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PETIÇÃO DO PTC-124

• Em busca de uma solução: sem verbas suficientes, associação deve encerrar pesquisas (31/10/09)
• Uso de oligonucleotídeos para a tratamento da distrofia muscular em um modelo de camundongo severamente afetado (25/10/2009)

Inglaterra - os autores utilizaram os oligonucleotídeos por via sistêmica em camundongos com ausência de distrofina/utrofina; este camundongo tem fraqueza muscular e alterações da coluna, com sintomas muito severos. Neste experimento o tratamento melhorou todos os músculos exceto o coração. Os animais ficaram com características de camundongos normais como pode ser visto no vídeo. O resumo em inglês do trabalho pode ser lido abaixo:

(Mol.Ther, 2009) Prevention of Dystrophic Pathology in Severely Affected Dystrophin/Utrophin-deficient Mice by Morpholino-oligomer-mediated Exon-skipping

Aurélie Goyenvalle1, Arran Babbs1, Dave Powell1, Ryszard Kole2, Sue Fletcher3, Steve D Wilton3 and Kay E Davies1
1MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK;
2AVI Biopharma, Corvallis, Oregon, USA;
3Center for Neuromuscular and Neurological Disorders, University of Western Australia, Perth, Western Australia,

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder caused by mutations in the dystrophin gene that result in the absence of functional protein.  Antisense-mediated exon-skipping is one of the most promising approaches for the treatment of DMD because of its capacity to correct the reading frame and restore dystrophin expression, which has been demonstrated in vitro and in vivo. In particular, peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) have recently been shown to induce widespread high levels of dystrophin expression in the mdx mouse model. Here, we report the effciency of the PPMO-mediated exon-skipping approach in the utrophin/dystrophin double-knockout mouse (dKO) mouse, which is a much more severe and progressive mouse model of DMD. Repeated intraperitoneal (i.p.) injections of a PPMO targeted to exon 23 of dystrophin pre-mRNA in dKO mice induce a near-normal level of dystrophin expression in all muscles examined, except for the cardiac muscle, resulting in a considerable improvement of their muscle function and dystrophic pathology. These fndings suggest great potential for PPMOs in systemic treatment of the DMD phenotype.

• Prevalência e impacto psicosocial dos sintomas do trato urinário baixo em pacientes com distrofia muscular de Duchenne (25/10/09)

Holanda - pacientes com Duchenne relatam sintomas do trato urinário em suas consultas para fisioterapia. Os autores decidiram enviar um cartão postal com um questionário sobre sintomas urinários De 199 pacientes com a doença, 170 (85%) apresentam sintomas urinários. Geralmente gotejamento pós-micional, esforço e sensação de incompleto esvaziamento da bexiga são os mais frequentes. 42% dos pacientes consideram estes sintomas como um problema e e 29% consideram que ele piora a qualidade de vida. O resumo em inglês pode ser lido abaixo:

(Neuromuscular Disorders 19 (2009) 754–758) Prevalence and psychosocial impact of lower urinary tract symptoms in patients with Duchenne muscular dystrophy

Evaline van Wijk,  Bert J. Messelink, Lily Heijnen, Imelda J.M. de Groot - The Netherlands

Patients with Duchenne muscular dystrophy (DMD) frequently report lower urinary tract symptoms at the outpatient rehabilitation clinic. The purpose of this study was to determine the prevalence of lower urinary tract symptoms in the Dutch male DMD population and their effect on quality of life. A postal questionnaire was sent to members of Dutch DMD patient organisations. 199 male patients with con-.rmed DMD and over the age of 3 years were included. 170/199 (85%) patients reported one or more lower urinary tract symptoms. Generally, post micturition dribble, straining and feeling of incomplete emptying were most frequently mentioned. 42% of patients (range 18–76%) experienced the symptoms as a problem. In 49/170 (29%) patients, it reduced quality of life. In conclusion, lower urinary tract symptoms in DMD patients are under reported and under diagnosed. However, the vast majority of male DMD patients with symptoms experience them as a problem, often reducing quality of life. 

