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Spinal muscular dystrophy treatment

David Gonzalez, Enrique Brandan
Connective tissue growth factor (CTGF/CCN2) is a matricellular protein that belongs to the CCN family of proteins. Since its discovery, it has been linked to cellular processes such as cell proliferation, differentiation, adhesion, migration, and synthesis of extracellular matrix (ECM) components, among others. The pro-fibrotic role of CTGF/CCN2 has been well-studied in several pathologies characterized by the development of fibrosis. Reduction of CTGF/CCN2 levels in mdx mice, a murine model for Duchenne muscular dystrophy (DMD), decreases fibrosis and improves skeletal muscle phenotype and function...
January 28, 2019: Molecular Neurobiology
Richard L Lieber, Jan Fridén
Skeletal muscle contractures represent the permanent shortening of a muscle-tendon unit, resulting in loss of elasticity and, in extreme cases, joint deformation. They may result from cerebral palsy, spinal cord injury, stroke, muscular dystrophy and other neuromuscular disorders. Contractures are the prototypic and most severe clinical presentation of increased passive mechanical muscle force in humans, often requiring surgical correction. Intraoperative experiments demonstrate that high muscle passive force is associated with sarcomeres that are abnormally stretched, although otherwise normal, with fewer sarcomeres in series...
December 20, 2018: Journal of Applied Physiology
Rocío de la Vega, Ivan R Molton, Jordi Miró, Amanda E Smith, Mark P Jensen
BACKGROUND: Perceived social support has been found to be associated with depression, subjective well-being and psychological health in cross-sectional studies in people with physical disabilities. No longitudinal studies have been conducted to examine these associations over time using a comprehensive measure of social support. OBJECTIVE/HYPOTHESIS: We hypothesized that: (1) the amount of perceived social support would be similar across individuals with different diagnoses often associated with disability (i...
October 5, 2018: Disability and Health Journal
Michael J Gait, Andrey A Arzumanov, Graham McClorey, Caroline Godfrey, Corinne Betts, Suzan Hammond, Matthew J A Wood
The review starts with a historical perspective of the achievements of the Gait group in synthesis of oligonucleotides (ONs) and their peptide conjugates toward the award of the 2017 Oligonucleotide Therapeutic Society Lifetime Achievement Award. This acts as a prelude to the rewarding collaborative studies in the Gait and Wood research groups aimed toward the enhanced delivery of charge neutral ON drugs and the development of a series of Arg-rich cell-penetrating peptides called Pip (peptide nucleic acid/phosphorodiamidate morpholino oligonucleotide [PNA/PMO] internalization peptides) as conjugates of such ONs...
October 16, 2018: Nucleic Acid Therapeutics
Eunyoung Kim, Han Eol Cho, Ji Ho Jung, Jang Woo Lee, Won Ah Choi, Seong-Woong Kang
In advanced Duchenne muscular dystrophy (DMD), patients with high bone fracture risk due to osteoporosis, it is difficult to measure spinal bone mineral density (BMD) because of maintaining proper posture. This study began with the idea that if we diagnose and manage osteoporosis by predicting spinal BMD through easily testable radial BMD, we could prevent fracture and improve quality of life in DMD patients. In 61 DMD patients aged 20 years or older who were admitted to Gangnam Severance Hospital from April 2013 to May 2015, radial BMD and spinal BMD were measured to compare their Z-scores...
October 2018: Medicine (Baltimore)
Dunhui Li, Frank L Mastaglia, Sue Fletcher, Steve D Wilton
Clinical implementation of two recently approved antisense RNA therapeutics - Exondys51® to treat Duchenne muscular dystrophy (Duchenne MD) and Spinraza® as a treatment for spinal muscular atrophy (SMA) - highlights the therapeutic potential of antisense oligonucleotides (ASOs). As shown in the Duchenne and Becker cases, the identification and specific removal of 'dispensable' exons by exon-skipping ASOs could potentially bypass lethal mutations in other genes and bring clinical benefits to affected individuals carrying amenable mutations...
November 2018: Trends in Pharmacological Sciences
Rika Maruyama, Toshifumi Yokota
Antisense-mediated exon skipping and exon inclusion have proven to be powerful tools for treating neuromuscular diseases. The approval of Exondys 51 (eteplirsen) and Spinraza (nusinersen) for the treatment of patients with Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA) was the most noteworthy accomplishment in 2016. Exon skipping uses short DNA-like molecules called antisense oligonucleotides (AONs) to correct the disrupted reading frame, allowing the production of functional quasi-dystrophin proteins, and ameliorate the progression of the disease...
