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Neurology. Genetics Jun 2024Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy...
BACKGROUND AND OBJECTIVES
Omigapil is a small molecule which inhibits the GAPDH-Siah1-mediated apoptosis pathway. Apoptosis is a pathomechanism underlying the congenital muscular dystrophy subtypes LAMA2-related dystrophy (LAMA2-RD) and COL6-related dystrophy (COL6-RD). Studies of omigapil in the (dy/dy) LAMA2-RD mouse model demonstrated improved survival, and studies in the (dy/dy) LAMA2-RD mouse model and the (Col6a1) COL6-RD mouse model demonstrated decreased apoptosis.
METHODS
A phase 1 open-label, sequential group, ascending oral dose, cohort study of omigapil in patients with LAMA2-RD or COL6-RD ages 5-16 years was performed (1) to establish the pharmacokinetic (PK) profile of omigapil at a range of doses, (2) to evaluate the safety and tolerability of omigapil at a range of doses, and (3) to establish the feasibility of conducting disease-relevant clinical assessments. Patients were enrolled in cohorts of size 4, with each patient receiving 4 weeks of vehicle run-in and 12 weeks of study drug (at daily doses ranging from 0.02 to 0.08 mg/kg). PK data from each cohort were analyzed before each subsequent dosing cohort was enrolled. A novel, adaptive dose-finding method (stochastic approximation with virtual observation recursion) was used to allow for dose escalation/reduction between cohorts based on PK data.
RESULTS
Twenty patients were enrolled at the NIH (LAMA2-RD: N = 10; COL6-RD: N = 10). Slightly greater than dose-proportional increases in systemic exposure to omigapil were seen at doses 0.02-0.08 mg/kg/d. The dose which achieved patient exposure within the pre-established target area under the plasma concentration-vs-time curve (AUC) range was 0.06 mg/kg/d. In general, omigapil was safe and well tolerated. No consistent changes were seen in the disease-relevant clinical assessments during the duration of the study.
DISCUSSION
This study represents the thus far only clinical trial of a therapeutic small molecule for LAMA2-RD and COL6-RD, completed with an adaptive trial design to arrive at dose adjustments. The trial met its primary end point and established that the PK profile of omigapil is suitable for further development in pediatric patients with LAMA2-RD or COL6-RD, the most common forms of congenital muscular dystrophy. While within the short duration of the study disease-relevant clinical assessments did not demonstrate significant changes, this study establishes the feasibility of performing interventional clinical trials in these rare disease patient populations.
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence of omigapil in a dose-finding phase 1 study.
TRIAL REGISTRATION INFORMATION
Clinical Trials NCT01805024.
PubMed: 38915423
DOI: 10.1212/NXG.0000000000200148 -
Journal of Clinical Research in... Jun 2024Delayed puberty is thought to be common in boys with Duchenne muscular dystrophy (DMD) treated with long term oral glucocorticoid. This study aims to report the...
BACKGROUND
Delayed puberty is thought to be common in boys with Duchenne muscular dystrophy (DMD) treated with long term oral glucocorticoid. This study aims to report the frequency of delayed puberty in DMD from examination by a paediatric endocrinologist alongside detailed endocrine investigations.
METHODS
All boys with DMD aged at least 14 years in January 2022 known to the paediatric neuromuscular service (2016-2022) were included in this study. Delayed puberty was defined based on testicular volume and genital staging in comparison to published puberty nomogram.
RESULTS
Twenty-four out of 37 boys (65%) had evidence of delayed puberty, 23/24 (96%) of those with delayed puberty were on glucocorticoid therapy all of whom were on daily glucocorticoid. On the other hand, 7/13 (54%) of those with normal timing of puberty were on glucocorticoid; 2/7 (29%) were on the intermittent regimen. Of those who were on daily glucocorticoid therapy at the time of assessment of puberty, 23/28 (82%) had evidence of delayed puberty. In boys with delayed puberty, endocrine investigations showed low luteinizing hormone (LH) with undetectable testosterone levels, a pre-pubertal response with lutenizing hormone releasing hormone test and sub-optimal testosterone levels with prolonged human chorionic gonadotropin stimulation.
CONCLUSION
The frequency of delayed puberty in boys with DMD was 65%. Eighty-two percent of adolescent boys with DMD on daily glucocorticoid had evidence of delayed puberty. Biochemical investigations point to functional central hypogonadism in these adolescents. Our data supports the routine monitoring of puberty in boys with DMD.
