Coréia do Sul – o salto de exon é uma das tecnologias promissoras para o tratamento da distrofia muscular de Duchenne, restaurando a distrofina, que é um dos componentes do músculo. O losartan, um bloqueador do receptor tipo 1 da angiotensina II, promove a diferenciação e regeneração muscular, baixando o nível de transformação de sinalização do fator de crescimento beta 1. Neste estudo os autores testaram a terapia combinada, sendo o losartan adminstrado duas semanas antes do salto de exon. Os resultados confirmaram os efeitos positivos do losartan promovendo a regeneração muscular encurtando o tempo de restabelecimento da estrutura muscular normal. No entanto, o tratamento combinado de salto de exon e o losartan diminuiu o restabelecimento da distrofina o que significa diminuição da eficiëncia do salto de exon.
Leia mais informações aqui.
França – arginina butirato é um composto atualmente utilizado para o tratamento da anemia falciforme em crianças, na cardiomiopatia, na deformação da coluna vertebral e em alterações eletromiográficas. O tratamento de camundongos com arginina butirato por via oral causou melhora da função cardíaca com redução da CK. Houve redução do grau da cifose. A arginina butirato é uma droga promissora para tratamento da distrofia muscular. Leia mais informações aqui. Fonte: http://distrofiamuscular.net/principal.htm
Japão – efeitos ruins da dieta rica em fósforo e da sobrecarga de fósforo foram descritos em várias doenças, o que motivou seu estudo em camundongos com distrofia muscular; os estudos demonstraram que a ingestão excessiva de fósforo e a sua sobrecarga acarretam piora das alterações patológicas dos músculos distróficos e a redução da ingestão de fósforo melhoraram as características dos músculos.
O resumo em inglês pode ser lido abaixo:
(The American Journal of Pathology,2014) Dietary Phosphorus Overload Aggravates the Phenotype of the Dystrophin-Deficient mdx mouse
Eiji Wada, Mizuko Yoshida, Yoriko Kojima, Ikuya Nonaka, Kazuya Ohashi, Yosuke Nagata, Masataka Shiozuka, Munehiro Date, Tetsuo Higashi, Ichizo Nishino, Ryoichi Matsuda – Japan
Duchenne muscular dystrophy is a lethal X-linked disease with no effective treatment. Progressive muscle degeneration, increased macrophage infiltration, and ectopic calcification are characteristic features of the mdx mouse, a murine model of Duchenne muscular dystrophy. Because dietary phosphorus/phosphate consumption is increasing and adverse effects of phosphate overloading have been reported in several disease conditions, we examined the effects of dietary phosphorus intake in mdx mice phenotypes. On weaning, control and mdx mice were fed diets containing 0.7, 1.0, or 2.0 g phosphorus per 100 g until they were 90 days old. Dystrophic phenotypes were evaluated in cryosections of quadriceps and tibialis anterior muscles, and maximal forces and voluntary activity were measured. Ectopic calcification was analyzed by electron microscopy to determine the cells initially responsible for calcium deposition in skeletal muscle. Dietary phosphorus overload dramatically exacerbated the dystrophic phenotypes of mdx mice by increasing inflammation associated with infiltration of M1 macrophages. In contrast, minimal muscle necrosis and inflammation were observed in exercised mdx mice fed a low-phosphorus diet, suggesting potential beneficial therapeutic effects of lowering dietary phosphorus intake on disease progression. To our knowledge, this is the first report showing that dietary phosphorus intake directly affects muscle pathological characteristics of mdx mice. Dietary phosphorus overloading promoted dystrophic disease progression in mdx mice, whereas restricting dietary phosphorus intake improved muscle pathological characteristics and function.
2. Ensaios clínicos em distrofia muscular de Duchenne e Becker: neste congresso serão apresentadas as pesquisas com 5 drogas que já estão em testes em pacientes com Duchenne e Becker com resultados promissores.
