Notícias

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Os resumos das notícias podem ser copiados livremente desde que citada a fonte.....Os resumos das notícias podem ser copiados livremente desde que citada a fonte...Os textos não assinados são de autoria de David Feder

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Trabalhos apresentados no Encontro Anual da Sociedade Americana de Genética Humana (31/10/04)

Canadá - neste Congresso realizado em Toronto de 26 a 30 de outubro de 2004 foram apresentados apenas dois trabalhos relatando experimentos em terapia das distrofias musculares.

No primeiro trabalho realizado nos Estados Unidos os pesquisadores apresentam uma nova forma de terapia gênica em camundongos; eles associaram ao vetor viral uma proteína (fator de crescimento do endotélio vascular); com esta terapia os camundongos passaram a expressar distrofina em quantidade suficiente para reduzir os sintomas da doença. O vetor viral foi injetado em uma veia, que é um passo importante para poder tratar todos os músculos; a forma de administração do gene da distrofia muscular é um dos problemas ainda não resolvido na terapia gênica da doença.

No segundo trabalho os pesquisadores holandeses estudam os oligonucleotídeos para "consertar" o gene da distrofina. Estudando células musculares humanas em laboratório ou camundongos com distrofia muscular eles tem conseguido demonstrar que esta forma de tratamento é viável. Estes oligonucleotideos tem que ser construidos para cada forma de mutação do gene e eles tem desenvolvido vários destes oligonucleotideos para utilização em seres humanos.

Os resumos destes dois trabalhos em inglês:

1) Body-wide delivery of a microdystrophin gene via intravascular administration of rAAV6 vectors for treatment of muscular dystrophy. P. Gregorevic, M. Blankinship, J. Allen, L. Meuse, S. Abmayr, J. Han, J. Chamberlain. Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, Dept. of Neurology, University of Washington, Seattle, WA.

Severe neuromuscular disorders, such as Duchenne muscular dystrophy (DMD), lead to reduced quality of life and premature mortality. Historically, genetic interventions for these diseases have been limited by an inability to achieve widespread gene transfer to the affected tissues. Here we demonstrate a method that, for the first time, enables transduction of the vast majority of both the cardiac and skeletal musculature of adult mammals via a single intravenous administration of pseudotype 6 recombinant adeno-associated virus (rAAV6) vectors. As a means to enhance gene transfer, we have determined that IV coadministration of vascular endothelium growth factor (VEGF) with rAAV6 vectors can significantly increase vector accumulation and transgene expression in striated muscles. Having established in reporter gene studies that this technique enables tolerable, high-level transgene expression, we sought to evaluate the potential of this technique for delivering a therapeutic transgene to the musculature of the mdx dystrophic mouse, a model of DMD. Using this technique, we have observed that treated mdx mice exhibit expression of microdystrophin throughout the striated musculature in a manner that is sufficient to reduce pathological features of the dystrophic phenotype. Compared with untreated mice, the muscles of treated animals exhibit reduced susceptibility to contraction-induced injury, and reduced serum creatine kinase levels, reflecting a global reduction in muscle degeneration. These data are the first to demonstrate body-wide amelioration of symptoms associated with dystrophin deficiency in an adult animal following a genetic intervention. In subsequent studies we have established that these techniques can be adapted to express alternate transgenes for the treatment of other muscle diseases. We are currently undertaking studies to determine whether the existing techniques are effective in animals more similar in size and immunology to humans, and present relevant data summarizing our progress

2) Therapeutic antisense-induced exon skipping for Duchenne muscular dystrophy. A. Aartsma-Rus¹, A. Janson¹, G. Platenburg², M. Bremmer-Bout¹, J.T. Den Dunnen¹, J.C.T. Van Deutekom¹, G-J.B. Van Ommen¹. 1) LUMC, Leiden, the Netherlands; 2) Prosensa, Leiden, the Netherlands.

