March, 2012

The Consensus Statement on Standard of Care for Congenital Myopathies was published in the March 2012 issue of the Journal of Child Neurology.
Read it in it's entirety HERE.
Abstract:  Recent progress in scientific research has facilitated accurate genetic and neuropathological diagnosis of congenital myopathies. However, given their relatively low incidence, congenital myopathies remain unfamiliar to the majority of care providers, and the levels of patient care are extremely variable. This consensus statement aims to provide care guidelines for congenital myopathies. The International Standard of Care Committee for Congenital Myopathies worked through frequent e-mail correspondences, periodic conference calls, 2 rounds of online surveys, and a 3-day workshop to achieve a consensus for diagnostic and clinical care recommendations. The committee includes 59 members from 10 medical disciplines. They are organized into 5 working groups: genetics/diagnosis, neurology, pulmonology, gastroenterology/nutrition/speech/oral care, and orthopedics/rehabilitation. In each care area the authors summarize the committee’s recommendations for symptom assessments and therapeutic interventions. It is the committee’s goal that through these recommendations, patients with congenital myopathies will receive optimal care and improve their disease outcome.
April, 2011

AFBS recently approved funding for 4 research projects summarized below. We are excited about the promise that each of these studies holds in terms of achieving our goal of developing a therapy for those affected with NM. And a special thanks to all of those who donated to make funding for this important research possible. Every dollar counts!

AFBS 2011 Funded Projects

1. Dr. Henk Granzier - University of Arizona Medical Research Building, Arizona, USA
Restoring Muscle Strength in Nemaline Myopathy

Lay Abstract: The long-term goal of our proposal is to understand the underlying causes of muscle weakness in patients with Nemaline Myopathy (NM) and, importantly, understand how muscle strength can be restored. We focus on the protein nebulin because in a large fraction of NM patients, mutations in nebulin are causative for the disease. Using biopsies from NM patients we have already shown that nebulin regulates the ability of muscle to generate force. To better understand the underlying mechanisms and develop methods to restore muscle strength, we have generated a mouse model that closely mimics a prominent nebulin exon deletion found in NM patients. Here we propose to study this new model, including the mechanisms that underlie muscle weakness. Importantly, we will also focus on exercise regimes and pharmacological agents for restoring muscle strength. A unique and important aspect of our work is its translational aspect with parallel experiments on muscle biopsies of NM patients that focus on using calcium sensitizers to restore muscle force. Our aim is to gain a greatly improved understanding of the mechanisms underlying muscle weakness in NM and how to increase muscle strength in patients, and provide thereby a strong rationale for clinical trials.


2. Prof Nigel G Laing - The Centre for Medical Research, The University of Western Australia, Australia
Viral therapy for ACTA1-based Nemaline Myopathy – efficacy studies in mouse models

Lay Abstract: Having identified many of the genes for nemaline myopathy, we now need to work on developing therapies. Our proposed project is to investigate treatment for nemaline myopathy caused by defects in the skeletal muscle actin gene, which account for approximately 25% of all nemaline myopathy patients, but around half of the most severe cases. We propose to investigate treatments using viral delivery of either heart or skeletal muscle actin. After finding the relationship between skeletal muscle actin and nemaline myopathy, we speculated that it might be possible to use heart actin to treat skeletal muscle actin nemaline myopathy. We showed that patients with recessive skeletal muscle actin nemaline myopathy have no skeletal muscle actin protein, but instead have heart actin in their skeletal muscle and some such patients do remarkably well. We then demonstrated, using gene technology, that mouse models of recessive skeletal muscle actin nemaline myopathy, which normally died within 9 days after birth, could be rescued to old age if heart actin was used to replace their missing skeletal muscle actin. This proposed project is to determine whether delivery of cardiac actin by a virus after birth is able to rescue these same recessive nemaline myopathy mice.

For a number of reasons, we believe that increasing the amount of normal actin in those with dominant skeletal muscle actin disease will help patients. Thus if we can dilute out the defective actin in more severely affected patients, we should be able to make their disease milder. One way to change the proportion of defective actin is to supply more normal actin, and we propose to do that via viral gene therapy. Much progress is being made in viral delivery of genes to treat skeletal muscle diseases, and actin genes are small and ideal for viral delivery.