2018: Methods in Molecular Biology
Kenji Rowel Q Lim, Toshifumi Yokota
Since its discovery in 1977, much has been known about RNA splicing and how it plays a central role in human development, function, and, notably, disease. Defects in RNA splicing account for at least 10% of all genetic disorders, with the number expected to increase as more information is uncovered on the contribution of noncoding genomic regions to disease. Splice modulation through the use of antisense oligonucleotides (AOs) has emerged as a promising avenue for the treatment of these disorders. In fact, two splice-switching AOs have recently obtained approval from the US Food and Drug Administration: eteplirsen (Exondys 51) for Duchenne muscular dystrophy, and nusinersen (Spinraza) for spinal muscular atrophy...
2018: Methods in Molecular Biology
J Kirschner, B Schoser
Advances in the understanding of the genetic mechanisms and pathophysiology of neuromuscular diseases have recently led to the development of new, innovative and often mutation-specific therapeutic approaches. Methods used include splicing modification by antisense oligonucleotides, read-through of premature stopcodons, use of viral vectors to introduce genetic information, or optimizing the effectiveness of enzyme replacement therapies. The first drugs have already been approved for the treatment of Duchenne muscular dystrophy and spinal muscular atrophy...
October 2018: Der Nervenarzt
Teodorico C Ramalho, Alexandre A de Castro, Tássia S Tavares, Maria C Silva, Daniela R Silva, Pedro H Cesar, Lucas A Santos, Elaine F F da Cunha, Eugenie Nepovimova, Kamil Kuca
Several rare or orphan diseases have been characterized that singly affect low numbers of people, but cumulatively reach ∼6%-10% of the population in Europe and in the United States. Human genetics has shown to be broadly effective when evaluating subjacent genetic defects such as orphan genetic diseases, but on the other hand, a modest progress has been achieved toward comprehending the molecular pathologies and designing new therapies. Chemical genetics, placed at the interface of chemistry and genetics, could be employed to understand the molecular mechanisms of subjacent illnesses and for the discovery of new remediation processes...
October 2018: Progress in Neurobiology
James T March, Golnoush Golshirazi, Viktorija Cernisova, Heidi Carr, Yee Leong, Ngoc Lu-Nguyen, Linda J Popplewell
Fibrosis results from the excessive accumulation of extracellular matrix in chronically injured tissue. The fibrotic process is governed by crosstalk between many signaling pathways. The search for an effective treatment is further complicated by the fact that there is a degree of tissue-specificity in the pathways involved, although the process is not completely understood for all tissues. A plethora of drugs have shown promise in pre-clinical models, which is not always borne out translationally in clinical trial...
June 25, 2018: Biomedicines
Ava Y Lin, Leo H Wang
PURPOSE OF REVIEW: To construct a framework to understand the different molecular interventions for muscular dystrophy. RECENT FINDINGS: The recent approval of antisense oligonucleotides treatment for Duchenne muscular dystrophy and spinal muscular atrophy and current clinical trials using recombinant adeno-associated virus for the treatment of those diseases suggests that we are at a tipping point where we are able to treat and potentially cure muscular dystrophies...
June 21, 2018: Current Treatment Options in Neurology
Shimaa Eissa, Nawal Alshehri, Mai Abduljabbar, Anas M Abdel Rahman, Majed Dasouki, Imran Y Nizami, Mohammad A Al-Muhaizea, Mohammed Zourob
Simultaneous and point-of-care detection of multiple protein biomarkers has significant impact on patient care. Spinal Muscular Atrophy (SMA), Cystic Fibrosis (CF) and Duchenne Muscular Dystrophy (DMD) are well known progressive hereditary disorders associated with increased morbidity as well as mortality. Therefore, rapid detection of biomarkers specific for these three disorders in newborns offers new opportunities for early diagnosis, delaying symptoms and effective treatment. Here, we report the development of a disposable carbon nanofiber (CNF)-based electrochemical immunosensor for simultaneous detection of survival motor neuron 1 (SMN1), cystic fibrosis transmembrane conductance regulator (CFTR) and DMD proteins...
October 15, 2018: Biosensors & Bioelectronics
David Gonzalez, Daniela L Rebolledo, Lina M Correa, Felipe A Court, Waldo Cerpa, Kenneth E Lipson, Brigitte van Zundert, Enrique Brandan
Amyotrophic lateral sclerosis (ALS) is a devastating adult-onset progressive neurodegenerative disease characterized by upper and lower motoneuron degeneration. A total of 20% of familial ALS (fALS) cases are explained by mutations in the superoxide dismutase 1 (SOD1) enzyme. Although more than 20 years have passed since the generation of the first ALS mouse model, the precise molecular mechanisms of ALS pathogenesis remain unknown. CTGF/CCN2 is a matricellular protein with associated fibrotic activity that is up-regulated in several chronic diseases...