   The severe Duchenne muscular dystrophy (DMD) is mostly caused by frame disrupting mutations in the dystrophin gene, which result in non-functional proteins. Mutations that keep the reading frame intact give rise to internally deleted, semi-functional dystrophins and result in the milder Becker muscular dystrophy (BMD). Antisense oligonucleotides (AONs) have the potential to modulate the pre-mRNA splicing such that a specific exon is skipped. As a result, the reading frame can be restored, which allows the synthesis of a BMD-like dystrophin.
   We have recently demonstrated the skipping of 20 different human DMD exons using 2'-O-methyl RNA AONs with a full-length phosphorothioate backbone (2OMePS), and confirmed the therapeutic applicability of this strategy in cultures from 10 different DMD patients. We now compare the efficacy and efficiency of 2OMePS AONs to morpholino, locked nucleic acid (LNA) and peptide nucleic acid (PNA) AONs. While LNA was most efficient in inducing exon skipping, we find that it acts in a less sequence-specific manner, probably due to its extremely high RNA affinity. Awaiting further improvements in oligochemistry, we therefore consider 2OMePS AONs currently the most favourable compounds.
   To facilitate clinical application, multiple in vivo studies in animal models are ongoing to develop safe and efficient AON-delivery methods. However, as exon skipping is a sequence-specific therapy, it is desirable to directly target the human DMD gene. We have therefore set up sequence-specific human exon skipping in vivo in transgenic mice carrying the an intact copy of the full-length 2.5 Mb human gene (hDMD). We injected 2OMePS AONs targeting human exons 44, 46 and 49 into the m. gastrocnemicus of hDMD mice, and showed skipping of the human (but not the murine) exons, which persisted for at least 28 days. Based on pre-clinical data obtained by our group and others, we are currently setting up a clinical trial aiming at local dystrophin restoration following intramuscular injections of exon 46 and 51 specific AONs.

Igf-1 reduz a necrose muscular precoce em camundongos com distrofia muscular (31/10/04)

Austrália - Igf-1 tem sido estudada para aumentar a força muscular na distrofia muscular. Neste estudo os pesquisadores criaram um camundongo com distofia muscular e que produzia grande quantidade de Igf-1. Os resultados demonstraram que Igf-1 reduz a necrose muscular precoce neste camundongo abrindo a possibilidade que o aumento da Igf-1 possa uma forma de retardar a evolução da distrofia muscular.

Mais notícias sobre o uso de células tronco em Distrofia Muscular de Duchenne na China (28/10/04)

China - em resposta as minhas perguntas o Dr. Zhang disse que o transplante utilizou células de cordão umbilical obtida de doador não aparentado; havia uma compatibilidade entre doador e receptor mas o paciente esta recebendo tratamento imunossupressor em conjunto. Ele está planejando utilizar esta terapia em outros pacientes. A resposta dele pode ser lida aqui:

"Dear Dr. David Feder,

Thank you for your email. Yes, we used a nonrelated cord blood stem cell. Because the HLA match is very well so the immune reaction is not obvious, but we still use some immunossupresor drugs now. We are preparing another boys for transplantation.

Best wishes,

Cheng Zhang"

Primeiro caso de transplante de células tronco em distrofia muscular de Duchenne na China (26/10/04)

China - recebi esta semana um relato do primeiro caso do transplante de células tronco em Distrofia Muscular de Duchenne; o procedimento foi realizado há 92 diasem um menino de 12 anos; previamente o paciente recebeu quimioterapia para destruir a sua médula óssea; em seguida recebeu na veia as células tronco do cordão umbilical; a biópsia realizada após 76 dias revelou que algumas fibras estava expressando a distrofina. Ele apresentou uma discreta melhora de força muscular. Este é o e-mail que recebi do Dr. Cheng Zhang que realizou o procedimento:

"Dear Dr. David Feder,

Thank you for your email. Today is 92 days that the DMD boy is transplanted by umbilical cord stem cells. He is twelve years old and he cannot walk for almost three years. The umbilical cord stem cells was transfer into his vein 92 days ago. The muscle biopsy was done after 76 days of the transplantation. We find that the dystrophin staining is weak positive in some muscle cells. We are conforming that the weak positive muscle cells come from the donor. The DMD boy has a little improvement in his locomotive function, for example, he touch his nose a little better than before. Now, the DMD boy is OK, he like watch TV, and sometimes play cards with nurse. We are still waiting and observing what happen on him.

