Newsletter - Institut de Myologie

Research highlights

:: from the Institute

Obituary: Ketty Schwartz (1937-2007)

On the 25th of December 2007, France lost one of its greatest scientific and medical figures, Professor Ketty Schwartz. Pharmacist, Doctor of Natural Sciences, emeritus CNRS-Inserm Research Director, Ketty Schwartz directed several research units. Ketty Schwartz had been a member of the scientific council of the AFM since its inauguration in 1981 and had been its president since 1998. Ketty Schwartz’s work has led to the development of molecular genetics in cardiology in France and internationally.

Ketty Schwartz’s research focused on the molecular mechanisms that regulate the function of mammalian skeletal muscle. Her team was responsible for the first studies of molecular biology in cardiology, which have greatly contributed to establish concepts of ‘phenoconversion’ and mecanogenic transduction of the mammalian heart during development, aging and disease processes.

> Read the complete article on Ketty Schwartz

Research at the Institute

The year 2007 was very fruitful as regards the number of publications emanating from the Institute of Myology. Besides publications in peer-reviewed journals, the Institute’s significant research activities have resulted in posters and oral presentations at various international congresses as well as numerous PhD and Masters theses. Throughout the year, several influential research papers have been published in major journals. However, the highlight is undoubtedly the recent Cell Stem Cell featured article in which research teams from the Institute of Myology coordinated by Dr. Luis Garcia describe a step forward in the muscle stem cell field by performing genetic correction of autologous stem cells from patients with muscular dystrophy. This study which was carried out at the Institute of Myology will help advance the development of autologous stem cell treatments for DMD.

> Access the detailed list of all the publications from the Institute.

Immunological consequences of intramuscular injections of AAV1 vectors

The team led by Dr. Luis Garcia has previously performed preclinical studies of AAV-mediated exon skipping in both mouse and dog models of Duchenne Muscular Dystrophy (DMD). In the golden retriever muscular dystrophy (GRMD) dog they obtained high levels of exon skipping with U7snRNAs carrying antisense sequences designed to mask determinants of exon 6 and 8. In mice, systemic administration of AAV2/1-U7 vectors resulted in widespread long-lasting dystrophin recovery including in the diaphragm and heart. The AAV2 vector is commonly employed in preclinical models but it has been demonstrated that the host immune response to the AAV2 capsid can decrease the efficiency of gene transfer following repeated injections in normal mice. Very little data exists about AAV1 immune rejection. In the present study, Dr. Luis Garcia and his colleagues have characterized the nature of the immune responses to AAV1 in dystrophic mice. They evaluated the efficiency of immunosuppressive treatments in minimizing the risk of immune rejection of the AAV1 vector. This is of particular importance for the restoration of muscle function in human DMD patients who will need repetitive AAV delivery in order to obtain widespread benefit. The authors observed that the immune response could be alleviated by a co-stimulation blockade protocol involving anti-CD40 antibodies and CTLA4/Fc fusion protein injections at the time of AAV-U7 administration. This allowed sequential treatments and the consequent rescue of dystrophin in multiple muscles. Full body treatment of DMD patients with AAV-U7 vectors would require the elaboration of an immunosuppressive protocol that would allow for at least a limited number of sequential vector administration.
Mol Ther. 2008 Jan 8; [Epub ahead of print]

:: international

AVI BioPharma Announces Commencement of Dosing in Clinical Trial for Duchenne Muscular Dystrophy

AVI BioPharma, Inc. has initiated dosing of the first patient in a proof-of-principle clinical trial using AVI-4658, AVI's lead drug candidate for Duchenne muscular dystrophy (DMD), based on the company's proprietary ESPRIT (Exon Skipping Pre-RNA Interference Technology) drug platform. AVI-4658 is designed to skip exon 51 of the dystrophin gene, and thus benefit DMD patients with certain types of mutations that impair dystrophin function.

