A5086564788- Neurogenetic and Muscular Disorders Research
- RNA modifications and cancer
- CRISPR and Genetic Engineering
- Amyotrophic Lateral Sclerosis Research
- RNA Research and Splicing
- Virus-based gene therapy research
- Musculoskeletal pain and rehabilitation
- Genetics and Neurodevelopmental Disorders
- Pluripotent Stem Cells Research
- RNA regulation and disease
- Muscle Physiology and Disorders
- Retinal Development and Disorders
- Lysosomal Storage Disorders Research
- Neuroinflammation and Neurodegeneration Mechanisms
- Viral Infections and Immunology Research
- CAR-T cell therapy research
- Neurogenesis and neuroplasticity mechanisms
- Thyroid Disorders and Treatments
- Cardiomyopathy and Myosin Studies
- Fibromyalgia and Chronic Fatigue Syndrome Research
- RNA Interference and Gene Delivery
- Prion Diseases and Protein Misfolding
- Nerve injury and regeneration
- Genomics and Rare Diseases
- Mitochondrial Function and Pathology
Nationwide Children's Hospital
2014-2024
The Ohio State University
2014-2024
The Ohio State University Wexner Medical Center
2022-2024
Pediatrics and Genetics
2023
Johannes Kepler University of Linz
2023
Klinik Lüneburger Heide
2022
University Hospital of Zurich
2005-2016
Sangamo BioSciences (United States)
2016
Point Richmond Tech Center
2016
University of Bern
2007-2014
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...
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...
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...
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...
Stem cell-derived motor neurons (MNs) are increasingly utilized for modeling disease in vitro and developing cellular replacement strategies spinal cord injury diseases such as muscular atrophy (SMA) amyotrophic lateral sclerosis (ALS). Human embryonic stem cell (hESC) differentiation into MNs, which involves retinoic acid (RA) activation of the sonic hedgehog (SHH) pathway is inefficient requires up to 60 days develop MNs with electrophysiological properties. This prolonged process has...
Significance Oligodendrocytes have been implicated in disease pathology amyotrophic lateral sclerosis (ALS) using transgenic mouse models. To date there is no human coculture system available to investigate oligodendrocyte involvement motor neuron (MN) death ALS. Our data highlight that oligodendrocytes derived from patients with familial and sporadic ALS induced pluripotent stem cells neural progenitor play an active role MN death. Oligodendrocyte toxicity mediated through soluble factors...
Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein, which results in motoneuron loss. Therapeutic strategies to increase SMN including drug compounds, antisense oligonucleotides, and scAAV9 gene therapy have proved effective mice. We wished determine whether reduction postnatal motoneurons resulted SMA a large animal model, could be corrected after development muscle weakness, the response clinically relevant biomarkers.Using intrathecal delivery...
Abstract Hexanucleotide repeat expansions in the C9ORF72 gene are commonest known genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Expression transcripts dipeptide proteins trigger multiple mechanisms neurotoxicity. How get exported from nucleus is unknown. Here, we show that depletion nuclear export adaptor SRSF1 prevents neurodegeneration locomotor deficits a Drosophila model C9ORF72-related disease. This intervention suppresses cell death patient-derived motor...
Human primary natural killer (NK) cells are being widely advanced for cancer immunotherapy. However, methods gene editing of these have suffered low transduction rates, high cell death, and loss transgene expression after expansion. Here, we developed a highly efficient method site-specific insertion in NK using CRISPR (Cas9/RNP) AAVs. We compared AAV vectors designed to mediate by different DNA repair mechanisms, homology arm lengths, virus concentrations. then validated the site-directed...
Catastrophizing plays an important role in models of pain chronicity, showing a consistent correlation with both intensity and disability. It is conceivable that these associations are mediated or confounded by other psychological attributes.To examine the relative influence catastrophizing variables on disability patients chronic low back pain.Seventy-eight completed Pain Scale, Roland Morris Disability Questionnaire, Fear-Avoidance Beliefs Questionnaire (work/activity), Modified Somatic...