PubMed: 38915199
DOI: 10.4274/jcrpe.galenos.2024.2024-2-18 -
BioDrugs : Clinical Immunotherapeutics,... Jun 2024Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs... (Review)
Review
Antisense oligonucleotides (ASOs) are single stranded nucleic acids that target RNA. The US Food and Drug Administration has approved ASOs for several diseases. ASOs utilize three principal modes of action (MOA). The first MOA is initiated by base-pairing between the ASO and its target mRNA, followed by RNase H-dependent mRNA degradation. The second MOA is triggered by ASOs that occlude splice acceptor sites in pre-mRNAs leading to skipping of a mutation-bearing exon. The third MOA involves ASOs that sterically hinder mRNA function, often inhibiting translation. ASOs contain a variety of modifications to the sugar-phosphate backbone and bases that stabilize the ASO or render them resistant to RNase activity. RNase H-dependent ASOs include inotersen and eplontersen (for hereditary transthyretin amyloidosis), fomiversen (for opportunistic cytomegalovirus infection), mipomersen (for familial hypercholesterolemia), and tofersen [for amyotrophic lateral sclerosis (ALS)]. Splice modulating ASOs include nursinersen (for spinal muscular atrophy) and eteplirsen, golodirsen, viltolarsen, and casimersen (all for the treatment of Duchenne muscular dystrophy). In addition, a designer ASO, milasen, was used to treat a single individual afflicted with Batten disease. Since ASO design relies principally upon knowledge of mRNA sequence, the bench to bedside pipeline for ASOs is expedient compared with protein-directed drugs. [Graphical abstract available.].
PubMed: 38914784
DOI: 10.1007/s40259-024-00665-2 -
Journal of Muscle Research and Cell... Jun 2024
Correction to: Validation of a novel western blot assay to monitor patterns and levels of alpha dystroglycan in skeletal muscle of patients with limb girdle muscular dystrophies.
PubMed: 38913101
DOI: 10.1007/s10974-024-09678-4 -
Iranian Journal of Public Health May 2024Plectinopathy-associated disorders are caused by mutations in the gene encoding Plectin protein. mutations cause a spectrum of diseases defined by varying degrees of...
BACKGROUND
Plectinopathy-associated disorders are caused by mutations in the gene encoding Plectin protein. mutations cause a spectrum of diseases defined by varying degrees of signs, mostly with epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and plectinopathy-related disorder is limb-girdle muscular dystrophy type 2Q (LGMD2Q). Here we report three cases with EBS-MD and LGMD2Q disorders analyzed by exome sequencing followed by mutation confirmation.
METHODS
A complete clinical examination was done by expert specialists and clinical geneticists in Next Generation Genetic polyclinic, Mashhad, Iran (NGC, years 2020_2021),. Genomic DNA was extracted and evaluated through whole-exome sequencing analysis followed by Sanger sequencing for co-segregation analysis of candidate variants.
RESULTS
We found three cases with the plectinopathy-related disease, two patients with limb-girdle muscular dystrophy type 2Q (LGMD2Q), and the other affected proband suffers from epidermolysis bullosa simplex combined with muscular dystrophy (EBS-MD) with variable zygosity mutations for . Motor development disorder and muscular dystrophy symptoms have different age onset in affected individuals. Patients with EBS demonstrated symptoms such as blistering, skin scars, neonatal-onset, and nail dystrophy.
CONCLUSION
We report plectinopathy-associated disorders to expand clinical phenotypes in different types of -related diseases. We suppose to design more well-organized research based on comprehensive knowledge about the genetic basis of plectinopathy diseases.
PubMed: 38912134
DOI: 10.18502/ijph.v53i5.15600 -
Molecular Therapy. Methods & Clinical... Jun 2024Excessive cytosolic calcium accumulation contributes to muscle degeneration in Duchenne muscular dystrophy (DMD). Sarco/endoplasmic reticulum calcium ATPase (SERCA) is a...
Excessive cytosolic calcium accumulation contributes to muscle degeneration in Duchenne muscular dystrophy (DMD). Sarco/endoplasmic reticulum calcium ATPase (SERCA) is a sarcoplasmic reticulum (SR) calcium pump that actively transports calcium from the cytosol into the SR. We previously showed that adeno-associated virus (AAV)-mediated SERCA2a therapy reduced cytosolic calcium overload and improved muscle and heart function in the murine DMD model. Here, we tested whether AAV SERCA2a therapy could ameliorate muscle disease in the canine DMD model. 7.83 × 10 vector genome particles of the AAV vector were injected into the extensor carpi ulnaris (ECU) muscles of four juvenile affected dogs. Contralateral ECU muscles received excipient. Three months later, we observed widespread transgene expression and significantly increased SERCA2a levels in the AAV-injected muscles. Treatment improved SR calcium uptake, significantly reduced calpain activity, significantly improved contractile kinetics, and significantly enhanced resistance to eccentric contraction-induced force loss. Nonetheless, muscle histology was not improved. To evaluate the safety of AAV SERCA2a therapy, we delivered the vector to the ECU muscle of adult normal dogs. We achieved strong transgene expression without altering muscle histology and function. Our results suggest that AAV SERCA2a therapy has the potential to improve muscle performance in a dystrophic large mammal.
