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1.
Eur J Endocrinol ; 184(1): 67-79, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33112266

RESUMO

Background: Pharmacological doses of glucocorticoids (GC) reduce inflammation and preserve muscle function in boys with Duchenne muscular dystrophy (DMD). Delayed puberty and bone fragility are consequences of GC treatment. The aim of this study was to determine the acceptability of a 2-year pubertal induction regimen using 4-weekly testosterone injections and examine changes in physique, bone integrity, muscle pathology (assessed by MRI) and muscle function. Methods: Fifteen prepubertal males with DMD, aged 12-17 years and receiving GC, were treated with an incremental testosterone regimen for 2 years. Participants completed a Treatment Satisfaction Questionnaire (TSQM). Data on BMI, bone density, muscle pathology and function were collected at baseline and 2 years later. Results: Testosterone injections were well tolerated, with high TSQM scores. Baseline BMI z-score was 2.16 (0.90) and 1.64 (1.35) 2 years later. Median testosterone levels were 9.7 nmol/L (IQR: 5.7-11.1) 6-9 months after the last injection with an associated increase in testicular volume. Lumbar spine z-score was 0.22 (s.d. 2.21) at baseline and 0.35 (s.d. 2.21) after 2 years. Upper and lower limb muscle contractile cross-sectional area increased in all participants during the trial (P = 0.05 and P < 0.01, respectively). There was a reduction in T2 relaxation times in most muscle groups with stable upper limb muscle function. Conclusion: Incremental monthly testosterone injections were well tolerated, promoted endogenous testosterone production and had a positive impact on the skeleton and contractile muscle bulk with evidence suggesting a beneficial impact on the underlying disease process.


Assuntos
Androgênios/administração & dosagem , Glucocorticoides/efeitos adversos , Distrofia Muscular de Duchenne/fisiopatologia , Puberdade Tardia/tratamento farmacológico , Testosterona/administração & dosagem , Adolescente , Índice de Massa Corporal , Densidade Óssea , Criança , Humanos , Injeções Intramusculares , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Satisfação do Paciente , Puberdade/efeitos dos fármacos , Puberdade Tardia/induzido quimicamente , Puberdade Tardia/fisiopatologia , Resultado do Tratamento
3.
Cells ; 9(12)2020 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-33322031

RESUMO

Myostatin inhibition therapy has held much promise for the treatment of muscle wasting disorders. This is particularly true for the fatal myopathy, Duchenne Muscular Dystrophy (DMD). Following on from promising pre-clinical data in dystrophin-deficient mice and dogs, several clinical trials were initiated in DMD patients using different modality myostatin inhibition therapies. All failed to show modification of disease course as dictated by the primary and secondary outcome measures selected: the myostatin inhibition story, thus far, is a failed clinical story. These trials have recently been extensively reviewed and reasons why pre-clinical data collected in animal models have failed to translate into clinical benefit to patients have been purported. However, the biological mechanisms underlying translational failure need to be examined to ensure future myostatin inhibitor development endeavors do not meet with the same fate. Here, we explore the biology which could explain the failed translation of myostatin inhibitors in the treatment of DMD.


Assuntos
Anticorpos/uso terapêutico , Distrofia Muscular de Duchenne/tratamento farmacológico , Miostatina/antagonistas & inibidores , Animais , Anticorpos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Camundongos , Músculo Esquelético/efeitos dos fármacos , Distrofia Muscular de Duchenne/genética , Falha de Tratamento
4.
Drugs Today (Barc) ; 56(8): 491-504, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33025945

RESUMO

Duchenne muscular dystrophy (DMD) is a life-shortening X-linked genetic disorder characterized by progressive wasting and weakening of muscles in boys. Loss-of-function mutations in the DMD gene, which codes for dystrophin, lead to this disease. The majority of mutations in this gene result in the exclusion of one or more exons from the transcript, eventually causing the remaining exons not to fit together correctly (i.e., out-of-frame mutations). Antisense oligonucleotides, e.g., phosphorodiamidate morpholino oligomers (PMOs), can induce therapeutic exon skipping during pre-mRNA processing to restore the reading frame of the primary transcript of DMD. As a result, truncated but partially functional dystrophin is produced, potentially slowing down the disease progression. Golodirsen is a provisionally approved PMO-based drug for approx. 8% of all DMD patients amenable to exon 53 skipping. This article summarizes golodirsen's pharmacology, efficacy and safety information. It also discusses some controversies that golodirsen met after the approval.