• Droga aumenta a regeneração de músculos de camundongos com distrofia muscular (24/10/09)

Itália - nesta pesquisa os autores estudaram um novo método de avaliação da membrana muscular de camundongos com distrofia muscular. Com este objetivo eles trataram os animais com molsidomine, um droga doadora de óxido nítrico, utilizada em doenças cardíacas (a droga não é utilizada no Brasil). Eles observaram uma melhora da membrana muscular que foi confirmada com menor grau de degeneração muscular e sinais de regeneração. O molsidomine já tinha sido testado em camundongos com distrofia muscular há alguns anos atrás, também com bons resultados. O resumo em inglês pode ser lido abaixo:

(Neurobiology of Disease, 2009; 36 (2): 252-258) MALDI reveals membrane lipid profile reversion in MDX mice

Farida Benabdellah, Hua Yu, Alain Brunelle, Olivier Laprévote, Sabine De La Porte  - France

Duchenne muscular dystrophy (DMD), the most common and severe X-linked myopathy, is characterized by the lack of dystrophin, a sub-sarcolemmal protein necessary for normal muscle functions. In a previous study of the lipid content of skeletal muscles of dystrophic (mdx) mice, the animal model for DMD, by in situ Matrix-Assisted Laser Desorption-Ionization Mass Spectrometry (MALDI-MS), an inversion of the phosphatidylcholine PC34:2/PC34:1 ion peaks intensity ratio was observed between destructured (abnormal fiber morphology) and structured (normal fiber morphology). A possible treatment for this dramatic disease is to introduce an exogenous nitric oxide (NO) donor into the organism, leading to an increase of utrophin and a regression of the dystrophic phenotype. In the present work, after confirmation by tandem mass spectrometry of the structure of these two phospholipids, their intensity ratio inversion was used to evidence a restoration of membrane lipid composition very similar to those of wild-type mice after the treatment of mdx mice with MOLSIDOMINE, a NO donor. This was associated with the observation by immunohistology of an increase of the regeneration process in the mice.

• Atualização sobre o uso de corticóides na distrofia muscular de Duchenne (24/10/2009)

Brasil -  revisão sobre as recentes pesquisas com o uso de corticóides em distrofia muscular de Duchenne.

• Caminho tortuoso até a Paulista (24/10/09)

São Paulo - texto de Leonardo Feder sobre as dificuldades de acessibilidade na cidade de São Paulo. Leia mais em "O desafio de Leonardo Feder nas ruas de São Paulo", "Ser cadeirante em São Paulo é um desafio" e " "Pessoa com  deficiência" não é deficiente".

• Células tronco mesenquimais como anti-inflamatórias: implicações para o tratamento da distrofia muscular de Duchenne (20/10/09)

USA - os autores fazem uma revisão das propriedades anti-inflamatórias das células tronco mesenquimais e a possibilidade de sua utilização na distrofia muscular de Duchenne; nesta forma da doença os cortícóides, que são anti-inflamatórios, são a melhor opção de tratamento. No meio da revisão eles descrevem um caso de Duchenne com 23 anos e que recebeu tratamento com células tronco de três origens diferentes (endometrial, cordão umbilical e placentária) por via venosa e intramuscular. Com este tratamento houve melhora da força dos membros superiores e pescoço, melhora da função pulmonar, redução do número de infecções respiratórias, ganho de peso e aumento da expressão da distrofina (acima de 50%). Não é um estudo clínico e nem há uma observação independente mas os resultados neste caso foram surpreendentes. O resumo em inglês e parte do artigo pode ser lido abaixo:

(Cellular Immunology, 2009) Mesenchymal Stem Cells as Anti-inflammatories: Implications for Treatment of Duchenne Muscular Dystrophy

1Thomas E. Ichim, 2Doru T. Alexandrescu, 3Fabio Solano, 3Fabian Lara, 4Rosalia De Necochea Campion, 5Eugenia Paris, 6Erik J Woods, 7Michael P Murphy, 8Constantin A Dasanu, 9Amit N Patel, 10Annette M Marleau, 1*Neil H. Riordan

1Medistem Inc, San Diego, USA; 2Georgetown Dermatology, Washington DC, USA;3Institute for Cellular Medicine, Panama City, Panama; 4University of California, San Diego, California; 5Hospital CIMA, San Jose, Costa Rica; 6General Biotechnology, Indianapolis, Indiana; 7Division of Medicine, Indiana University School of Medicine, Indiana, USA; 8Department of Hematology and Medical Oncology, St Francis Hospital and Medical Center, Hartford, CT; 9Dept of Cardiothoracic Surgery, University of Utah, Salt Lake City, Utah, USA; 10Department of Surgery, University of Nebraska Medical Centre, Omaha Nebraska