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant or digenic disorder linked to derepression of the toxic DUX4 gene in muscle. There currently no pharmacological treatment. The emergence enabled development cell and animal models that could be used for basic translational research. Since toxic, model has been challenging, but progress made, revealing tight regulation expression critical creating viable animals develop myopathy. Here, we report such a —...
RNA helicases constitute a large protein family implicated in cellular homeostasis and disease development. Here, we show that the helicase IGHMBP2, linked to neuromuscular disorder spinal muscular atrophy with respiratory distress type 1 (SMARD1), associates polysomes impacts translation of mRNAs containing short, GC-rich, structured 5′ UTRs. The absence IGHMBP2 causes ribosome stalling at start codon target mRNAs, leading reduced efficiency. main mRNA targets IGHMBP2-mediated regulation...
In spinal muscular atrophy (SMA), the leading genetic cause of early childhood death, survival motor neuron 1 gene ( SMN1 ) is deleted or inactivated. The nearly identical SMN2 has a silent mutation that impairs utilization exon 7 and production functional protein. It been hypothesized therapies boosting inclusion might prevent cure SMA. Exon can be stimulated in cell culture by oligonucleotides intracellularly expressed RNAs, but evidence for an vivo improvement SMA symptoms lacking. Here,...
Objective Preclinical therapies that restore survival motor neuron (SMN) protein levels can dramatically extend in spinal muscular atrophy (SMA) mouse models. Biomarkers are needed to effectively translate these promising clinical trials. Our objective was investigate electrophysiological biomarkers of compound muscle action potential (CMAP), unit number estimation (MUNE) and electromyography (EMG) using an SMA model. Methods Sciatic CMAP, MUNE, EMG were obtained SMN∆7 mice at ages 3–13 days...
CLN6-Batten disease, a form of neuronal ceroid lipofuscinosis is rare lysosomal storage disorder presenting with gradual declines in motor, visual, and cognitive abilities early death by 12-15 years age. We developed self-complementary adeno-associated virus serotype 9 (scAAV9) vector expressing the human CLN6 gene under control chicken β-actin (CB) hybrid promoter. Intrathecal delivery scAAV9.CB.hCLN6 into cerebrospinal fluid (CSF) lumbar spinal cord 4-year-old non-human primates was safe,...
Abstract Astrocytes are highly specialised cells, responsible for CNS homeostasis and neuronal activity. Lack of human in vitro systems able to recapitulate the functional changes affecting astrocytes during ageing represents a major limitation studying mechanisms potential therapies aiming preserve health. Here, we show that induced from fibroblasts donors their childhood or adulthood display age‐related transcriptional differences functionally diverge spectrum age‐associated features, such...
De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like ( IRF2BPL ) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of causes neural dysfunction, we examined its function Drosophila and zebrafish. Overexpression either or Pits , the ortholog, represses Wnt transcription flies. In contrast, neuronal depletion leads increased wingless wg levels brain is associated with axonal loss, whereas inhibition Wg signaling neuroprotective. Moreover,...
Spinal muscular atrophy (SMA) is a lethal hereditary disease caused by homozygous deletion/inactivation of the survival motoneuron 1 (SMN1) gene. The nearby SMN2 gene, despite its identical coding capacity, only an incomplete substitute, because single nucleotide difference impairs inclusion seventh exon in messenger RNA (mRNA). This splicing defect can be corrected (transiently) specially designed oligonucleotides. Here we have developed more permanent correction strategy based on...
Of familial amyotrophic lateral sclerosis (fALS) cases, 20% are caused by mutations in the gene encoding human cytosolic Cu/Zn superoxide dismutase (hSOD1). Efficient translation of therapeutic potential RNAi for treatment SOD1-ALS patients requires development vectors that free significant off-target effects and with reliable biomarkers to discern sufficient target engagement correct dosing. Using adeno-associated virus serotype 9 deliver against hSOD1 SOD1G93A mouse model, we found...