Assuntos
Distrofia Muscular de Duchenne/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Distrofina , Éxons , Humanos , Morfolinos/uso terapêutico , Oligonucleotídeos Antissenso/uso terapêutico
5.
PLoS Med ; 17(9): e1003222, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32956407

RESUMO

BACKGROUND: Treatment with corticosteroids is recommended for Duchenne muscular dystrophy (DMD) patients to slow the progression of weakness. However, chronic corticosteroid treatment causes significant morbidities. Vamorolone is a first-in-class anti-inflammatory investigational drug that has shown evidence of efficacy in DMD after 24 weeks of treatment at 2.0 or 6.0 mg/kg/day. Here, open-label efficacy and safety experience of vamorolone was evaluated over a period of 18 months in trial participants with DMD. METHODS AND FINDINGS: A multicenter, open-label, 24-week trial (VBP15-003) with a 24-month long-term extension (VBP15-LTE) was conducted by the Cooperative International Neuromuscular Research Group (CINRG) and evaluated drug-related effects of vamorolone on motor outcomes and corticosteroid-associated safety concerns. The study was carried out in Canada, US, UK, Australia, Sweden, and Israel, from 2016 to 2019. This report covers the initial 24-week trial and the first 12 months of the VBP15-LTE trial (total treatment period 18 months). DMD trial participants (males, 4 to <7 years at entry) treated with 2.0 or 6.0 mg/kg/day vamorolone for the full 18-month period (n = 23) showed clinical improvement of all motor outcomes from baseline to month 18 (time to stand velocity, p = 0.012 [95% CI 0.010, 0.068 event/second]; run/walk 10 meters velocity, p < 0.001 [95% CI 0.220, 0.491 meters/second]; climb 4 stairs velocity, p = 0.001 [95% CI 0.034, 0.105 event/second]; 6-minute walk test, p = 0.001 [95% CI 31.14, 93.38 meters]; North Star Ambulatory Assessment, p < 0.001 [95% CI 2.702, 6.662 points]). Outcomes in vamorolone-treated DMD patients (n = 46) were compared to group-matched participants in the CINRG Duchenne Natural History Study (corticosteroid-naïve, n = 19; corticosteroid-treated, n = 68) over a similar 18-month period. Time to stand was not significantly different between vamorolone-treated and corticosteroid-naïve participants (p = 0.088; least squares [LS] mean 0.042 [95% CI -0.007, 0.091]), but vamorolone-treated participants showed significant improvement compared to group-matched corticosteroid-naïve participants for run/walk 10 meters velocity (p = 0.003; LS mean 0.286 [95% CI 0.104, 0.469]) and climb 4 stairs velocity (p = 0.027; LS mean 0.059 [95% CI 0.007, 0.111]). The vamorolone-related improvements were similar in magnitude to corticosteroid-related improvements. Corticosteroid-treated participants showed stunting of growth, whereas vamorolone-treated trial participants did not (p < 0.001; LS mean 15.86 [95% CI 8.51, 23.22]). Physician-reported incidences of adverse events (AEs) for Cushingoid appearance, hirsutism, weight gain, and behavior change were less for vamorolone than published incidences for prednisone and deflazacort. Key limitations to the study were the open-label design, and use of external comparators. CONCLUSIONS: We observed that vamorolone treatment was associated with improvements in some motor outcomes as compared with corticosteroid-naïve individuals over an 18-month treatment period. We found that fewer physician-reported AEs occurred with vamorolone than have been reported for treatment with prednisone and deflazacort, and that vamorolone treatment did not cause the stunting of growth seen with these corticosteroids. This Phase IIa study provides Class III evidence to support benefit of motor function in young boys with DMD treated with vamorolone 2.0 to 6.0 mg/kg/day, with a favorable safety profile. A Phase III RCT is underway to further investigate safety and efficacy. TRIAL REGISTRATION: Clinical trials were registered at www.clinicaltrials.gov, and the links to each trial are as follows (as provided in manuscript text): VBP15-002 [NCT02760264] VBP15-003 [NCT02760277] VBP15-LTE [NCT03038399].


