September 18, 2007
Boston, MA
Dear Friend,
Thank you for considering participation in our research on myotubular/centronuclear myopathy (MTM and CNM) and related congenital myopathies. Through the generous support of many friends of Joshua Frase and the Frase Foundation, we have developed a comprehensive MTM/CNM-research program at Children’s Hospital and Harvard Medical School. With your help, we hope to improve the lives of children and their families by developing effective diagnostic tests and treatments.
My laboratory hopes to understand and find a cure for MTM and CNM by studying the changes that cause muscle weakness in children with these diseases. We are looking for patients and families to help by enrolling in our research studies. More details on participation can be found on the accompanying “fact sheet.” Anyone interested in participating should contact Elizabeth Taylor DeChene by phone at (617) 919-2169; by mail at Children's Hospital Boston, Genetics Division, 300 Longwood Ave, Enders 5, Boston, MA 02115; or by email at edechene@enders.tch.harvard.edu. At that time, we’ll be happy to answer all your questions and arrange for your informed consent and participation if you so desire.
Thank you again for your help! The assistance of patients and families such as yours is critical to our success in finding a cure.
With all best wishes and thanks,
Alan H. Beggs, Ph.D
Associate Professor of Pediatrics
http://www.childrenshospital.org/research/beggs/
The Congenital Myopathies: Information for Patients and Families
Download the factsheet here. (PDF file)
Myotubular/Centronuclear Myopathy: Information for Patients and Families
Download the factsheet here. (PDF file)
Introduction
We are a group of scientists and doctors studying myotubular myopathy at the Children's Hospital/Harvard Medical School in Boston, Massachusetts. We are trying to understand the changes that occur in the muscle of patients with myotubular myopathy, with the hope that this will lead to improved treatment for these conditions. In order to carry out our research, we need the help of families. If you are the parent of a child with myotubular myopathy, or if you yourself are affected, you may be able to make an important contribution toward scientific knowledge of these and other muscular conditions.
Participation Consists Of:
Informed Consent
Each family member who decides to participate will need to sign a consent form. If the participant is a minor, a parent/guardian will be the one who provides consent.
Medical Information and Family History
We will ask your permission to obtain relevant medical records, such as a muscle biopsy report, from your physician. We may also ask you some questions about your family medical history. This can be done through a brief telephone interview.
Blood Sample
We ask for a small blood sample from all consenting family members in order to look for genes involved in myotubular/centronuclear myopathy. We can arrange for you to have blood drawn through your physician or at a nearby medical facility. All costs for the procedure are paid by the study. If you have already had genetic testing for myotubular/centronuclear myopathy, we may not need to ask for a blood sample.
Muscle Tissue from an Existing Biopsy
Studying muscle from a person who has myotubular/centronuclear myopathy can tell us a lot about the genes and proteins involved in the disease. We can help find out if any frozen tissue is still available from an existing muscle biopsy and, with your permission, arrange to have it shipped to our laboratory. Alternatively, if you or your child is scheduled to undergo a surgical procedure in the near future, this may provide an opportunity to donate a muscle specimen. With some procedures, it is possible for the surgeon to remove a small piece of muscle without any additional risk or discomfort to the patient.
Cost and Time Commitment:
Participation in this study is free of charge. Travel to Boston is not required and individuals from anywhere in the world may participate. The telephone interview, blood draw, and paperwork should take no more than two hours to complete.
Reporting of Results:
It is possible that we may identify a gene mutation as the cause of the muscle disease in your family. In this case, and with your permission, we will be happy to make this information available to you via your healthcare provider. As a research laboratory, we are not authorized to release participant's results, but we can refer your physician to a clinical diagnostic laboratory that would confirm our findings and provide clinically useful results.
Contact Us:
If you would like to enroll or if you have questions about this study, please contact:
Elizabeth Taylor, M.S.
Division of Genetics
Enders Building 5,
300 Longwood Avenue
Boston, MA 02115
Telephone: 617-919-2169
Fax: 617-730-0253
Email: etaylor@enders.tch.harvard.edu
The fundamental goals of the Beggs Laboratory are to understand the molecular basis for congenital myopathies and use this information to develop improved diagnostic and therapeutic methods. The congenital myopathies are a group of rare genetic disorders that result in muscular weakness, often from birth. Severe cases may lead to death in early infancy, often from an inability to breathe independently. Patients with milder cases may survive infancy and learn to walk, however, significant muscle weakness persists for life. Some of the specific diseases we study include myotubular myopathy, centronuclear myopathy and nemaline myopathy and we are generally interested in other forms of congenital myopathy, including undefined cases without firm diagnoses.
To attain our goals, we are taking three complementary approaches in the laboratory. The first is to find and study new muscle-specific genes and proteins and learn as much as possible about their basic biology, including their normal structure and function. The underlying assumption is that these new genes are likely to include ones that are defective in patients with various congenital myopathies. After learning about the normal genes, we are then in a position to look for abnormalities of these genes in patients with muscle weakness, as described below.