The trial is being conducted by research teams at the Imperial College London, in collaboration with the United Kingdom-based MDEX Consortium. The trial will include up to nine boys with DMD, each of whom will receive a single intramuscular (IM) administration of the drug. Two to three weeks following the injection, the muscle will be biopsied and examined for molecular evidence of corrected dystrophin production. Preclinical studies have demonstrated that AVI-4658 restores proper RNA reading frame and production of dystrophin in cells from patients with certain types of deletions in the gene that codes for dystrophin production.

This trial will be the first to assess the drug's effect in patients. The principal investigator for the U.K. study is Professor Francesco Muntoni, Department of Paediatrics, Hammersmith Hospital Campus, Imperial College, London. The coordinating investigator of the project is Professor Dominic Wells, M.A., VetMB, Ph.D., MRCVS, Department of Cellular and Molecular Neuroscience, Imperial College Faculty of Medicine. Imperial College will serve as the sponsor for the trial, with AVI BioPharma serving as its clinical development collaborator. AVI recently announced it has received a translational research grant of $2.45 million from Charley's Fund to support the selection and development of a lead molecule designed to skip exon 50 and restore production of functional dystrophin. This therapeutic approach is similar to that of AVI-4658, but targets patients with a different set of mutations. In addition, in November, AVI announced that the U.S. Food and Drug Administration (FDA) granted orphan drug designation for AVI-4658 for treatment of DMD. Earlier this month, the FDA also granted Fast Track status to the same product candidate. In parallel with the U.K. study, AVI is moving toward initiating clinical trials evaluating longer-term systemic administration of AVI-4658. AVI's DMD research and development programs are being conducted in conjunction with the company's DMD cross-licensing and development partner, Ercole Biotech Inc.

More information: http://www.avibio.com/

Latest research highlights

Discover our selection of scientific and medical publications in the fields of myology and neuromuscular diseases: a summary of each publication aimed at the general reader, highlighting the main points of the article and the authors’ conclusions is provided.

Myoglobinuria: a potential complication of corticosteroid treatment - Read
Iplex receives orphan drug status - Read
Reliability of clinical outcome measures in Charcot-Marie-Tooth disease - Read
ADAM12: a negative regulator of muscle regeneration - Read
Efficacy of dantrolene in Miyoshi myopathy - Read
Curcumin treatment partially alleviates the clinical and neuropathological phenotype of Trembler-J mice - Read
Launch of DuchenneConnect - a resource for the Duchenne/Becker community - Read
Muscular dystrophy symptom reversible? - Read
SMN plays a protective role in motor neurons by increasing chaperone activity - Read
A clinically relevant gene therapy approach for Duchenne muscular dystrophy by vascular delivery of micro-dystrophin - Read

>> Access the complete list of myology research highlights

Conferences & Meetings

1-2 March 2008 - Third Eastern European Conference on Rare Diseases and Orphan Drugs
Rare diseases – Prevention, Diagnosis, Treatment
Plovdiv, Bulgari

Participants from Bulgaria and Eastern Europe will present their achievements in the field of prevention, diagnosis and treatment of rare diseases with oral presentations and posters. During the conference, a specialized workshop with speakers from leading USA, European and Bulgarian organizations and institutions will be carried out, who will discuss the best practices in the field of rare diseases and orphan drugs access.

> For more information

8–12 march 2008 - ESF-UB Conference in Biomedicine
Rare diseases: Channels and transporters
Sant Feliu de Guixols, Spain

The conference is devoted to channels and transporters involved in rare inherited diseases. Specifically TRP and CLC channels, connexins, mitochondrial transporters, heteromeric amino acid transporters, neurotransmitter transporters and ABC transporters and related diseases will be covered. Invited speakers have been selected to broadly address aspects of structural biology, genetics, physiology, biochemistry and clinical aspects.

> For more information

12-19 april - AAN 60th Annual Meeting
Chicago, Illinois, USA
> For more information

27-30 April 2008 - Third New Directions in Biology and Disease of Skeletal Muscle Meeting
New Orleans, LA, USA.
> For more information

26 april - Myotonic Dystrophy Support Group Conference
West Midlands, USA
date to be confirmed.
> For more information

9-12 april - Conference on Pediactic and Neonatal Ventilation
Montreux, Switzterland
> For more information

1-3 may - Translating ELSI : Global Perspectives on the Ethical, Legal and Social Implications of Human Genome Research
Cleveland, Ohio, USA
> For more information

8-10 May - 9th European Congress of Neuropathology
Athens, Greece
Old and new techniques in muscle pathology : mini symposium (nb 13) on sat. may 10.