Sincerely yours,

Cheng Zhang, MD, PhD - Professor and Chair, Department of Neurology

First Affiliated Hospital - Sun Yat-sen University - Guangzhou, Guangdong, 510080

P. R. China"

Terapia gênica intra-útero na distrofia muscular experimental (16/10/04)

USA - a terapia gênica o mais precoce possível poderia impedir a degeneração muscular. Neste estudo os pesquisadores demonstram um bom resultado com o uso da terapia gênica intrauterina em camundongos com distrofia muscular. A terapia gênica na fase intrauterina seria muito importante mas difícil de se realizar pela dificuldade do diagnóstico tão precoce (só se já houvessem outros casos na família seria tentado o diagnóstico tão precoce).

Bons resultados obtidos na terapia gênica da hemofilia em cães pode auxiliar nos estudos da terapia gênica das distrofias musculares (16/10/04)

USA - a hemofilia é uma doença genética que causa hemorragias por falta de um fator de colagulação; neste artigo os autores descrevem sucesso a longo prazo (3 anos) com a terapia gênica de cães com hemofilia que receberam por via vascular vírus contento o gene da hemofilia que se expressou nos músculos dos cães levando a correção da doença. Esta mesma técnica pode ser utilizada na distrofia muscular.

Informações úteis sobre o uso de corticóides em distrofia muscular de Duchenne (16/10/04)

USA - em julho eu já tinha divulgado os resultados do encontro de especialistas que discutiram o uso dos corticóides na distrofia muscular de Duchenne. Nesta semana eles divulgaram as mesmas informações na forma de perguntas e respostas e as principais informações sobre o uso dos corticóides, em especial os efeitos colaterais. Estas informações estão em inglês e na medida do possível iremos traduzí-las.

Ultrasom dos músculos em crianças pode permitir identificação de alterações musculares das doenças neuromusculares (16/10/04)

Holanda - este estudo avalia a capacidade do ultrasom identificar as alterações musculares nas doenças neuromusculares. Muitos pesquisadores procuram estudar o ultrassom e a ressonância com a finalidade de reduzir a necessidade de biópsias e poder acompanhar o tratamento com medicamentos nas distrofias. Os autores concluem que, apesar da necessidade de novos estudos, o ultrasom pode utilizar no acompanhamento de pacientes com doenças neuromusculares.

IMPORTANTE: Meu primeiro estudo experimental em distrofia muscular -Tamoxifeno aumenta a força muscular de camundongos com distrofia muscular experimental (07/10/2004)

São Paulo - em 2003 eu decidi realizar pesquisas com camundongos com distrofia muscular na Faculdade de Medicina da Fundação do ABC, além de apoiar as pesquisas que estão sendo realizadas em Ribeirão Preto, no Centro de Pesquisas em Distrofia Muscular da AADM. O meu primeiro estudo experimental foi aprovado para apresentação no 44^o Encontro Anual da Sociedade Americana em Biologia Celular. Neste trabalho eu estudei a droga tamoxifeno, que é utilizada para tratamento de mulheres com câncer de mama. Eu decidi estudar esta droga porque ela atua sobre as TGF beta, um grupo de proteínas que está alterado na distrofia muscular de Duchenne. Para este estudo eu utilizei a droga nos camundongos mdx, que tem uma mutação do gene da distrofina. Os animais que receberam a droga apresentaram aumento da força muscular após a quinta semana que se manteve até o final do experimento na 12a semana. Biópsias musculares foram realizadas e estão ainda sob análise (no Centro de Estudos do Genoma Humano). As primeiras análises demonstram que os animais tratados com tamoxifeno tem menor grau de degeneração muscular do que os não tratados. Há ainda outros estudos bioquímicos que estão sendo realizados nos músculos dos animais cujos resultados serão conhecidos em breve. Neste mês estamos iniciando o estudo de uma segunda droga no mesmo modelo experimental. O resumo do meu trabalho que será apresentado em Washington, USA, em dezembro de 2004 é o seguinte:

Tamoxifen increases muscular strength of the mdx dystrophic mice NEW

(Abstract from 44th Annual Meeting - American Society for Cell Biology (December, 4-8, 2004, Washington)