Assuntos
Atividade Motora/efeitos dos fármacos , Distrofia Muscular de Duchenne/tratamento farmacológico , Pregnadienodiois/uso terapêutico , Corticosteroides/efeitos adversos , Criança , Pré-Escolar , Progressão da Doença , Glucocorticoides/efeitos adversos , Humanos , Masculino , Prednisona/uso terapêutico , Pregnadienodiois/metabolismo , Resultado do Tratamento , Caminhada/fisiologia
6.
Neurology ; 95(10): e1381-e1391, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32611643

RESUMO

OBJECTIVE: To evaluate the suitability of real-world data (RWD) and natural history data (NHD) for use as external controls in drug evaluations for ambulatory Duchenne muscular dystrophy (DMD). METHODS: The consistency of changes in the 6-minute walk distance (Δ6MWD) was assessed across multiple clinical trial placebo arms and sources of NHD/RWD. Six placebo arms reporting 48-week Δ6MWD were identified via literature review and represented 4 sets of inclusion/exclusion criteria (n = 383 patients in total). Five sources of RWD/NHD were contributed by Universitaire Ziekenhuizen Leuven, DMD Italian Group, The Cooperative International Neuromuscular Research Group, ImagingDMD, and the PRO-DMD-01 study (n = 430 patients, in total). Mean Δ6MWD was compared between each placebo arm and RWD/NHD source after subjecting the latter to the inclusion/exclusion criteria of the trial for baseline age, ambulatory function, and steroid use. Baseline covariate adjustment was investigated in a subset of patients with available data. RESULTS: Analyses included ∼1,200 patient-years of follow-up. Differences in mean Δ6MWD between trial placebo arms and RWD/NHD cohorts ranged from -19.4 m (i.e., better outcomes in RWD/NHD) to 19.5 m (i.e., worse outcomes in RWD/NHD) and were not statistically significant before or after covariate adjustment. CONCLUSIONS: We found that Δ6MWD was consistent between placebo arms and RWD/NHD subjected to equivalent inclusion/exclusion criteria. No evidence for systematic bias was detected. These findings are encouraging for the use of RWD/NHD to augment, or possibly replace, placebo controls in DMD trials. Multi-institution collaboration through the Collaborative Trajectory Analysis Project rendered this study feasible.


Assuntos
Avaliação de Medicamentos/métodos , Distrofia Muscular de Duchenne/tratamento farmacológico , Ensaios Clínicos Pragmáticos como Assunto/métodos , Projetos de Pesquisa , Criança , Humanos , Masculino , Teste de Caminhada
8.
Artigo em Inglês | MEDLINE | ID: mdl-32707682

RESUMO

Duchenne muscular dystrophy (DMD) is a severe muscle-wasting disease. Although the lack of dystrophin protein is the primary defect responsible for the development of DMD, secondary disease complications such as persistent inflammation contribute greatly to the pathogenesis and the time-dependent progression of muscle destruction. The immunoproteasome is a potential therapeutic target for conditions or diseases mechanistically linked to inflammation. In this study, we explored the possible effects of ONX-0914 administration, an inhibitor specific for the immunoproteasome subunit LMP7 (ß5i), on motor performance, muscular pathology and protein degradation in 7-week old MDX mice, an age when the dystrophic muscles show extensive degeneration and regeneration. ONX-0914 (10 mg/kg) was injected subcutaneously on Day 2, 4, and 6. The mice were evaluated for physical performance (walking speed and strength) on Day 1 and 8. We show that this short-term treatment of ONX-0914 in MDX mice did not alter strength nor walking speed. The physical performance findings were consistent with no change in muscle inflammatory infiltration, percentage of central nuclei and proteasome content. Taken together, muscle structure and function in the young adult MDX mouse model are not altered with ONX-0914 treatment, indicating the administration of ONX-0914 during this critical time period does not exhibit any detrimental effects and may be an effective treatment of secondary complications of muscular dystrophy after further investigations.