> For more information

> > Access the complete list of upcoming conferences and meeting.

In Brief

Recent publications from the Institute

Rachid Benchaouir, Mirella Meregalli, Andrea Farini, Giuseppe D’Antona, Marzia Belicchi, Aurélie Goyenvalle, Maurizio Battistelli, Nereo Bresolin, Roberto Bottinelli, Luis Garcia and Yvan Torrente.
Restoration of Human Dystrophin Following Transplantation of Exon-Skipping-Engineered DMD Patient Stem Cells into Dystrophic Mice.
Cell Stem Cell. December 13 2007.
Bigot A, Jacquemin V, Debacq-Chainiaux F, Butler-Browne GS, Toussaint O, Furling D, Mouly V.
Replicative aging down regulates the myogenic regulatory factors in human myoblasts.
Biol Cell. 2007 Nov 7; [Epub ahead of print]
Chappert P, Leboeuf M, Rameau P, Stockholm D, Liblau R, Danos O, Davoust JM, Gross DA.
Antigen-driven interactions with dendritic cells and expansion of foxp3+ regulatory T cells occur in the absence of inflammatory signals.
J Immunol. 2008 Jan 1;180(1):327-34
Benayoun B, Baghdiguian S, Lajmanovich A, Bartoli M, Daniele N, Gicquel E, Bourg N, Raynaud F, Pasquier MA, Suel L, Lochmuller H, Lefranc G, Richard I.
NF-{kappa}B-dependent expression of the antiapoptotic factor c-FLIP is regulated by calpain 3, the protein involved in limb-girdle muscular dystrophy type 2A.
FASEB J. 2007 Dec 11; [Epub ahead of print]
Guy-Coichard C, Nguyen DT, Delorme T, Boureau F.
Pain in Hereditary Neuromuscular Disorders and Myasthenia Gravis: A National Survey of Frequency, Characteristics, and Impact.
J Pain Symptom Manage. 2007 Nov 1; [Epub ahead of print]
Boërio D, Hogrel JY, Bassez G, Lefaucheur JP.
Neuromuscular excitability properties in myotonic dystrophy type 1.
Clin Neurophysiol. 2007 Nov;118(11):2375-82. Epub 2007 Sep 24

>> Access the complete list of publications from the Institute

Press Releases

09/12/2007 - Telethon 2007 : 96 228 136 euros - One more week for the great turning point for treatments to succeed

On behalf of patients and their families, the AFM would like to express its deepest gratitude to all those who once again have given it their support. Despite difficult weather conditions, the French people did not fail to mobilize. At a time when innovative therapies are undergoing their first trials on humans, the AFM is more than ever determined in its combat against disease. Though substantial, the income from this 21st Téléthon, could nevertheless slow down the development of treatments.
> Read the complete press release

27/12/2007 - Exon-skipping therapy in Duchenne myopathy - Tolerance trial successful in patients

With the support of the AFM through Téléthon donations, the first ever phase I clinical trial (for feasibility and tolerance) based on the exon-skipping technique has been successfully carried out on children affected with Duchenne myopathy in the Netherlands. Conducted by the biotechnology company Prosensa in collaboration with the Leiden University Medical Centre, this trial used antisense oligonucleotides – small pieces of laboratory-synthesised DNA – placed on the pre-messenger RNA during its conversion to messenger RNA. Thus placed, the genetic mutation is shielded in the messenger RNA so as to allow production of the missing protein.
> Read the complete press release

In May 2008 the AFM is organising two international scientific and medical congresses on neuromuscular diseases at the Parc Chanot in Marseille.

From 26 to 30 May 2008, Myology 2008, the international congress of myology experts, presided by Thomas Voit, a neuropaediatrician, specialist in diseases of the muscle and medical and scientific director of the Myology Institute in Paris. This third myology congress will bring together nearly 1000 researchers and physicians specialising in the muscle and its diseases, and will continue the dynamic of the turning point for treatments initiated by the AFM.