PubMed: 38911286
DOI: 10.1016/j.omtm.2024.101268 -
Molecular Therapy : the Journal of the... Jun 2024Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had...
Dual FKRP/FST gene therapy in a single AAV normalizes ambulation, increases muscle strength, decreases muscle pathology, and amplifies gene expression in the FKRP model of LGMDR9.
Recent clinical studies of single gene replacement therapy for neuromuscular disorders have shown they can slow or stop disease progression, but such therapies have had little impact on reversing muscle disease that was already present. In order to reverse disease in patients with muscular dystrophy, new muscle mass and strength must be rebuilt at the same time that gene replacement prevents subsequent disease. Here, we show that treatment of FKRP mice with a dual FKRP/FST gene therapy packaged into a single AAV vector can build muscle strength and mass that exceed levels found in wild-type mice and can induce normal ambulation endurance in a one-hour walk test. Dual FKRP/FST therapy also showed more even increases in muscle mass and amplified muscle expression of both genes relative to either single gene therapy alone. These data suggest that treatment with a single AAV bearing dual FKRP/FST gene therapies can overcome loss of ambulation by improving muscle strength at the same time it prevents subsequent muscle damage. This design platform could be used to create therapies for other forms of muscular dystrophy that may improve patient outcomes.
PubMed: 38910327
DOI: 10.1016/j.ymthe.2024.06.028 -
Biomedicine & Pharmacotherapy =... Jun 2024Duchenne muscular dystrophy (DMD) is the most common muscular disorder affecting children. It affects nearly 1 male birth over 5000. Oxidative stress is a pervasive...
Duchenne muscular dystrophy (DMD) is the most common muscular disorder affecting children. It affects nearly 1 male birth over 5000. Oxidative stress is a pervasive feature in the pathogenesis of DMD. Recent work shows that the main generators of ROS are NADPH oxidases (NOX), suggesting that they are an early and promising target in DMD. In addition, skeletal muscles of mdx mice, a murine model of DMD, overexpress NOXes. We investigated the impact of diapocynin, a dimer of the NOX inhibitor apocynin, on the chronic disease phase of mdx mice. Treatment of these mice with diapocynin from 7 to 10 months of age resulted in decreased hypertrophy of several muscles, prevented force loss induced by tetanic and eccentric contractions, improved muscle and respiratory functions, decreased fibrosis of the diaphragm and positively regulated the expression of disease modifiers. These encouraging results ensure the potential role of diapocynin in future treatment strategies.
PubMed: 38908198
DOI: 10.1016/j.biopha.2024.116957 -
Journal of Neurology Jun 2024
PubMed: 38907024
DOI: 10.1007/s00415-024-12431-z -
International Journal of Medical... 2024Dasatinib is one of the second-generation tyrosine kinase inhibitors used to treat chronic myeloid leukemia and has a broad target spectrum, including KIT, PDGFR, and...
Dasatinib is one of the second-generation tyrosine kinase inhibitors used to treat chronic myeloid leukemia and has a broad target spectrum, including KIT, PDGFR, and SRC family kinases. Due to its broad drug spectrum, dasatinib has been reported at the basic research level to improve athletic performance by eliminating senescent cell removal and to have an effect on muscle diseases such as Duchenne muscular dystrophy, but its effect on myoblasts has not been investigated. In this study, we evaluated the effects of dasatinib on skeletal muscle both under normal conditions and in the regenerating state. Dasatinib suppressed the proliferation and promoted the fusion of C2C12 myoblasts. During muscle regeneration, dasatinib increased the gene expressions of myogenic-related genes (, , and ), and caused abnormally thin muscle fibers on the CTX-induced muscle injury mouse model. From these results, dasatinib changes the closely regulated gene expression pattern of myogenic regulatory factors during muscle differentiation and disrupts normal muscle regeneration. Our data suggest that when using dasatinib, its effects on skeletal muscle should be considered, particularly at regenerating stages.
Topics: Dasatinib; Animals; Mice; Regeneration; Cell Differentiation; Muscle Development; Muscle, Skeletal; Myoblasts; Cell Proliferation; Humans; Cell Line; Protein Kinase Inhibitors
PubMed: 38903922
DOI: 10.7150/ijms.94938