Assuntos
Distrofina , Músculo Esquelético , Distrofia Muscular de Duchenne/tratamento farmacológico , Oligopeptídeos , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Músculo Esquelético/efeitos dos fármacos , Oligopeptídeos/farmacologia , Fenótipo , Adulto Jovem
9.
PLoS One ; 15(6): e0232870, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32555695

RESUMO

The timed 4-stair climb (4SC) assessment has been used to measure function in Duchenne muscular dystrophy (DMD) practice and research. We sought to identify prognostic factors for changes in 4SC, assess their consistency across data sources, and the extent to which prognostic scores could be useful in DMD clinical trial design and analysis. Data from patients with DMD in the placebo arm of a phase 3 trial (Tadalafil DMD trial) and two real-world sources (Universitaire Ziekenhuizen, Leuven, Belgium [Leuven] and Cincinnati Children's Hospital Medical Center [CCHMC]) were analyzed. One-year changes in 4SC completion time and velocity (stairs/second) were analyzed. Prognostic models included age, height, weight, steroid use, and multiple timed function tests and were developed using multivariable regression, separately in each data source. Simulations were used to quantify impacts on trial sample size requirements. Data on 1-year changes in 4SC were available from the Tadalafil DMD trial (n = 92) Leuven (n = 67), and CCHMC (n = 212). Models incorporating multiple timed function tests, height, and weight significantly improved prognostic accuracy for 1-year change in 4SC (R2: 29%-36% for 4SC velocity, and 29%-34% for 4SC time) compared to models including only age, baseline 4SC and steroid duration (R2:8%-17% for 4SC velocity and 2%-13% for 4SC time). Measures of walking and rising ability contributed important prognostic information for changes in 4SC. In a randomized trial with equal allocation to treatment and placebo, adjustment for such a prognostic score would enable detection (at 80% power) of a treatment effect of 0.25 stairs/second with 100-120 patients, compared to 170-190 patients without prognostic score adjustment. Combining measures of ambulatory function doubled prognostic accuracy for 1-year changes in 4SC completion time and velocity. Randomized clinical trials incorporating a validated prognostic score could reduce sample size requirements by approximately 40%. Knowledge of important prognostic factors can also inform adjusted comparisons to external controls.


Assuntos
Teste de Esforço , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Adolescente , Criança , Simulação por Computador , Progressão da Doença , Teste de Esforço/métodos , Seguimentos , Humanos , Masculino , Distrofia Muscular de Duchenne/fisiopatologia , Fármacos Neuromusculares/uso terapêutico , Prognóstico , Tamanho da Amostra , Tadalafila/uso terapêutico , Caminhada
11.
PLoS One ; 15(5): e0229753, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32407333

RESUMO

Serum activities of alanine and aspartate aminotransferases (ALT and AST) are used as gold standard biomarkers for the diagnosis of hepatocellular injury. Since ALT and AST lack liver specificity, the diagnosis of the onset of hepatocellular injury in patients with underlying muscle impairments is severely limited. Thus, we evaluated the potential of glutamate dehydrogenase (GLDH) as a liver specific alternative biomarker of hepatocellular injury. In our study, serum GLDH in subjects with Duchene muscular dystrophy (DMD) was equivalent to serum GLDH in age matched healthy subjects, while serum ALT was increased 20-fold in DMD subjects. Furthermore, serum GLDH in 131 subjects with variety of muscle impairments was similar to serum GLDH of healthy subjects while serum ALT corelated with serum creatine kinase, a widely accepted biomarker of muscle impairment. In addition, significant elevations of ALT, AST, and CK were observed in a case of a patient with rhabdomyolysis, while serum GLDH stayed within the normal range until the onset of hypoxia-induced liver injury. In a mouse model of DMD (DMDmdx), serum GLDH but not serum ALT clearly correlated with the degree of acetaminophen-induced liver injury. Taken together, our data support the utility of serum GLDH as a liver-specific biomarker of liver injury that has a potential to improve diagnosis of hepatocellular injury in patients with underlying muscle impairments. In drug development, GLDH may have utility as a biomarker of drug induced liver injury in clinical trials of new therapies to treat muscle diseases such as DMD.