3. Estudos experimentais em distrofia muscular de Duchenne: pesquisas experimentais em camundongos com distrofia muscular,envolvendo terapia gênica ou drogas que poderão ser utilizadas no futuro em distrofia muscular.
4. Estudos clínicos sobres ossos, rins e intestino em Distrofia Muscular de Duchenne: osteoporose e constipação são problemas comuns em distrofia muscular de Duchenne; a doença muscular dificulta a avaliação da função renal; fraturas e suas complicações são problemas igualmente comuns. Neste congresso serão apresentados estudos referentes a estes problemas.
USA – amitriptilina é um antidepressivo ainda bastante utilizado. O uso desta droga em camundongos com distrofia muscular causou redução da inflamação dos músculos e redução da ansiedade e depressão com aumento da quantidade de serotonina no sistema nervoso central.
Leia mais informações aqui.
A pesquisa de fase 3, multicêntrica, que objetiva avaliar a eficácia do medicamento da PTC (Ataluren), em um ensaio clínico de 48 meses de duração em um grupo grande de meninos com Distrofia Muscular de Duchenne foi autorizada pelos órgão regulatórios nacionais (CONEP, ANVISA, e Comitês de Ética em Pesquisa locais). A inclusão de pacientes no mundo todo se encerra na próxima semana e no Brasil contamos com a participação de equipe de pesquisa na cidade de São Paulo (USP) e na cidade do Rio de Janeiro (IPPMG/UFRJ).
Esta substância se mostrou capaz de modificar a produção da proteína chamada distrofina. Esta proteína é ausente em todos os meninos com a Distrofia Muscular de Duchenne. No entanto existem diferentes alterações do gene da distrofina que geram a perda da produção desta proteína. A substância em teste atua apenas nos casos daqueles que tem como alteração genética as mutações de ponto que geram um codon de parada. Portanto casos que tenham deleção ou duplicação do gene da distrofina não tem benefício com a substância e não são incluídos na pesquisa.
Fazem parte dos critérios de inclusão para este estudo a comprovação desta alteração genética (presença de mutação determinando codon de parada) pelo exame chamado de sequenciamento genético, ter idade entre 7 e 16 anos, estar andando, em uso de corticoide em alguns esquemas específicos há mais de 6 meses de forma estável (sem mudança de dose ou forma de administração).
Diane M. Goetz | Senior Director, Patient and Professional Advocacy | PTC Therapeutics
USA – os autores já tinham demonstrado que em cultura de células de distrofia muscular os oligonucleotídeos tinham a capacidade corrigir o defeito genético. Nesta pesquisa as células satélites musculares corrigidas em laboratório foram injetadas em camundongos com distrofia muscular. Os resultados mostraram a expressão progressiva da distrofina e melhora das alterações patológicas musculares. O método se mostrou viável e permitiria corrigir as células do próprio paciente, evitando reações imunológicas.
O resumo em inglês pode ser lido abaixo:
(Stem Cells, 2014;32(7): 1817-30) Ex Vivo Gene Editing of the Dystrophin Gene in Muscle Stem Cells Mediated by Peptide Nucleic Acid Single Stranded Oligodeoxynucleotides Induces Stable Expression of Dystrophin in a Mouse Model for Duchenne Muscular Dystrophy
Farnoosh Nik-Ahd and Carmen Bertoni – USA
Duchenne muscular dystrophy (DMD) is a fatal disease caused by mutations in the dystrophin gene, which result in the complete absence of dystrophin protein throughout the body. Gene correction strategies hold promise to treating DMD. Our laboratory has previously demonstrated the ability of peptide nucleic acid single-stranded oligodeoxynucleotides (PNA-ssODNs) to permanently correct single-point mutations at the genomic level. In this study, we show that PNA-ssODNs can target and correct muscle satellite cells (SCs), a population of stem cells capable of self-renewing and differentiating into muscle fibers. When transplanted into skeletal muscles, SCs transfected with correcting PNA-ssODNs were able to engraft and to restore dystrophin expression. The number of dystrophin-positive fibers was shown to significantly increase over time. Expression was confirmed to be the result of the activation of a subpopulation of SCs that had undergone repair as demonstrated by immunofluorescence analyses of engrafted muscles using antibodies specific to full-length dystrophin transcripts and by genomic DNA analysis of dystrophin-positive fibers. Furthermore, the increase in dystrophin expression detected over time resulted in a significant improvement in muscle morphology. The ability of transplanted cells to return into quiescence and to activate upon demand was confirmed in all engrafted muscles following injury. These results demonstrate the feasibility of using gene editing strategies to target and correct SCs and further establish the therapeutic potential of this approach to permanently restore dystrophin expression into muscle of DMD patients.