August 15, 2018: Human Molecular Genetics
Sara Aguti, Alberto Malerba, Haiyan Zhou
The well-defined genetic causes and monogenetic nature of many neuromuscular disorders, including Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), present gene therapy as a prominent therapeutic approach. The novel variants of adeno-associated virus (AAV) can achieve satisfactory transduction efficiency of exogenous genes through the central nervous system and body-wide in skeletal muscle. Areas covered: In this review, we summarize the strategies of AAV gene therapy that are currently under preclinical and clinical evaluation for the treatment of degenerative neuromuscular disorders, with a focus on diseases such as DMD and SMA...
June 2018: Expert Opinion on Biological Therapy
Yi Wei, Anna McCormick, Alex MacKenzie, Erin O'Ferrall, Shannon Venance, Jean K Mah, Kathryn Selby, Hugh J McMillan, Garth Smith, Maryam Oskoui, Gillian Hogan, Laura McAdam, Gracia Mabaya, Victoria Hodgkinson, Josh Lounsberry, Lawrence Korngut, Craig Campbell
Introduction: Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments. Methods: In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry...
February 2018: Paediatrics & Child Health
Holly L Peay, Barbara B Biesecker, Benjamin S Wilfond, Jill Jarecki, Kendall L Umstead, Diana M Escolar, Aad Tibben
BACKGROUND/AIMS: Pediatric rare disease presents a challenging situation of high unmet need and a limited pool of potential clinical trial participants. Understanding perspectives of parents of children who have not participated in trials may facilitate approaches to optimize participation rates. The objective of this study was to explore factors associated with parental interest in enrolling children with pediatric neuromuscular disorders in clinical trials. METHODS: Parents of individuals with Duchenne or Becker muscular dystrophy and spinal muscular atrophy were recruited through advocacy organizations, a registry, and clinics...
April 2018: Clinical Trials: Journal of the Society for Clinical Trials
Lotfi Miladi, Mathilde Gaume, Nejib Khouri, Michael Johnson, Vicken Topouchian, Christophe Glorion
STUDY DESIGN: A retrospective review. OBJECTIVE: To report the results of an alternative technique using a minimally invasive fusionless surgery. The originality is based on the progressive correction of the deformities with proximal and distal fixation and on the reliability of the pelvic fixation using iliosacral screws on osteoporotic bones. SUMMARY OF BACKGROUND DATA: Spinal deformities are common in neuromuscular diseases. Conventional treatment involves bracing, followed by spinal instrumented fusion...
August 2018: Spine
Kelly M Martinovich, Nicole C Shaw, Anthony Kicic, André Schultz, Sue Fletcher, Steve D Wilton, Stephen M Stick
Antisense oligonucleotides are an emerging therapeutic option to treat diseases with known genetic origin. In the age of personalised medicines, antisense oligonucleotides can sometimes be designed to target and bypass or overcome a patient's genetic mutation, in particular those lesions that compromise normal pre-mRNA processing. Antisense oligonucleotides can alter gene expression through a variety of mechanisms as determined by the chemistry and antisense oligomer design. Through targeting the pre-mRNA, antisense oligonucleotides can alter splicing and induce a specific spliceoform or disrupt the reading frame, target an RNA transcript for degradation through RNaseH activation, block ribosome initiation of protein translation or disrupt miRNA function...
February 6, 2018: Molecular and Cellular Pediatrics
Lina Yan, Yaling Liu, Can Sun, Qian Zheng, Pengli Hao, Jingxu Zhai, Yuanyuan Liu
BACKGROUND Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive muscular dystrophy and paralysis; most ALS patients die from respiratory failure within 3 to 5 years, and there is currently no effective treatment. Some studies have indicated sex differences in the incidence of ALS, and evidence suggests a neuroprotective role for estrogen. MATERIAL AND METHODS We used human Cu/Zn superoxide dismutase (hSOD1-G93A) transgenic mice to determine the effects of ovariotomy on the onset of disease and behavior; we also used Western blotting to measure the expression of aromatase and estrogen receptors, as well as the inflammatory cytokines and apoptosis markers, in the lumbar spinal cord to determine the mechanism of estrogen-mediated neuroprotection...
February 2, 2018: Medical Science Monitor: International Medical Journal of Experimental and Clinical Research
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