On 30, 31 May and 1 June 2008, the Fifth International Congress of Rehabilitation in Neuromuscular Diseases, presided by Vincent Gauthron, rehabilitation physician at the Saint-Etienne University Hospital. The aim of this congress, which takes place every two years and was last held in Denmark in 2006, is to compare best practices in Europe as regards the clinical management of neuromuscular diseases. It brings together more than 200 physicians and paramedical personnel to evaluate the advances made in this field.

For the first time, these two conferences will take place in France and will share a day in common, the 30 May. This will be an opportunity for the exchange of opinions between scientific experts of the muscle, physicians and paramedical personnel about the different scales of evaluation necessary in the therapeutic trials at present being carried out on humans.

> Read the complete press release

>> Access all the press releases

Online report

Parent Project Muscular Dystrophy Annual Connect Conference report

More than 400 people attended the 2007 annual conference of the American Parent Project Muscular Dystrophy (PPMD) in Philadelphia from 12 – 14 July 2007. Over three days, about 60 presentations on therapeutic research, medical and social management, and legal affairs were presented. Günter Scheuerbrandt has produced a report on the research presentations of this meeting for the Duchenne boys and young men and their families, who wish to know how the work of the researchers and other experts is progressing to find effective therapies for Duchenne dystrophy.

> Download the full report

Books

Autologous And Cancer Stem Cell Gene Therapy (Progress in Gene Therapy)
Edited by Roger Bertolotti & Keiya Ozawa

Adult or postnatal stem cells offer life-long cell replacement in tissues and organs, and are thus unavoidable targets of long-term and transient regenerative/epigenetic gene therapy for both inherited and acquired diseases; and effective anticancer therapy. This timely book highlights the pioneering translation of adult pluripotent stem cells as a substitute for tissue-specific stem cells, thereby pinpointing the invaluable potential for stem cell gene therapy applications of autologous cells to contribute to all three germ players. Pathologies are discussed in terms of stem cell repopulation dynamics, with appropriate niches (long-term engraftment) and tissues (cell turnover). Focus is also placed on the increasing number of identified tissue-specific cancer stem cells as the ultimate targets for recurrence-free cancer recovery, and on the development of armed stem cells as tumor-homing vectors for targeted anticancer stem cell gene therapy.

> Autologous And Cancer Stem Cell Gene Therapy

My Heart vs. the Real World: Children with Heart Disease, In Photographs & Interviews
By Max S. Gerber

My Heart vs. the Real World is a photo documentary volume that explores the lives of children with congenital heart disease (CHD) through striking black-and-white photographs and interviews with subjects and their families. Ten chapters each spotlight a single child and in an additional chapter, the author writes about his own experience of growing up and living with CHD. The images and personal accounts reveal how, compared with someone healthy, a chronically ill child develops adult attitudes in a much different way. These are stories of how CHD patients and their families cope with and overcome extraordinary obstacles and learn about themselves during the process.

> My Heart vs. the Real World: Children with Heart Disease, In Photographs & Interviews

Recruitement

New post available for a physiotherapist/ trials coordinator at the Newcastle Muscle Centre, UK

We have a post available from the beginning of 2008 until March 2011 for a physiotherapist with trials experience to work with the neuromuscular team in supporting clinical trials and clinical research activity, including standardised assessments of patients. Experience in trials and/ or research would be very useful, as would familiarity with the principles of good clinical practice, though training in these can be provided. The postholder would work under the direction of consultant physiotherapist Michelle Eagle, as well as interacting directly with the clinical trials co-ordinator and the TREAT-NMD team. The post will be advertised via the University of Newcastle website shortly, but in the meantime we would welcome any approaches from people who would like to discuss the post informally.
For further details contact the TREAT-NMD office (info(a)treat-nmd.eu),
Michelle Eagle (michelle.eagle(a)btinternet.com) or
Prof Kate Bushby (kate.bushby(a)ncl.ac.uk)

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