Duchenne muscular dystrophy (DMD) is a lethal X-linked musculodegenerative condition consisting of an underlying genetic defect whose manifestation is augmented by inflammatory mechanisms. Previous treatment approaches using gene replacement, exon-skipping or allogeneic cell therapy have been relatively unsuccessful. The only intervention to mediate improvement in survival, albeit minor, is glucocorticoid treatment. Given this modality appears to function via suppression of underlying inflammation; we focus this review on the inflammatory response as a target for mesenchymal stem cell (MSC) therapy. In contrast to other cell based therapies attempted in DMD, MSC have the advantages of: a) ability to fuse with and genetically complement dystrophic muscle; b) possess anti-inflammatory activities; and c) produce trophic factors that may augment activity of endogenous repair cells. We conclude by describing one practical scenario of stem cell therapy for DMD.

...."Case Report of Stem Cell Therapy for DMD

We report a case study of a 23 year old male diagnosed with DMD at age 3, who manifested a progressive decrease in muscular strength and became wheelchair bound at age of 12. Supportive treatment with intermittent courses of prednisone, pain management, along with physical therapy was provided. Frequent respiratory infections secondary to a poor respiratory effort with decrease clearance of the secretions were managed with standard antibiotic therapy. On August 5-14th, 2008, the patient was treated with a combination of ERC and CD34 umbilical cord blood, mixed lymphocyte reaction-matched positive cells,subsequently on November 25-28, the patient received another course of therapy including placental matrix derived mesenchymal stem cells (Table 1). Cells were prepared and administered as previously described by us [148, 149]. No adverse events were associated with the stem cell infusion. A significant increase in muscle strength occurred in all the muscle groups, and was accompanied by an increase in the functional capacity of the patient. Thus, a pre-transplantation strength of 2-2.5/5 in the neck, shoulder, upper, and lower extremities began to improve after each of the two stem cell administrations, and reached a final 4/5 level 1 month after second transplantation treatment. The increments in muscle strength after the two stem cell administration appeared to be additive, with most benefit recorded after the second. Upper extremity improvement in strength evolved from the incapacity to lift against
gravity before the transplantation towards the ability to lift 2 lbs weights after the procedure. Trunk balance and strength were also markedly improved. The patient gained 20 lbs, along with an increased general activity level. The frequency of respiratory infections decreased from 3-4/year before stem cell therapy to none. The inspiratory effort improved from -32 to -40 cm H20. A muscle biopsy taken in January 2009 demonstrated normal (>50%, normal = 50-100% expression of normal-molecular size) levels of muscular dystrophin. The improvement in muscular strength, clinical respiratory function, and general level of activity are maintained to date.
To our knowledge this is the first report of profound dystrophin expression occurring in a non-ambulatory DMD patient after ERC treatment .......

• "Pai" de célula tronco embrionária diz que uso é sonho (17/10/09)

Recife -  notícia da Folha de São Paulo, 10 de outubro de 2009: Cauteloso, James Thomson, considerado o "pai" das células-tronco embrionárias humanas, afirma que nos próximos dez anos a grande aplicação delas será em testes de novas drogas. O resto, como o uso contra doenças, por exemplo, ainda é um "sonho", afirma ele.
Thomson está no Recife participando de um simpósio sobre o tema. Ele disse que não sentia que estava fazendo história no fim dos anos 1990, quando isolou pela primeira vez as células embrionárias. "Durante um ano havia muito estresse. Para obter os resultados e publicar logo", comentou Thomson.
Sobre as células iPS (células-tronco adultas que, reprogramadas, voltam ao estado embrionário), Thomson disse que "são um caminho forte para o futuro", mas que ainda não se conhece o verdadeiro potencial delas. (EG)
 

• Benefícios a longo prazo do uso de oligonucleotídeos associados a peptídeos na doença cardíaca do camundongo com distrofia muscular (10/10/09)

USA - os oligonucleotídeos associados a sequência de aminoácidos (peptídeos) tem demonstrado melhor resultado do que o uso isolado de oligonucleotídeos. Nesta pesquisa os autores observaram uma melhora a longo prazo da doença cardíaca dos camundongos com distrofia muscular apesar da pouca expressão da distrofina obtida com o tratamento. O resumo em inglês pode ser lido abaixo:

(Cardiovasc Res, Oct 2009) Long-Term Improvement in mdx Cardiomyopathy after Therapy with Peptide-conjugated Morpholino Oligomers

Natee Jearawiriyapaisarn^1,2, Hong M. Moulton³, Peter Sazani³, Ryszard Kole^1,3 and Monte S. Willis^4,5

¹ Department of Pharmacology and Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
² Thalassemia Research Center and Institute of Molecular Biology and Genetics, Mahidol University, Bangkok, Thailand
³ AVI BioPharma, Inc., Corvallis, Oregon, USA
⁴ McAllister Heart Institute, University of North Carolina, Chapel Hill, NC
⁵ Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC

Aims: The cardiomyopathy found in Duchenne muscular dystrophy (DMD) is responsible for death due to heart failure in 30% of patients and additionally contributes to many DMD morbidities. Strategies to bypass DMD-causing mutations to allow an increase in body-wide dystrophin have proven promising, but increasing cardiac dystrophin continues to be challenging. The purpose of this study was to determine if therapeutic restoration of cardiac dystrophin improved the significant cardiac hypertrophy and diastolic dysfunction identified in X-linked muscular dystrophy (mdx) dystrophin-null mouse due to a truncation mutation over time after treatment.

Methods and Results: Mice lacking dystrophin due to a truncation mutation (mdx) were given an arginine-rich, cell-penetrating, peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that delivered a splice-switching oligonucleotide-mediated exon skipping therapy to restore dystrophin in mdx mice before the development of detectable cardiomyopathy. PPMO successfully restored cardiac dystrophin expression, preserved cardiac sarcolemma integrity, and prevented the development of cardiac pathology that develops in mdx-null mice over time. By echocardiography and Doppler analysis of the mitral valve, we identified that PPMO treatment of mdx mice prevented the cardiac hypertrophy and diastolic dysfunction identified in sham-treated, age-matched mdx mice, characteristic of DMD patients early in the disease process, in as little as 5-6 weeks after the initiation of treatment. Surprisingly, despite the short-term replacement of cardiac dystrophin (<1% present after 12 weeks by PCR), PPMO therapy also provided a durable cardiac improvement in cardiac hypertrophy and diastolic dysfunction for up to 7 months after the initiation of treatment.

Conclusions: These results demonstrate for the first time that PPMO-mediated exon skipping therapy early in the course of DMD may effectively prevent or slow down associated cardiac hypertrophy and diastolic dysfunction with significant long-term impact.

• Atualização sobre o uso de oligonucleotídeos na distrofia muscular de Duchenne  (10/10/09)

Alemanha - Günter Scheuerbrandt é um bioquímico alemão que publica resumos das principais pesquisas em distrofia muscular de Duchenne; no texto atual ele atualiza as informações sobre o uso de oligonucleotídeos no tratamento da distrofia muscular de Duchenne; a maioria das informações apresentadas já foram amplamente divulgadas e comentadas.

• Avaliação dos inibidores da anidrase carbônica em dois modelos experimentais de distrofia muscular (10/10/09)

França - inibidores da anidrase carbônica são diuréticos usados no tratamento do glaucoma. Nesta pesquisa eles foram testados em um parasita deficiente em distrofina (C elegans) e no camundongo mdx. Nos dois modelos estudados as drogas reduziram as alterações patológicas dos músculos e aumentaram a força muscular. O resumo em inglês pode ser lido abaixo:

(Hum. Mol. Genet., Nov 2009; 18:4089 - 4101) Evaluation of the therapeutic potential of carbonic anhydrase inhibitors in two animal models of dystrophin deficient muscular dystrophy

Jean Giacomotto^1,, Cordula Pertl^2,, Caroline Borrel¹, Maggie C. Walter², Stefanie Bulst², Bob Johnsen³, David L. Baillie³, Hanns Lochmüller⁴, Christian Thirion² and Laurent Ségalat^1,*

¹ Centre de Génétique Moléculaire et Cellulaire, UMR 5534, Université Lyon 1, 69622 Villeurbanne Cedex, France ² Laboratory of Molecular Myology, Department of Neurology, Friedrich Baur Institute, Ludwig Maximilians University of Munich, Munich, Germany ³ Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada, V5A 1S6 ⁴ Institute of Human Genetics, Newcastle University, Newcastle upon Tyne, UK