Assuntos
Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Glutamato Desidrogenase/sangue , Distrofia Muscular de Duchenne/sangue , Acetaminofen/efeitos adversos , Adolescente , Adulto , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/complicações , Doença Hepática Induzida por Substâncias e Drogas/patologia , Criança , Pré-Escolar , Creatina Quinase/sangue , Modelos Animais de Doenças , Diagnóstico Precoce , Feminino , Humanos , Hipóxia/sangue , Hipóxia/complicações , Fígado/lesões , Fígado/patologia , Masculino , Camundongos , Distrofia Muscular de Duchenne/complicações , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/patologia , Rabdomiólise/sangue , Rabdomiólise/complicações , Rabdomiólise/patologia
12.
Nat Commun ; 11(1): 1990, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332749

RESUMO

Up-regulation of utrophin in muscles represents a promising therapeutic strategy for the treatment of Duchenne Muscular Dystrophy. We previously demonstrated that eEF1A2 associates with the 5'UTR of utrophin A to promote IRES-dependent translation. Here, we examine whether eEF1A2 directly regulates utrophin A expression and identify via an ELISA-based high-throughput screen, FDA-approved drugs that upregulate both eEF1A2 and utrophin A. Our results show that transient overexpression of eEF1A2 in mouse muscles causes an increase in IRES-mediated translation of utrophin A. Through the assessment of our screen, we reveal 7 classes of FDA-approved drugs that increase eEF1A2 and utrophin A protein levels. Treatment of mdx mice with the 2 top leads results in multiple improvements of the dystrophic phenotype. Here, we report that IRES-mediated translation of utrophin A via eEF1A2 is a critical mechanism of regulating utrophin A expression and reveal the potential of repurposed drugs for treating DMD via this pathway.


Assuntos
Distrofia Muscular de Duchenne/tratamento farmacológico , Fator 1 de Elongação de Peptídeos/antagonistas & inibidores , Biossíntese de Proteínas/efeitos dos fármacos , Utrofina/genética , Regiões 5' não Traduzidas/genética , Animais , Betaxolol/farmacologia , Betaxolol/uso terapêutico , Linhagem Celular , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Humanos , Sítios Internos de Entrada Ribossomal/genética , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Distrofia Muscular de Duchenne/genética , Mioblastos , Fator 1 de Elongação de Peptídeos/genética , Fator 1 de Elongação de Peptídeos/metabolismo , Pravastatina/farmacologia , Pravastatina/uso terapêutico , Biossíntese de Proteínas/genética , Regulação para Cima/efeitos dos fármacos , Utrofina/metabolismo
13.
Sci Adv ; 6(6): eaaz2736, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32128386

RESUMO

Duchenne muscular dystrophy (DMD) is a devastating disease caused by mutations in dystrophin that compromise sarcolemma integrity. Currently, there is no treatment for DMD. Mutations in transient receptor potential mucolipin 1 (ML1), a lysosomal Ca2+ channel required for lysosomal exocytosis, produce a DMD-like phenotype. Here, we show that transgenic overexpression or pharmacological activation of ML1 in vivo facilitates sarcolemma repair and alleviates the dystrophic phenotypes in both skeletal and cardiac muscles of mdx mice (a mouse model of DMD). Hallmark dystrophic features of DMD, including myofiber necrosis, central nucleation, fibrosis, elevated serum creatine kinase levels, reduced muscle force, impaired motor ability, and dilated cardiomyopathies, were all ameliorated by increasing ML1 activity. ML1-dependent activation of transcription factor EB (TFEB) corrects lysosomal insufficiency to diminish muscle damage. Hence, targeting lysosomal Ca2+ channels may represent a promising approach to treat DMD and related muscle diseases.


Assuntos
Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Canais de Receptores Transientes de Potencial/agonistas , Animais , Biomarcadores , Biópsia , Modelos Animais de Doenças , Distrofina/genética , Imunofluorescência , Expressão Gênica , Camundongos , Camundongos Endogâmicos mdx , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Distrofia Muscular de Duchenne/patologia , Miocárdio/metabolismo , Miocárdio/patologia
14.
Neurology ; 94(15): e1622-e1633, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32184340