A. Cavalsan,¹ R. F. Vasquez,¹ R. C. Lin,¹ S. B. Zyngier,¹ F. J. Velloso,² B. H. Santos,² L. L. Fogaca,² M. Vainzof,² D. Feder¹ ; ¹ Pharmacology, ABC Faculty of Medicine, Santo Andre, Brazil, ² Human Genome Research Center - IB USP, Sao Paulo, Brazil

The mdx mice is a well-known model of Xp21 dystrophin-deficient muscular dystrophy. Although a good genetic and biochemical model, the mdx shows no muscle weakness, but under physical exercise, a loss of muscular strength can be detected. Here we have tested the possible therapeutic beneficial effect of Tamoxifen in the degenerative process of the dystrophic muscle, analyzing muscle strength of tamoxifen treated mdx mice, under intensive physical exercise. A total of 22 mices aged 4 weeks were divided into 3 groups: control (n= 8) treated with 0.5 mL saline ip, Tamoxifen 5 mg/Kg body weight ip (n= 8) daily and Tamoxifen 10 mg/Kg ip (n=6) daily. The exercise protocol was done in a wheel revolving at 18 cm/s, for 10 minutes, twice a day, 5 days/week, up to 12 weeks. Whole-body strength was measured weekly using a force transducer coupled to a computer. Mice tails were attached via a non-flexibile nylon cord to the transducer, the animals were electricly stimulated to run, and the force to pull the cord was registered continuously. Results were analyzed by the Kruskal-Wallis test. The mice treated either with 5 mg/Kg (6.26+ 1.44 dynes/g body weight) or 10 mg/Kg (6.46+ 2.52) showed a significant increase of muscular strength (p<0.05) compared to the control group (3.66+ 0.77) starting in the 5^th week, and maintaining significance up to the end of the experiment. Histological and histochemical analysis of the complex of the gastrocnemius muscle are under analysis, but preliminary results suggest a less degree of degeneration in the Tamoxifen treated groups.
Tamoxifen is an anti tumoral drug and act on TGF-beta. Its possible therapeutic effect in the degenerative process of the dystrophic muscle could ameliorates the clinical course of dystrophic patients. FAPESP-CEPID, CNPq, PRONEX, NEPAS-FMABC.

Outros estudos do 44^o Encontro Anual da Sociedade Americana em Biologia Celular (07/10/04)

USA - neste Congresso que se realizará em dezembro em Washington, além da minha pesquisa sobre tamoxifeno outros estudos serão apresentados:

1) um estudo fala dos resultados positivos com o uso do gene da distrofina retiniana humana utilizado em camundongos sem distrofina e utrofina que melhoram os sintomas musculares; de uma forma severa de distrofia eles passaram a apresentar poucos sintomas musculares;

2) o segundo estudo fala da relação entre calcificação ectópica de musculos com distrofia muscular pode ser um sinal de regeneração e auxiliar na avaliação do tratamento com medicamentos;

3) o terceiro estudo trata dos níveis de protoglicans em distrofia muscular de Duchenne em relação às outras formas da doença; há redução dos níveis de protoglicans em Duchenne pode estar relacionado aos altos níveis de TGF beta e TNF

4) O quarto estudo demonstra que as células tronco originadas de músculos de camundongos fêmeas com distrofia muscular são mais eficientes para a terapia gênica do que as células dos machos.

Os resumos em inglês destes estudos estão a seguir:

Human Retinal Dystrophin Transgene Converts Lethal Muscular Dystrophy into Viable Mild Myopathy in Dystrophin-Utrophin Null Mice
R. Gaedigk,^1,2 D. J. Law,³ K. M. Fitzgerald-Gustafson,^4,2 S. G. McNulty,¹ N. N. Nsumu,¹ A. C. Modrcin,⁵ R. J. Rinaldi,⁵ D. Pinson,⁶ S. C. Fowler,⁷ M. Bilgen,^4,8 J. Burns,⁹ S. D. Hauschka,¹⁰ R. A. White^1,2 ; ¹ Medical Research, Children's Mercy Hospitals & Clinics, Kansas City, MO, ² Pediatrics, UMKC School of Medicine, Kansas City, MO, ³ School of Biological Sciences, Univ. of Missouri-Kansas City, Kansas City, MO, ⁴ Hoglund Brain Imaging Center, Univ. of Kansas Medical Center, Kansas City, KS, ⁵ Rehabilitation Medicine, Children's Mercy Hospitals & Clinics, Kansas City, MO, ⁶ Pathology & Laboratory Medicine, Univ. of Kansas Medical Center, Kansas City, KS, ⁷ Pharmacology & Toxicology, Univ. of Kansas, Lawrence, KS, ⁸ Molecular & Integrative Physiology, Univ. of Kansas Medical Center, Kansas City, KS, ⁹ Veterinary Imaging Services, Topeka, KS, ¹⁰ Biochemistry, Univ. of Washington, Seattle, WA

