1,029 research outputs found
Gapmer Antisense Oligonucleotides Suppress the Mutant Allele of COL6A3 and Restore Functional Protein in Ullrich Muscular Dystrophy
Dominant-negative mutations in the genes that encode the
three major a chains of collagen type VI, COL6A1, COL6A2,
and COL6A3, account for more than 50% of Ullrich congenital
muscular dystrophy patients and nearly all Bethlem myopathy
patients. Gapmer antisense oligonucleotides (AONs) are
usually used for gene silencing by stimulating RNA cleavage
through the recruitment of an endogenous endonuclease
known as RNase H to cleave the RNA strand of a DNA-RNA
duplex. In this study, we exploited the application of the
allele-specific silencing approach by gapmer AON as a potential
therapy for Collagen-VI-related congenital muscular
dystrophy (COL6-CMD). A series of AONs were designed to
selectively target an 18-nt heterozygous genomic deletion in
exon 15 of COL6A3 at the mRNA and pre-mRNA level. We
showed that gapmer AONs can selectively suppress the expression
of mutant transcripts at both pre-mRNA and mRNA
levels, and that the latter strategy had a far stronger efficiency
than the former. More importantly, we found that silencing
of the mutant transcripts by gapmer AONs increased the deposition
of collagen VI protein into the extracellular matrix, thus
restoring functional protein production. Our findings provide
a clear proof of concept for AON allele-specific silencing as a
therapeutic approach for COL6-CM
Genetic therapies for inherited neuromuscular disorders
Inherited neuromuscular disorders encompass a broad group of genetic conditions, and the discovery of these underlying genes has expanded greatly in the past three decades. The discovery of such genes has enabled more precise diagnosis of these disorders and the development of specific therapeutic approaches that target the genetic basis and pathophysiological pathways. Such translational research has led to the approval of two genetic therapies by the US Food and Drug Administration: eteplirsen for Duchenne muscular dystrophy and nusinersen for spinal muscular atrophy, which are both antisense oligonucleotides that modify pre-mRNA splicing. In this Review we aim to discuss new genetic therapies and ongoing clinical trials for Duchenne muscular dystrophy, spinal muscular atrophy, and other less common childhood neuromuscular disorders
The NorthStar Ambulatory Assessment in Duchenne muscular dystrophy: considerations for the design of clinical trials.
With the emergence of experimental therapies for Duchenne muscular dystrophy (DMD), it is fundamental to understand the natural history of this disorder to properly design clinical trials. The aims of this study were to assess the effects produced on motor function by different DMD genotypes and early initiation of glucocorticoids
Lipid nanoparticles as vehicles for oral delivery of insulin and insulin analogs: preliminary ex vivo and in vivo studies
Gene therapy in Duchenne muscular dystrophy: Identifying and preparing for the challenges ahead
Screening of Neonatal UK Dried Blood Spots Using a Duplex SMN1 Screening Assay
Spinal muscular atrophy (SMA) is an autosomal inherited neuromuscular genetic disease caused, in 95% of cases, by homozygous deletions involving the SMN1 gene exon 7. It remains the leading cause of death in children under 2 years of age. New treatments have been developed and adopted for use in many countries, including the UK. Success of these treatments depends on early diagnosis and intervention in newborn babies, and many countries have implemented a newborn screening (NBS) or pilot NBS program to detect SMN1 exon 7 deletions on dried blood spots. In the UK, there is no current NBS program for SMA, and no pilot studies have commenced. For consideration of adoption of NBS for a new condition, numerous criteria must be satisfied, including critical assessment of a working methodology. This study uses a commercially available real-time PCR assay to simultaneously detect two different DNA segments (SMN1 exon 7 and control gene RPP30) using DNA extracted from a dried blood spot. This study was carried out in a routine clinical laboratory to determine the specificity, sensitivity, and feasibility of SMA screening in a UK NBS lab setting. Just under 5000 normal DBSs were used alongside 43 known SMA positive DBSs. Study results demonstrate that NBS for SMA using real-time PCR is feasible within the current UK NBS Laboratory infrastructure using the proposed algorithm
Glargine insulin loaded lipid nanoparticles: Oral delivery of liquid and solid oral dosage forms
The transgenic expression of LARGE exacerbates the muscle phenotype of dystroglycanopathy mice
Histopathological Defects in Intestine in Severe Spinal Muscular Atrophy Mice Are Improved by Systemic Antisense Oligonucleotide Treatment
Acknowledgments This study is supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (FM and HZ), the Medical Research Council grant (grant reference MR/L013142/1, FM), SMA-Europe grant (FM and HZ) and Great Ormond Street Hospital Childrenās Charity grants (FM and HZ). JEM is supported by Great Ormond Street Hospital Childrenās Charity. PS is supported by Bill Marshall Fellowship and The CP Charitable Trust at Great Ormond Street Hospital and UCL. SHP is supported by SMA Trust and Euan MacDonald Centre for Motor Neurone Disease Research.Peer reviewedPublisher PD
- ā¦