A5105023737- Neurogenetic and Muscular Disorders Research
- RNA modifications and cancer
- RNA Research and Splicing
- Congenital Anomalies and Fetal Surgery
- Muscle Physiology and Disorders
- Cancer-related gene regulation
- RNA and protein synthesis mechanisms
- Mitochondrial Function and Pathology
- Genetic Neurodegenerative Diseases
- High-Energy Particle Collisions Research
- Hereditary Neurological Disorders
- DNA and Nucleic Acid Chemistry
- Fuel Cells and Related Materials
- Particle physics theoretical and experimental studies
- Quantum Chromodynamics and Particle Interactions
- Genetics and Neurodevelopmental Disorders
- Mechanical Circulatory Support Devices
- Cardiac Structural Anomalies and Repair
- Muscle activation and electromyography studies
- Endoplasmic Reticulum Stress and Disease
- RNA regulation and disease
- DNA Repair Mechanisms
Northwestern University
2013-2023
Lurie Children's Hospital
2013-2023
Google (United States)
2021
Istituto Nazionale di Fisica Nucleare, Sezione di Napoli
2018
Memorial Medical Center
2009-2010
Ottawa Hospital
2001
Ottawa Hospital Research Institute
2001
Case Western Reserve University
1997
University School
1997
Centre Hospitalier Universitaire Sainte-Justine
1997
Spinal muscular atrophy (SMA) is caused by loss of the survival motor neuron gene (SMN1) and retention SMN2 gene. The copy number affects amount SMN protein produced severity SMA phenotype. While mouse Smn embryonic lethal, two copies prevents this lethality resulting in a with severe that dies 5 days after birth. Here we show expression full-length under prion promoter (PrP) rescues mice. PrP results high levels neurons at day 15. Mice homozygous for PrP-SMN lacking survive an average 210...
Proximal spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality. Traditionally, SMA has been described as a motor neuron disease; however, there growing body evidence that arrhythmia and/or cardiomyopathy may present in patients at an increased frequency. Here, we ask whether model mice possess such phenotypes. We find suffer from severe bradyarrhythmia characterized by progressive heart block and impaired ventricular depolarization. Echocardiography further confirms...
Proximal spinal muscular atrophy (SMA) is a neuromuscular disorder for which there no available therapy. SMA caused by loss or mutation of the survival motor neuron 1 gene, SMN1, with retention nearly identical copy SMN2. In contrast to most SMN2 transcripts lack exon 7. This alternatively spliced transcript, Δ7-SMN, encodes truncated protein that rapidly degraded. Inhibiting this degradation may be therapeutic value treatment SMA. Recently aminoglycosides, decrease translational fidelity...
Spinal muscular atrophy (SMA) is caused by insufficient levels of the survival motor neuron (SMN) protein due to functional loss SMN1 gene and inability its paralog, SMN2, fully compensate reduced exon 7 splicing efficiency. Since SMA patients have at least one copy drug discovery campaigns sought identify SMN2 inducers. C5-substituted quinazolines increase promoter activity in cell-based assays a derivative, RG3039, has progressed clinical testing. It orally bioavailable, brain-penetrant...
Abstract Background Data on combining molecular therapies that increase survival motor neuron protein for spinal muscular atrophy type 1 (SMA1) is lacking. Methods This was a retrospective study describing our centers' experiences in treating SMA1 patients with combination therapy. Results Five children received nusinersen and onasemnogene abeparvovec‐xioi (onasemnogene). Four were receiving prior to onasemnogene. Nusinersen continued three. Marked liver enzyme elevations resulted prolonged...
Because of a 500-kb inverted duplication, there are two copies the survival motor neuron (SMN) gene in humans, cenSMN and telSMN. Both genes produce identical ubiquitously expressed transcripts; however, only mutations telSMN responsible for spinal muscular atrophy (SMA), second most common autosomal recessive childhood disease. We have cloned murine homolog Smn mapped to Chromosome 13 within conserved syntenic region human chromosome 5q13. show that transcript (1.4 kb) is as early embryonic...
The candidate region for spinal muscular atrophy (SMA) has been defined as a 750 kb interval on 5q13. In this study, we performed allelic association studies in 154 German SMA families with the multicopy markers Ag1-CA (D5S1556); C212 (D5F149S1/S2) and correlated genotype data deletion of genes. Both recognize 0–3 alleles pro chromosome. Deletions were detected all copies (C272) 13 88 (15%) type I patients three 48 (6%) II patients. informative cases, was inherited from one parent. two...