The second major project is to find and enroll patients and families with various congenital myopathies into our research program and then study their genetic material (DNA) and muscle to find the causes of their disorders. In the past few years, we have made much progress in understanding the causes of another related condition called nemaline myopathy, including the identification of three genes involved in this disorder. Finding the causative mutation allows us to confirm the diagnosis and identify other family members who may be at risk to develop the disorder or pass it on to their children. For those who are interested, it opens the possibility for them to undergo genetic counseling and prenatal diagnosis for any future pregnancies. Finally, we hope that knowing the genetic basis for each congenital myopathy will allow us to design specific and effective treatments for some of these diseases.
The third complementary approach is to learn as much as possible about the physiologic state of diseased muscle from patients with congenital myopathy. One frustrating aspect of medical genetics today, is that knowing the exact genetic defect has often not allowed us to fully understand how the disease is caused and, more importantly, how we can cure it. Utilizing recent advances in microarray technology, we are studying the expression of thousands of different genes simultaneously to understand the “downstream” or secondary consequences of particular genetic mutations. In particular, patients with myotubular myopathy have a defect in their “myotubularian” gene that results in incomplete muscle maturation. If we can learn about each of the results of myotubularian defects, we hope to identify critical pathways of muscle differentiation which may be targets for pharmacologic treatment.
Over the past 10 years the team at the Wake Forest Institute for Regenerative Medicine (Director: Anthony Atala) has focused on developing skeletal muscle cell therapy applications using tissue engineering and regenerative medicine approaches for clinical translation. The team of exceptionally dedicated experts from multiple disciplines, including cell biology, medicine, materials sciences, physiology, pharmacology, molecular genetics and engineering, have worked together to bring new therapies to patients suffering from muscle disorders. Toward this defined goal, the research team has taken four systematic and effective strategic approaches: 1) Develop methods of cell-based therapies, 2) harness microenvironment in vivo for the survival and maintenance of implanted muscle cells and tissue, 3) develop systems that accelerate muscle tissue maturation and function, and 4) develop a reliable and powerful stem cell system for regenerating normal muscle tissue for clinical use.
The initial studies focused on establishing methods for culture and expansion of the skeletal muscle progenitor cells (cells that are committed to become mature muscle cells) using mammalian species including the human. The team has successfully established muscle cell expansion systems which allowed for the creation of functional muscle tissues in vivo using several model systems. To test the effectiveness of muscle tissue replacement therapy, it was necessary to create muscle defect models. Successful working models were created in several species, followed by treating tissue defects with new muscle in the form of injection and surgical implant. The team has demonstrated functional recovery of the tissue defects, which indicates the clinical feasibility of this approach. Ongoing development efforts are focused toward translating this technology to patients. These include refining cell expansion systems that are compliant with regulatory agencies (i.e., FDA), generating standard operating procedures (SOP) that can be used widely and developing cell-based systems that can be applied to all age groups of patients with muscular disorders. The team is currently working actively with an FDA consultant to obtain approval for a clinical trial. In addition, the cell and tissue processing facility for clinical trial has been designed and planned for completion in 2008.
One of the continued challenges in transplantation is the inadequate blood supply to implanted tissues. The team has recognized the need to control the microenvironment where new tissue could adapt and receive sufficient amounts of blood for muscle survival. To overcome this limitation, the team has sought methods to enhance blood supply to muscle tissue through stimulating the tissue environment with biologic factors (VEGF, vascular endothelial growth factor) that promote new vessel formation. Several growth factor delivery methods (protein and gene delivery) were developed and confirmed of the effectiveness in the body. Ongoing research focus is directed toward developing an implant system that provides sufficient amount of nutrients and oxygen to cells for tissue survival and maturation in the body.
Another arm of the team’s research efforts has focused on developing a system that would result in rapid functional tissue restoration in vivo. The research team has successfully developed a muscle bioreactor system that preconditions muscle and accelerates tissue maturation and function in vitro. The computerized bioreactor system is designed to exercise muscle for functional enhancement. The levels of muscle tissue maturation and contractile function were distinctively enhanced when the bioreactor system was applied. Further investigation is currently being performed to refine the system for application in vivo.
The existing defective muscle cells are destined to become dysfunctional with time. The research team has recognized the need to overcome this challenge for successful clinical translation. The goal was to develop a reliable and potent stem cell system for regenerating normal muscle tissue for clinical use. Amniotic fluid and placenta were identified as reliable sources of stem cells that can be used for muscle tissue regeneration. Stem cells, isolated from amniotic fluid and placenta, behave similarly to embryonic stem cells, and these cells are able to become multiple cell types, including muscle, when they are guided appropriately. The stem cells can be easily obtained through a routine amniocentesis procedure or from the placenta after the baby is born. The team continues to investigate a means to utilize these stem cells for muscle tissue regeneration applications.
During the past decade, the team has made an enormous leap toward the development of skeletal muscle cell therapies for clinical applications. The comprehensive and systematic approaches employed in this program are designed to converge into the ultimate goal of delivering new therapies to patients with muscular disorders. The technological progress made in each of the four tracks could be used as a stand-alone or as an integrated system for specific utility. A decade of continued technological developments would not have been possible without the generous and consistent support of the Joshua Frase Foundation. The Wake Forest Institute for Regenerative Medicine is fortunate to have the Joshua Frase Foundation as its partner in a mission to treat patients with muscular disorders and eventually improve the quality of their lives.
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