James J. Dowling
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View article: Gene therapy for children with X-linked myotubular myopathy: a plain language summary of publication for the ASPIRO study
Gene therapy for children with X-linked myotubular myopathy: a plain language summary of publication for the ASPIRO study Open
What is this summary about? This summary describes the results of a research study (clinical trial) called ASPIRO that was published in the Lancet Neurology in 2023. This study looked at an investigational gene therapy called resamirigene …
View article: Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort
Clinical applications of and molecular insights from RNA sequencing in a rare disease cohort Open
Background RNA sequencing (RNA-seq) is emerging as a valuable tool for identifying disease-causing RNA transcript aberrations that cannot be identified by DNA-based testing alone. Previous studies demonstrated some success in utilizing RNA…
View article: Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel
Clinical validity of congenital myopathy genes determined by the ClinGen Congenital Myopathies Expert Panel Open
Background: Congenital myopathies are a group of neuromuscular disorders that typically present at birth or early childhood with hypotonia and non-progressive or slowly progressive muscle weakness. They are classically subclassified by cha…
View article: Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion
Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion Open
View article: microRNA-133a as an indicator of disease progression and treatment response in X-linked myotubular myopathy
microRNA-133a as an indicator of disease progression and treatment response in X-linked myotubular myopathy Open
View article: X-linked myopathy with excessive autophagy: characterization and therapy testing in a zebrafish model
X-linked myopathy with excessive autophagy: characterization and therapy testing in a zebrafish model Open
View article: Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies
Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights From Comprehensive Multicenter Preclinical Studies Open
BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PAs) and progressive increase in pulmonary vascular resistance leading to right ventricular failure. Al…
View article: Characterization of a novel zebrafish model of <i>MTMR5</i>-associated Charcot-Marie-Tooth disease type 4B3
Characterization of a novel zebrafish model of <i>MTMR5</i>-associated Charcot-Marie-Tooth disease type 4B3 Open
Biallelic loss of expression/function variants in MTMR5/SBF1 cause the inherited peripheral neuropathy Charcot-Marie-Tooth type 4B3. There is an incomplete understanding of the disease pathomechanism(s) underlying Charcot-Marie-Tooth type …
View article: Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion
Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion Open
View article: Equitable Access to Disease-Modifying Therapies for Canadian Children with SMA and Four <i>SMN2</i> Copies
Equitable Access to Disease-Modifying Therapies for Canadian Children with SMA and Four <i>SMN2</i> Copies Open
View article: Human <i>ITGAV</i> variants are associated with immune dysregulation, brain abnormalities, and colitis
Human <i>ITGAV</i> variants are associated with immune dysregulation, brain abnormalities, and colitis Open
Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three in…
View article: Cyprocide selectively kills nematodes via cytochrome P450 bioactivation
Cyprocide selectively kills nematodes via cytochrome P450 bioactivation Open
Left unchecked, plant-parasitic nematodes have the potential to devastate crops globally. Highly effective but non-selective nematicides are justifiably being phased-out, leaving farmers with limited options for managing nematode infestati…
View article: AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient
AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient Open
There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disea…
View article: Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies
Exploring Integrin α5β1 as a Potential Therapeutic Target for Pulmonary Arterial Hypertension: Insights from Comprehensive Multicenter Preclinical Studies Open
Pulmonary arterial hypertension (PAH) is characterized by obliterative vascular remodeling of the small pulmonary arteries (PA) and progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular (RV) failure. Alth…
View article: A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and in silico methods
A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and in silico methods Open
View article: Characterization of a novel zebrafish model of<i>MTMR5</i>-associated CMT4B3
Characterization of a novel zebrafish model of<i>MTMR5</i>-associated CMT4B3 Open
Biallelic loss of expression/function variants in MTMR5 cause the inherited peripheral neuropathy Charcot-Marie-Tooth (CMT) Type 4B3. There is an incomplete understanding of the disease pathomechanism(s) underlying CMT4B3, and despite its …
View article: Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy
Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy Open
Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode pro…
View article: Standardization of zebrafish drug testing parameters for muscle diseases
Standardization of zebrafish drug testing parameters for muscle diseases Open
Skeletal muscular diseases predominantly affect skeletal and cardiac muscle, resulting in muscle weakness, impaired respiratory function and decreased lifespan. These harmful outcomes lead to poor health-related quality of life and carry a…
View article: P171: Developing an approach to screening rare genetic diagnoses for amenability to bespoke genetic therapy development
P171: Developing an approach to screening rare genetic diagnoses for amenability to bespoke genetic therapy development Open
Rare genetic diseases are collectively common. These diseases are major contributors to pediatric morbidity and mortality, but few have specialized or targeted treatments. Proof-of-concept exists for precision genetic therapies like antise…
View article: P541: Development of a provincial genetics program in Ontario
P541: Development of a provincial genetics program in Ontario Open
As genomic testing is increasingly being used for personalized medicine, oversight and coordination at a provincial level is needed to build genetic testing services that are connected and sustainable to fulfill the government's vision of …
View article: Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial
Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial Open
Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).
View article: Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial
Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial Open
Astellas Gene Therapies.
View article: Two zebrafish <i>cacna1s</i> loss-of-function variants provide models of mild and severe <i>CACNA1S</i>-related myopathy
Two zebrafish <i>cacna1s</i> loss-of-function variants provide models of mild and severe <i>CACNA1S</i>-related myopathy Open
CACNA1S-related myopathy, due to pathogenic variants in the CACNA1S gene, is a recently described congenital muscle disease. Disease associated variants result in loss of gene expression and/or reduction of Cav1.1 protein stability. There …
View article: The myotubular and centronuclear myopathy patient registry: a multifunctional tool for translational research
The myotubular and centronuclear myopathy patient registry: a multifunctional tool for translational research Open
View article: Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy
Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy Open
X-linked myotubular myopathy (XLMTM) is a fatal congenital disorder caused by mutations in the MTM1 gene. Currently, there are no approved treatments, although AAV8-mediated gene transfer therapy has shown promise in animal models and prel…
View article: A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and<i>in silico</i>methods
A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and<i>in silico</i>methods Open
Background/Objectives Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to ACMG criterion PVS1). However, the exact nature and predic…
View article: Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects
Variants in ACTC1 underlie distal arthrogryposis accompanied by congenital heart defects Open
View article: Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors
Optimization of a series of novel, potent and selective Macrocyclic SYK inhibitors Open
View article: Trio RNA sequencing in a cohort of medically complex children
Trio RNA sequencing in a cohort of medically complex children Open
Genome sequencing (GS) is a powerful test for the diagnosis of rare genetic disorders. Although GS can enumerate most non-coding variation, determining which non-coding variants are disease-causing is challenging. RNA sequencing (RNA-seq) …
View article: Variants in<i>ACTC1</i>underlie distal arthrogryposis accompanied by congenital heart defects
Variants in<i>ACTC1</i>underlie distal arthrogryposis accompanied by congenital heart defects Open
Contraction of the human sarcomere is the result of interactions between myosin cross-bridges and actin filaments. Pathogenic variants in genes such as MYH7 , TPM1 , and TNNI3 that encode parts of the cardiac sarcomere cause muscle disease…