Irlanda e USA – a amitriptilina é um depressivo antigo mas ainda bastante utilizado. Camundongos com distrofia muscular tem um grau de ansiedade maior que os camundongos controles. Nesta pesquisa os autores observaram que o tratamento com amitriptilina melhora o humor dos camundongos com distrofia muscular. Além disso ocorreu uma redução das citocinas inflamatórias nos músculos e no sistema nervoso central.
O resumo em inglês desta pesquisa pode ser lido abaixo:
(Exp Physiol, Jun 2014) Amitriptyline is efficacious in ameliorating muscle inflammation and depressive symptoms in the mdx mouse model of Duchenne muscular dystrophy
Jennifer Manning, Rebecca Kulbida, Prerana Rai, Lindsay Jensen, Judith Bouma, Sanjay P. Singh, Dervla O’Malley, and Deniz Yilmazer-Hanke – Ireland and USA
Mutations in the structural protein dystrophin underlie muscular dystrophies characterized by progressive deterioration of muscle function. Dystrophin deficient mdx mice are considered a model for Duchenne Muscular Dystrophy (DMD). DMD sufferers are also susceptible to mood disorders such as depression and anxiety. Therefore, the study objectives are to investigate the effects of the tricyclic antidepressant, amitriptyline on mood, learning, central cytokine expression and skeletal muscle inflammation in mdx mice. Amitriptyline‐induced effects (10 mg kg−1 daily SC injections, 25 days) on the behaviour of mdx mice were investigated using the open field arena and tail suspension tests. The effects of chronic amitriptyline treatment on inflammatory markers were studied in the muscle and plasma of mdx mice and mood‐associated monoamine and cytokine concentrations were measured in the amygdala, hippocampus, prefrontal cortex, striatum, hypothalamus and midbrain. Mdx mice exhibited increased levels of anxiety and depressive‐like behaviour compared to wild‐type mice. Amitriptyline‐treatment had anxiolytic and anti‐depressant effects in mdx mice associated with elevations in serotonin levels in the amygdala and hippocampus. Inflammation in mdx skeletal muscle tissue was also reduced following amitriptyline treatment as indicated by decreased immune cell infiltration of muscle and lower levels of the pro‐inflammatory cytokines tumour necrosis factor‐alpha (TNF‐α) and interleukin‐6 (IL‐6) in the forelimb flexors. IL‐6 mRNA expression was remarkably reduced in the amygdala of mdx mice by chronic amitriptyline treatment. Positive effects of amitriptyline on mood, in addition to its anti‐inflammatory effects in skeletal muscle, may make it an attractive therapeutic option for individuals with DMD.
Dinamarca – estudos experimentais demonstraram que o sildenafil, indicado para disfunção erétil, pode melhorar a força muscular, melhorar a oxigenação dos músculos, melhorar a função cardíaca entre outras ações. Nesta pesquisa 16 pacientes com Becker foram tratados com sildenafil e não apresentaram nenhuma melhora tanto na força muscular quanto na função cardíaca. Os pacientes não apresentaram efeitos colaterais.