Duchenne muscular dystrophy (DMD) is a progressive muscle disease caused by severe dystrophin gene mutations that often result in death by the third decade. The mdx mouse is the most commonly used DMD model. Although they lack dystrophin and have underlying muscle disease, mdx mice appear physically normal. This may be partially due to compensatory expression of the dystrophin-related protein, utrophin. In contrast, double mutant mice (DM), deficient for both dystrophin and utrophin (mdx/+, utrn -/-), die by 3 months of age and suffer from severe muscle weakness, pronounced growth retardation, kyphosis, weight loss, slack posture, and immobility (Deconinck et al. (1997) Cell 90: 717-727; Grady et al. (1997) Cell 90: 729-738). These features make them an excellent physiological model for DMD research. The capacity of a naturally occurring isoform, human retinal dystrophin (Dp260), to compensate for the missing muscle isoform Dp427 was tested in DM mice. The expression of this transgene prevents premature death and reduces the severe muscular dystrophy phenotype to a mild myopathy. Electromyography (EMG), histology, radiography, magnetic resonance imaging, and behavior studies show that DM transgenic mice grow normally, have normal spinal curvature and locomotion, and have reduced muscle pathology. EMG and histologic data from transgenic DM mice are typical of mild myopathy, while the DM mice exhibit severe abnormalities commonly seen in human dystrophinopathies. The expression of human Dp260 in DM mice converts a severe and lethal muscular dystrophy into a non-lethal mild myopathy. Muscle-specific expression of Dp260 could have several advantages over other treatments of DMD

Visualization of Ectopic Calcification in mdx Mouse Skeletal Muscle
N. Kikkawa, T. Ohno, M. Shiozuka, R. Matsuda; The Graduate School of Arts and Sciences, The University of Tokyo, Tokyo, Japan

It has been demonstrated that osteogenic differentiation of skeletal muscle cells are induced by osteogenic factors, such as bone morphogenetic proteins, both in vitro and in vivo. Spontaneous ectopic bone formation in vivo has also been reported in, for instance, fibrodysplasia ossificans progressiva, which is a rare bone disorder. Another example of self-generating ectopic calcification has been found in skeletal muscle of mdx mouse, a model of Duchenne muscular dystrophy (DMD).
We observed the ectopic calcification in mdx mouse thigh muscle by using x-ray micro CT-scanner SkyScan-1074, which gives resolution of 22um. The x-ray images were reconstructed into three dimentional visions. Calcifications were found as spicular structures running parallel to the muscle fiber. Paraffin sections of the regions found by X-ray microtomography were Von Kossa stained to confirm calcium deposits. We also detected ectopic calcifications of living mice with mouse-whole-body x-ray CT-scanner of Aloka. No ectopic calcification was observed in skeletal muscle of B10 mouse, which possesses normal dystrophin gene and was used as a negative control.
Calcified regions of mdx mouse thigh did not overlap with the Evans blue-positive areas but corresponded to some of the regenerating areas. Thus, ectopic calcification can be a diagnostic marker of muscle regeneration in mdx mice, and be available to determine the effects of drug or gene therapies.