Spinal muscular atrophy (SMA) is caused by low survival motor neuron (SMN) levels and patients represent a clinical spectrum due primarily to varying copies of the neuron-2 (SMN2) gene. Patient animals studies show that disease severity abrogated as SMN increase. Since therapies currently being pursued target induction SMN, it will be important understand dosage, timing cellular requirements for etiology potential therapeutic intervention. This requires new mouse models can induce temporally...
Recent reports underscore the unparalleled potential of antisense-oligonucleotide (ASO)-based approaches to ameliorate various pathological conditions. However, in vivo studies validating effectiveness a short ASO (<10-mer) context human disease have not been performed. One with proven amenability ASO-based therapy is spinal muscular atrophy (SMA). SMA neuromuscular caused by loss-of-function mutations survival motor neuron 1 (SMN1) gene. Correction aberrant splicing remaining paralog, SMN2,...
Spinal muscular atrophy (SMA) is caused by bi-allelic, recessive mutations of the survival motor neuron 1 (SMN1) gene and reduced expression levels (SMN) protein. Degeneration alpha neurons in spinal cord causes progressive skeletal muscle weakness. The wide range disease severities, variable rates decline, heterogenous clinical responses to approved disease-modifying treatment remain poorly understood limit ability optimize for patients. Validation a reliable biomarker(s) with potential...
Abstract A better understanding of the permittivity property skeletal muscle is essential for development new diagnostic tools and approaches neuromuscular evaluation. However, there remain important knowledge gaps in our this healthy diseased muscle, which hinder its translation into clinical application. Here, we report gastrocnemius wild type mice murine models spinal muscular atrophy, dystrophy, diabetes, amyotrophic lateral sclerosis a model myofiber hypertrophy. Data were measured ex...
Objective The aim of this study was to investigate the role ubiquitin C-terminal hydrolase-L1 (UCHL1) for motor neuron circuitry and especially in spinal (SMN) health, function, connectivity. Methods Since mutations UCHL1 gene leads dysfunction patients, we investigated on SMN survival, axon connectivity with muscle, by employing molecular cellular marker expression analysis electrophysiological recordings, healthy wild-type Uchl1nm3419 (UCHL1−/−) mice, which lack all function. Results There...
Spinal muscular atrophy is an autosomal recessive neurodegenerative disorder that affects the motor neurons responsible for movement of proximal muscles trunk and body. To date, disease can be classified into 3 main categories based on severity age onset. During October 18th symposium held in Pittsburgh, Pennsylvania, researchers met to (1) describe current diagnostic strategies, (2) discuss recent thoughts pathogenesis, (3) review therapies clinical trials, (4) define future research...
Proximal spinal muscular atrophy (SMA) is caused by mutations in the survival motor neuron gene (SMN1). In humans, two nearly identical copies of SMN exist and differ only a single non-polymorphic C→T nucleotide transition exon 7. SMN1 contains 'C' at +6 position 7 produces primarily full-length transcripts, whereas SMN2 'T' high levels transcript that lacks low level transcripts. All SMA patients lack functional but retain least one copy SMN2, suggesting protein produced from sufficient for...
We report a 3.0-Mb YAC contig of the region 5q11.2-q13.3, which is where spinal muscular atrophy gene has been localized. Three total genomic libraries were screened by polymerase chain reaction (PCR), and 45 YACs recovered. These characterized for sequence tag site (STS) content, overlaps confirmed vectorette PCR. Of YACs, 20 isolated with polymorphic marker CATT-1, demonstrates significant allelic association SMA maps within 850-kb interval defined markers D5S557 D5S823. Haplotyping these...
Proximal spinal muscular atrophy is caused by deletion or mutation of the survival motor neuron 1 gene, SMN1. Rentention a nearly identical copy SMN2, enables but unable to fully compensate for loss The SMN1 and SMN2 genes differ single nucleotide that results in alternative splicing exon 7 due disruption binding site an essential factor. This alternatively spliced form encodes partially functional truncated protein. Because present patients with atrophy, it ideal therapeutic target. Some...
C5-substituted 2,4-diaminoquinazoline inhibitors of the decapping scavenger enzyme DcpS (DAQ-DcpSi) have been developed for treatment spinal muscular atrophy (SMA), which is caused by genetic deficiency in Survival Motor Neuron (SMN) protein. These compounds are claimed to act as SMN2 transcriptional activators but data underlying that claim equivocal. In addition it unclear whether effects on a direct consequence inhibitor or might be lysosomotropism, known neuroprotective. DAQ-DcpSi were...