studies have focused on male mouse models...
Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma®) gene replacement therapy, are emerging.This study evaluated effectiveness in infants with spinal compared a prospective natural history cohort and healthy infants.Twelve SMA1 received proposed therapeutic dose (NCT02122952). Where possible, following outcomes were (n = 16) 27) enrolled NeuroNEXT (NN101) (NCT01736553): event-free...
Adult multipotent neural progenitor cells can differentiate into neurons, astrocytes, and oligodendrocytes in the mammalian central nervous system, but molecular mechanisms that control their differentiation are not yet well understood. Insulin-like growth factor I (IGF-I) promote of already committed to an oligodendroglial lineage during development. However, it is unclear whether IGF-I affects cells. Here, we show stimulates adult rat hippocampus-derived oligodendrocytes. Modeling analysis...
Increasing the size and strength of muscles represents a promising therapeutic strategy for musculoskeletal disorders, interest has focused on myostatin, negative regulator muscle growth. Various myostatin inhibitor approaches have been identified tested in models disease with varying efficacies, depending age at which inhibition occurs. Here, we describe one-time gene administration myostatin-inhibitor-proteins to enhance mass normal dystrophic mouse >2 years, even when delivered aged...
Proximal spinal muscular atrophy (SMA) is a debilitating neurological disease marked by isolated lower motor neuron death and subsequent of skeletal muscle. Historically, SMA pathology was thought to be limited neurons the muscles they control, yet there are several reports describing coincidence cardiovascular abnormalities in patients. As new therapies for emerge, it necessary determine whether these non-neuromuscular systems need targeted. Therefore, we have characterized left ventricular...
The Cre/ lox P system is increasingly showing promise for investigating genes involved in neural function. Here, we demonstrate that vivo modification of the mouse brain can be accomplished a spatial- and temporal-specific manner by targeted delivery an adeno-associated virus (AAV) encoding green fluorescent protein/Cre recombinase (GFP/Cre) fusion protein. By using reporter mouse, which Cre activates β-galactosidase expression, long-term recombination neurons hippocampus, striatum, septum...
Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been sporadic ALS, as misfolded reported affected tissues patients and toxicity astrocytes derived from ALS neurons be reduced by lowering the synthesis SOD1. We now report slowed disease onset progression two mouse models following therapeutic delivery using a single...