O resumo em inglês do artigo pode ser lido abaixo:
(Annals of Neurology, 2014) Effect of sildenafil on skeletal and cardiac muscle in Becker muscular dystrophy
N Witting, C Kruuse, B Nyhuus, KP Prahm, G Citirak, SJ Lundgaard, S von Huth, N Vejlstrup, U Lindberg, TO Krag and J Vissing – Dennark
Background; patients with Becker and Duchenne muscular dystrophies, (BMD and DMD) lack neuronal nitric oxide synthase (nNOS). nNOS mediates physiological sympatholysis, thus ensuring adequate blood supply to working muscle. In mice lacking dystrophin, restoration of nNOS effects by a phosphodiesterase 5 (PDE5) inhibitor (sildenafil), improves skeletal and cardiac muscle performance. Sildenafil also improves blood flow in patients with BMD. We therefore hypothesized that sildenafil would improve blood flow, maximal work capacity and heart function in patients with BMD.
Methods; a randomised, double-blind, placebo-controlled crossover design with two 4-week periods of treatment, separated by 2-week wash-out was used. We assessed brachial artery blood flow during maximal handgrip exercise, six minutes walk test, maximal oxidative capacity, life quality, and cardiac function was evaluated by MRI at rest and during maximal handgrip exercise. Muscle nNOS and PDE5 was tested with western blotting in 5 patients
Findings; sixteen patients completed all skeletal muscle evaluations and 13 the cardiac MRI investigations. Sildenafil had no effect on any of the outcome parameters. No serious adverse effects were recorded. PDE5 and nNOS were deficient in 5/5 biopsies
Interpretation; despite positive evidence from animal models of dystrophinopathy and physiological findings in patients with BMD, this double-blind, placebo-controlled clinical study showed no effect of sildenafil on blood flow, maximal work capacity and heart function in adults with BMD. This discrepancy may be explained by a significant down-regulation of PDE5 in muscle.
USA – estudos experimentais demonstraram que o sildenafil, indicado para disfunção erétil pode causar melhora da função cardíaca e muscular na distrofia de Duchenne/ Becker. Neste estudo com 15 pacientes os resultados sugeriam uma piora da função cardíaca e a pesquisa foi interrompida. Apesar do número pequeno de pessoas neste estudo o resultado com o uso de sildenafil foi negativo.
O resumo em inglês pode ser lido abaixo:
Objective: Duchenne and Becker muscular dystrophy (DBMD) are allelic disorders caused by mutations in dystrophin. Adults with DBMD develop life-threatening cardiomyopathy. Inhibition of phosphodiesterase 5 (PDE5) improves cardiac function in mouse models of DBMD. To determine if the PDE5-inhibitor sildenafil benefits human dystrophinopathy, we conducted a randomized, double-blind, placebo-controlled trial (ClinicalTrials.gov, number NCT01168908).
Methods: Adults with DBMD and cardiomyopathy (ejection fraction ≤50%) were randomized to receive sildenafil (20mg three times daily) or placebo for 6 months. All subjects received an additional 6 months of open-label sildenafil. The primary endpoint was change in left ventricular end-systolic volume (LVESV) on cardiac MRI. Secondary cardiac endpoints, skeletal muscle function, and quality of life were also assessed.
Results: An interim analysis (performed after 15 subjects completed the blinded phase) revealed that 29% (4/14) of subjects had a ≥10% increase in LVESV after 6 months of sildenafil compared to 13% (1/8) of subjects receiving placebo. Subjects with LVESV >120ml at baseline were more likely to worsen at 12 months regardless of treatment assignment (p=0.035). Due to the higher number of subjects worsening on sildenafil, the Data and Safety Monitoring Board recommended early termination of the study. There were no statistically significant differences in outcome measures between treatment arms.
Interpretation: Due to the small sample size, comparisons between groups must be interpreted with caution. However, this trial suggests that sildenafil is unlikely to improve cardiac function in adults with DBMD.
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11 de fevereiro de 2020