3. Craig Munns - Institute of Endocrinology and Diabetes The Children’s Hospital at Westmead, Australia
Whole Body Vibration Training for Nemaline Myopathy

Lay Abstract: Nemaline myopathy results in varying degrees of muscle weakness due to abnormalities within the muscle cell. There are no effective pharmacological treatments or exercise regimes that currently exist to improve the muscle weakness. In children with nemaline myopathy the muscle weakness leads to decreased physical function and exercise tolerance. An exercise regime that was not onerous, could be performed at home and could increase muscle size and strength, has the potential to improve mobility and the quality of life of children with nemaline myopathy. Children with muscle weakness are also at risk of having weak bones that fracture easily. Increasing muscle strength could therefore also increase bone strength.

Whole body vibration training (WBVT) using a vibration platform is an emerging, simple and safe training method, which has been shown to improve muscle function and fitness in adults and children. In addition, WBVT has been shown to improve osteoporosis (weak bones) in various populations. With this in mind, we plan to undertake a study to see if WBVT improves muscle and bone function in children with nemaline myopathy.

Home-based Exercise Program for Children with Nemaline Myopathy: Ten children with nemaline myopathy, 4 – 18 years old, will be enrolled into this study. The children will undertake a WBVT program at home 7 days a week for a 24 week (six-month) period. WBVT will involve them standing on a vibration plate for 9 minutes per day. The WBVT period will be preceded by a 6-month observation period. Using a series of investigations at baseline, the end of 6 months of observation and after 6 months of WBVT, we will look at the effects of WBVT on muscle strength (force, power and efficiency), muscle size, lower limb function, bone strength and quality of life.


4. Katarina Pelin, PhD - University of Helsinki, Finland (student of Carina Wallgren-Pettersson)
Development of RNA-based therapies for Nemaline Myopathy

Lay Abstract: A common cause of nemaline myopathy is mutations in the nebulin gene (NEB). The patients usually inherit two different NEB mutations, one from the mother and another from the father.

NEB is one of the biggest genes found in the human genome and it produces hundreds of size variants of the nebulin protein, which is important for proper muscle structure and function. Development of conventional gene replacement therapies for nemaline myopathy caused by mutations in NEB is not feasible due to the large size and complexity of NEB. It has, however, been shown for several other genes that it is possible to correct mutations at the RNA level, before the protein is produced. This technique is known as spliceosome-mediated RNA transsplicing or exon exchange. The principle is to introduce into the muscles small RNA molecules carrying a normal copy of the mutated part of the gene, and with the help of the cell’s own RNA-editing machinery (the spliceosome) the mutated part of the gene is replaced by the normal counterpart. My research group is developing the exon exchange technique for correction of NEB mutations. We have achieved successful exon exchange for the first tested region of NEB in a cell culture system. These results prove that it is possible to correct NEB mutations at the RNA level. Our aim is to develop efficient correction molecules for all mutated regions of NEB. The results from the research project will form the basis for the development of RNA therapies for nemaline myopathy caused by mutations in NEB. The experience gained from this project will also be helpful for development of the exon exchange technique for the other major nemaline myopathy-causing gene ACTA1.


5. James Dowling, MD, PhD University of Michigan Ann Arbor, MI
Drug Discovery in a Novel Vertebrate Model of Nemaline Myopathy

Nemaline myopathy is one of the most severe muscle conditions of childhood. It is associated with impaired motor skills including delayed motor development, impaired walking, and difficulties with oro-motor skills. Currently no treatments or disease modifying therapies exist for nemaline myopathy. Furthermore, few potential candidate drugs have been identified. The overall goal of our research is to develop novel therapeutic approaches to treat this devastating disorder of childhood.

To accomplish our goal of identifying disease modifying therapies for nemaline myopathy, we are utilizing a novel zebrafish model of the disease. Zebrafish offer many advantages for the study of muscle disease: they breed in large numbers, they develop quickly, and they share most if not all attributes of human skeletal muscle. Zebrafish present a unique advantage in terms of new therapy identification because they enable the ability to rapidly test hundreds of potential drugs in a living vertebrate in a very short period of time. In our proposal, we will first thoroughly characterize a novel zebrafish model of nemaline myopathy and will then use this model to screen a large library of FDA approved chemicals for their ability to improve the impaired swimming ability of these “nemaline” zebrafish. Positive “hits” will be further evaluated for their effect on specific muscle related properties and on survival. In the end, the best candidate(s) identified will represent new and outstanding potential therapeutics that will advance our understanding of the nemaline disease process and that can ultimately be test for efficacy in patients with nemaline myopathy.


January, 2011