Muscle Proteoglycan Levels in Duchenne Muscular Dystrophy Differ from Other Muscular Dystrophies
S. Zanotti, E. Canioni, F. Cornelio, L. Morandi, M. Mora; Neuromuscular Diseases and Neuroimmunology, National Neurological Institute C. Besta, Milano, Italy

Biglycan and decorin are small leucine-rich extracellular proteoglycans that interact with several matrix proteins particularly collagens, and also with cytokines whose activity they may modulate. To better understand the role of these proteoglycans in muscle fibrosis in muscular dystrophies, we investigated the expression of their transcripts and proteins in several forms of muscular dystrophy compared to age-matched controls. mRNAs of both proteoglycans were significantly downregulated in Duchenne muscular dystrophy and significantly upregulated in Becker muscular dystrophy, sarcoglycanopathies and dysferlinopathy. By immunohistochemistry, decorin and biglycan were mainly localized in connective tissue and apparently increased with age. Their presence increased in relation to increased fibrosis in all types of dystrophic muscle.
The increase in biglycan and decorin in most muscle diseases indicates a role of these proteoglycans in the extracellular matrix organization. The significant decrease of decorin and biglycan mRNA in DMD distinguishes this disease from the other studied and may be related to the high levels of TGF-beta1 and TNF-alpha found in this disease.

Sex Differences in Muscle Stem Cell Transplantation Efficiency
B. Deasy,¹ A. Lu,¹ K. Urish,¹ J. Tebbets,¹ B. Gharaibeh,¹ R. Rubin,² J. Huard¹ ; ¹ University of Pittsburgh, Pittsburgh, PA, ² Allegheny General Hospital, Pittsburgh, PA

We previously demonstrated that muscle-derived stem cells (MDSCs) efficiently regenerate skeletal muscle tissue after transplantation into dystrophic mdx mice, which model muscular dystrophy. Here we show that transplantation of female MDSC (F-MDSC) rather than male MDSCs (M-MDSC) significantly improves skeletal muscle regeneration.
We transplanted F-MDSCs into the gastrocnemius muscles of female mdx mice and the same number of M-MDSCs into the gastrocnemius muscles of male mdx mice. We used a previously described protocol to measure the cells’ regeneration index (RI)_the number of dystrophin-positive fibers in the host muscle per 10⁵ donor cells_two weeks after transplantation. The F-MDSCs elicited significantly superior muscle regeneration equivalent to a 6-fold increase in efficiency (F-MDSC RI=686±120 versus M-MDSCs RI=105±25, P< 0.01). Sex-crossed transplantation also demonstrated the same trend for the donor cells. We hypothesize that this difference may be related to reduced ability of the M-MDSC to self-renew or to tolerate hypoxic stress. F-MDSCs maintained CD34 expression (>80% of total cells) for up to 200 population doublings, whereas M-MDSCs exhibited a rapid drop in CD34 expression (from >80% to <30% of total cells) after only 45 population doublings. To support the notion that the F-MDSC are more tolerant to stress, we also found that proliferation of F-MDSC was less affected by low O₂ conditions as compared with M-MDSC.
Our discovery of sex-related differences in muscle stem cell biology reveals clear limitations to using male stem and progenitor cells for cell-tracking purposes. This finding also warrants careful consideration by researchers working to identify optimal populations of stem and progenitor cells for use in cell therapy and tissue engineering, clinicians who perform bone marrow stem cell transplantation, and basic scientists investigating cell and developmental biology.

Corticóide reduz as alterações patológicas dos camundongos com distrofia através da via calcineurina/NF-AT (02/10/04)

Canadá - os corticóides, em especial o deflazacort, podem retardar a evolução da distrofia muscular de Duchenne mas o mecanismo de ação é desconhecido. Neste estudo em camundongos os pesquisadores demonstraram que o deflazacort reduz a necrose muscular, provavelmente pela ativação da via da calcineurina/NF-AT1.

Influência do sexo na regeneração dos músculos de camundongos com distrofia muscular (02/10/04)

Brasil - este estudo realizado na Universidade Federal Fluminense tem commo objetivo avaliar os efeitos do sexo do camundongo nas alterações musculares da distrofia, a capacidade de regeneração e a quantidade de fibrose dos músculos. A análise dos músculos demonstrou que as fêmeas tem menor inflamação muscular, menor necrose e maior regeneração muscular que os camundongos machos em torno da 6a semana de vida. A retirada dos ovários reduziu a regeneração muscular. Camundongos velhos, tanto machos ou fêmeas, apresentam o mesmo grau de lesão muscular. Os autores concluíram que há uma influência dos hormônios femininos na necrose dos músculos e que estes podem promover regeneração e reduzir a inflamação muscular.

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