RESUMO

OBJECTIVE: To quantify disease progression in individuals with Duchenne muscular dystrophy (DMD) using magnetic resonance biomarkers of leg muscles. METHODS: MRI and magnetic resonance spectroscopy (MRS) biomarkers were acquired from 104 participants with DMD and 51 healthy controls using a prospective observational study design with patients with DMD followed up yearly for up to 6 years. Fat fractions (FFs) in vastus lateralis and soleus muscles were determined with 1H MRS. MRI quantitative T2 (qT2) values were measured for 3 muscles of the upper leg and 5 muscles of the lower leg. Longitudinal changes in biomarkers were modeled with a cumulative distribution function using a nonlinear mixed-effects approach. RESULTS: MRS FF and MRI qT2 increased with DMD disease duration, with the progression time constants differing markedly between individuals and across muscles. The average age at half-maximal muscle involvement (µ) occurred 4.8 years earlier in vastus lateralis than soleus, and these measures were strongly associated with loss-of-ambulation age. Corticosteroid treatment was found to delay µ by 2.5 years on average across muscles, although there were marked differences between muscles with more slowly progressing muscles showing larger delay. CONCLUSIONS: MRS FF and MRI qT2 provide sensitive noninvasive measures of DMD progression. Modeling changes in these biomarkers across multiple muscles can be used to detect and monitor the therapeutic effects of corticosteroids on disease progression and to provide prognostic information on functional outcomes. This modeling approach provides a method to transform these MRI biomarkers into well-understood metrics, allowing concise summaries of DMD disease progression at individual and population levels. CLINICALTRIALSGOV IDENTIFIER: NCT01484678.


Assuntos
Biomarcadores/análise , Perna (Membro)/fisiopatologia , Músculo Esquelético/patologia , Distrofia Muscular de Duchenne/fisiopatologia , Adolescente , Corticosteroides/metabolismo , Corticosteroides/farmacologia , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Perna (Membro)/patologia , Imagem por Ressonância Magnética/métodos , Espectroscopia de Ressonância Magnética/métodos , Masculino , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Distrofia Muscular de Duchenne/diagnóstico , Distrofia Muscular de Duchenne/tratamento farmacológico , Caminhada/fisiologia
15.
Neurology ; 94(21): e2270-e2282, 2020 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-32139505

RESUMO

OBJECTIVE: To report safety, pharmacokinetics, exon 53 skipping, and dystrophin expression in golodirsen-treated patients with Duchenne muscular dystrophy (DMD) amenable to exon 53 skipping. METHODS: Part 1 was a randomized, double-blind, placebo-controlled, 12-week dose titration of once-weekly golodirsen; part 2 is an ongoing, open-label evaluation. Safety and pharmacokinetics were primary and secondary objectives of part 1. Primary biological outcome measures of part 2 were blinded exon skipping and dystrophin protein production on muscle biopsies (baseline, week 48) evaluated, respectively, using reverse transcription PCR and Western blot and immunohistochemistry. RESULTS: Twelve patients were randomized to receive golodirsen (n = 8) or placebo (n = 4) in part 1. All from part 1 plus 13 additional patients received 30 mg/kg golodirsen in part 2. Safety findings were consistent with those previously observed in pediatric patients with DMD. Most of the study drug was excreted within 4 hours following administration. A significant increase in exon 53 skipping was associated with ∼16-fold increase over baseline in dystrophin protein expression at week 48, with a mean percent normal dystrophin protein standard of 1.019% (range, 0.09%-4.30%). Sarcolemmal localization of dystrophin was demonstrated by significantly increased dystrophin-positive fibers (week 48, p < 0.001) and a positive correlation (Spearman r = 0.663; p < 0.001) with dystrophin protein change from baseline, measured by Western blot and immunohistochemistry. CONCLUSION: Golodirsen was well-tolerated; muscle biopsies from golodirsen-treated patients showed increased exon 53 skipping, dystrophin production, and correct dystrophin sarcolemmal localization. CLINICALTRIALSGOV IDENTIFIER: NCT02310906. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that golodirsen is safe and Class IV evidence that it induces exon skipping and novel dystrophin as confirmed by 3 different assays.