Duchenne Muscular Dystrophy is an inherited muscle degeneration disease for which there is still no efficient treatment. However, compounds active on the disease may already exist among approved drugs but are difficult to identify in the absence of cellular models. We used the Caenorhabditis elegans animal model to screen a collection of 1000 already approved compounds. Two of the most active hits obtained were methazolamide and dichlorphenamide, carbonic anhydrase inhibitors widely used in human therapy. In C. elegans, these drugs were shown to interact with CAH-4, a putative carbonic anhydrase. The therapeutic efficacy of these compounds was further validated in long-term experiments on mdx mice, the mouse model of Duchenne Muscular Dystrophy. Mice were treated for 120 days with food containing methazolamide or dichlorphenamide at two doses each. Musculus tibialis anterior and diaphragm muscles were histologically analyzed and isometric muscle force was measured in M. extensor digitorum longus. Both substances increased the tetanic muscle force in the treated M. extensor digitorum longus muscle group, dichlorphenamide increased the force significantly by 30%, but both drugs failed to increase resistance of muscle fibres to eccentric contractions. Histological analysis revealed a reduction of centrally nucleated fibers in M. tibialis anterior and diaphragm in the treated groups. These studies further demonstrated that a C. elegans-based screen coupled with a mouse model validation strategy can lead to the identification of potential pharmacological agents for rare diseases.

• Estudo da ciclosporina A na distrofia muscular de Duchenne (05/10/09)

Alemanha - este estudo foi realizado em vários centros da Alemanha com participação de 153 pacientes com distrofia muscular de Duchenne. A ciclosporina A é uma medicação imunossupressora usada em pacientes transplantados. O uso da medicação  isoladamente ou associada aos corticóides não causou aumento da força muscular em relação aos que estavam tomando somente cortícoides. O estudo não demonstrou benefícios com o uso de ciclosporina A. O resumo em inglês pode ser lido abaixo:

(Neuropediatrics, 2008) Treatment of Duchenne muscular dystrophy with cyclosporin A - A randomized, double-blind, placebo controlled trial

J Kirschner, J Schessl, G Ihorst,  R Korinthenberg, Muskeldystrophie Netzwerk MD-NET - Germany

Treatment with steroids has shown to slow down progression of muscle weakness in patients with Duchenne muscular dystrophy (DMD) but its use is limited by side effects. In a randomized, multi-centre, double-blind placebo-controlled trial we investigated the effect of cyclosporin A (CSA) in DMD. 153 patients were randomized to receive either placebo or 4mg/kg CSA. After three months both groups received additional treatment with intermittent prednisone (0.75mg/kg, 10 days on/10 days off) for another 12 months. In each group 73 patients were available for intention to treat analysis. Baseline characteristics were comparable in both groups. There was no significant difference between the two groups concerning primary (manual muscle strength according to MRC) and secondary (myometry, loss of ambulation, side effects) outcome measures. Peak CSA values were measured blindly and ranged from 12-658ng/ml (mean 210ng/ml) in the verum group. In conclusion, CSA does not improve muscle strength as a monotherapy and does not improve the efficacy of intermittent prednisone in DMD. Networks of rare diseases such as the BMBF-funded MD-NET facilitate the conduction of meaningful multicentre trials even in rare diseases.

The study was supported by BMBF, aktion bennie und co e.V., Novartis Pharma, and Deutsche Gesellschaft für Muskelkranke e.V. Participating trial sites were Basel, Berlin, Essen, Freiburg, Göttingen, Kiel, Mainz, Munich, Neuss, and Vienna.

• Avaliação cardíaca na fase avançada da distrofia muscular de Duchenne (03/10/2009)

Holanda - as manifestações cardíacas são frequentes na distrofia muscular de Duchenne; o ecocardiograma é o exame frequentemente pedido para avaliação da função cardíaca, mas há algumas limitações técnicas pela dificuldade em posicionar corretamente os pacientes devido a escoliose. A cintilografia do miocárdico não sofre estas limitações técnicas mas é um exame mais sofisticado. Nesta pesquisa os autores avaliaram três maneiras de estudar a função cardíaca: o ecocardiograma, a cintilografia miocárdica e a dosagem sanguínea de NT-proBNP, um fator já conhecido de avaliação cardíaca. O estudo demonstrou que o Ecocardiograma associado a dosagem de NT-proBNP trás resultados tão bons e fiéis da função cardíaca do que a cintilografia miocárdica.

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