Assuntos
Distrofina/biossíntese , Distrofia Muscular de Duchenne/tratamento farmacológico , Administração Intravenosa , Adolescente , Criança , Relação Dose-Resposta a Droga , Método Duplo-Cego , Distrofina/genética , Imunofluorescência , Humanos , Masculino , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/sangue , Distrofia Muscular de Duchenne/genética , Deleção de Sequência/efeitos dos fármacos
16.
Expert Opin Pharmacother ; 21(7): 841-851, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32133879

RESUMO

INTRODUCTION: Duchenne muscular dystrophy (DMD) is the result of X-chromosome-linked mutations to the dystrophin protein gene that prevent the normal development and repair of muscles leading to muscle deterioration. The condition affects nearly 1 in 3,500 males worldwide. Current therapeutics have not been sufficient in providing a cure or resulting in a significant extension in life expectancy, but many therapeutic options are currently under investigation. AREAS COVERED: This article provides an overview of the current and emerging therapies for DMD giving particular focus to synthetic therapeutic options. The authors further provide their expert opinion. EXPERT OPINION: Many discrepancies in primary outcomes of trials have led to questions of efficacy for medications, as well as difficulty in securing FDA approval. A standardization of primary outcome strategies, as well as better access to investigational medications, may alleviate some of the controversy and pressures that exist on medication approvals. Many trials have identified cohorts who responded more favorably to medications, despite a lack of significance in the overall intent-to-treat populations. This indicates that more medication screening and personalized treatment with patient-specific targeting might deliver more clinically significant results.


Assuntos
Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Drogas em Investigação/uso terapêutico , Distrofina/genética , Distrofia Muscular de Duchenne/tratamento farmacológico , Animais , Ensaios Clínicos como Assunto , Terapia Genética , Humanos , Masculino , Distrofia Muscular de Duchenne/genética , Mutação , Transplante de Células-Tronco
18.
Drugs ; 80(3): 329-333, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32026421

RESUMO

Golodirsen (Vyondys 53™), an antisense oligonucleotide of the phophorodiamidate morpholino oligomer (PMO) subclass designed to induce exon 53 skipping, has been developed by Sarepta Therapeutics for the treatment of Duchenne muscular dystrophy (DMD). In December 2019, intravenous golodirsen received its first global approval in the USA for the treatment of DMD in patients with a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, based on positive results from a phase I/II clinical trial. Golodirsen is in phase III clinical development for the treatment of DMD worldwide. This article summarizes the milestones in the development of golodirsen leading to this first approval for DMD.


Assuntos
Aprovação de Drogas , Distrofia Muscular de Duchenne/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Desenvolvimento de Medicamentos , Humanos , Distrofia Muscular de Duchenne/genética , Oligonucleotídeos/administração & dosagem
19.
Clin Chim Acta ; 505: 92-97, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32070725

RESUMO

INTRODUCTION: Carnitine is essential for long-chain fatty acid oxidation in muscle and heart. Tissue stores are regulated by organic cation/Cn transporter plasmalemmal Octn2. We previously demonstrated low carnitine in quadriceps/gluteus and heart of adult mdx mice. METHODS: We studied protein and mRNA expression of Octn2, mitochondrial Octn1 and peroxisomal Octn3 in adult male C57BL/10ScSn-DMD mdx/J quadriceps, heart, and diaphragm compared to C57BL/10SnJ mice. RESULTS: We demonstrated reduction in mOctn2 expression on Western blot and similar expression of mOctn1 and mOctn3 in mdx quadriceps, heart and diaphragm. There was a significant upregulation of mOctn1 and mOctn2 mRNA by qRT-PCR in mdx quadriceps and of mOctn2 and mOctn3 mRNA in mdx heart. We showed upregulation of mdx mOctn1 and mOctn3 mRNA but no increase in protein expression. DISCUSSION: Dystrophin deficiency likely disrupts Octn2 expression decreasing muscle carnitine uptake thus contributing to membranotoxic long-chain acyl-CoAs with sarcolemmal and organellar membrane oxidative injury providing a treatment rationale for early L-carnitine in DMD.


Assuntos
Carnitina/química , Carnitina/uso terapêutico , Músculo Esquelético/química , Distrofia Muscular de Duchenne/tratamento farmacológico , Distrofia Muscular de Duchenne/genética , Miocárdio/química , Proteínas de Transporte de Cátions Orgânicos/biossíntese , Proteínas de Transporte de Cátions Orgânicos/genética , Membro 5 da Família 22 de Carreadores de Soluto/biossíntese , Membro 5 da Família 22 de Carreadores de Soluto/genética , Simportadores/biossíntese , Simportadores/genética , Animais , Carnitina/metabolismo , Diafragma/metabolismo , Homeostase , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Miocárdio/metabolismo , RNA Mensageiro/biossíntese , RNA Mensageiro/genética
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