where your money is going

In October 2013, A Foundation Building Strength hosted a Nemaline Myopathy consortium which coincided with the World Muscle Society Conference. 40 scientists from around the world attended. At that consortium A Foundation Building Strength announced its Building Muscle Initiative – a $1 million award to the best proposal to treat NM. This is how you can help Liv and all of the children currently living with NM.

2016

Gene Therapy for Nebulin-Based NM

Henk Grenzier, PhD,
Jeff Chamberlain, PhD

Summary. The long life span of the conditional Neb KO model and the finding that the model phenocopies NM makes it possible for the first time to test treatment strategies. Here we will test the effect of gene therapy with mini-nebulins, using the rAAV6 delivery approach that has been shown to be successful in providing functional improvements in other types of myopathies. Although the full nebulin gene far exceeds the holding capacity of the rAAV delivery system, nebulin is so large that different regions of the molecule perform distinct functions and by expressing these regions separately a beneficial effect on muscle structure and function is likely. For this work, the mouse model and extensive experience in characterizing nebulin deficient muscle is in hand. The Chamberlain laboratory has extensive experience with expressing muscle proteins using rAAV delivery systems. Thus we expect this work to be successful. We are excited about this work because the combination of strong basic science and a translational focus is likely to advance understanding of the patho-mechanisms in NM and most importantly, test gene expression as a therapy to treat muscle weakness. A positive outcome of our study would be an important step towards a clinical trial in NM patients.

2015

Factors That Rescue Nebulin-Knockout Mice
Siegfried Labeit, MD, PhD

Nebulin-NM Mechanisms and Treatment
Henk Grenzier, PhD

Safety and Efficacy Clinical Trial of Exercise in Patients with NM
Jahannaz Dastgir, DO

Myofiblar Mechanics to Investigate Muscle Weakness in NM
Coen Ottenheijm, PhD

ACTA1 NM Therapeutic Approaches
Kristen Nowak, PhD

2014

One project that could greatly impact Liv’s life needs funding to get started.

A Novel NM Mouse Model for Testing Therapies to Increase Muscle

Strength. (needs $100,000)

Dr. Henk Granzier, Department of Physiology, University of Arizona.

Background. Patients with nemaline myopathy (NM) have muscle weakness and muscle atrophy. No effective therapies exist for NM and our goal is to develop a mouse model to test treatment strategies. We focus on nebulin because mutations in the nebulin gene account for the majority of NM cases. In our previous work mouse models were made in which nebulin was genetically deleted. This did cause a NM-like disease but its severity far exceeds that of the typical form seen in NM patients and all mice die soon after birth, severely limiting the usefulness of the existing models for evaluating therapies. Hence developing a mouse model that more faithfully mimics the typical form of the disease in NM patients is urgent.

In collaboration with Dr. Carina Wallgren-Pettersson (a leading NM scientist who discovered that nebulin mutations are a major cause of NM, University of Helsinki) and Dr. Coen Ottenheijm (a leading NM scientist at the University of Amsterdam), we have focused on a missense mutation in the nebulin gene that causes in multiple families the typical form of NM. We propose to engineer a mouse model that contains this missense mutation and determine the suitability of the novel model as a platform for therapeutic testing. Our goals are:

Aim 1. Make a novel mouse model that mimics typical NM. Background. Existing nebulin-based NM models have phenotypes that are so severe that testing of therapies is not realistic.

Work plan: Engineer a mouse model with a typical form of NM, mimicking a missense mutation known to occur in NM patients. A targeting construct will be assembled by cloning arms of homology from genomic DNA into a vector that carries the mutation and that will be electroporated into ES cells with the mutation selected by negative selection against thymidine kinase and positive selection for neomyosin resistance. The surviving ES cell clones will be verified and used to produce mice by injection into blastocysts. The neomycin cassette will be removed with a FLP deleter strain. A colony of mice homozygous, heterozygous and wildtype for the missense mutation will then be established.

Hypothesis: Unlike the existing models the novel NM model mimics typical NM and thus survives long enough to test therapies.

Aim 2. Determine the phenotype of the new model and the degree to which this model reproduces characteristics of NM.

Background: Our prior work on existing models with nebulin deletions revealed complete nebulin deficiency, with a phenotype much more severe than is seen in typical human NM (mice die soon after birth). We anticipate that the new model will more faithfully represent typical NM. Work plan: Evaluate novel model with respect to survival, animal/muscle size, muscle pathology, muscle contractility (force-frequency relation and fatigue), nebulin expression and hypertrophic signaling.

Hypotheses: The new model will mimic functional and pathological characteristics of NM patients.

For this work, all expertise is present in our teams. We are excited about this work because the combination of our strong basic science and a translational focus is likely to advance understanding of the patho-mechanisms in NM and lead to much needed therapeutic means to treat NM.

Projects Funded in 2013

1) Dr. Henk Granzier – University of Arizona Medical Research Building, Arizona, USA
Restoring Muscle Strength in Nemaline Myopathy (needs $30,000 to continue)

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) Michael W. Lawlor, M.D., Ph.D – Medical College of Wisconsin
Inhibition of Activin Type IIB Receptor Signaling as a Treatment for Nemaline Myopathy (needs $150,000 over the next 2 years)

Lay Abstract: While nemaline myopathy (NM) is diagnosed due to the presence of characteristic nemaline rods within muscle fibers, the number of nemaline rods in a patient’s biopsy does not correlate well with their degree of weakness. Another feature of many NM muscle biopsies is muscle fiber smallness, and this finding has a clearer relationship with insufficient muscle fiber strength. Fortunately, muscle fiber smallness is also an abnormality that can be treated, as a number of agents are currently being developed to produce muscle fiber growth, or hypertrophy. In our prior work, we have used a hypertrophic agent called ActRIIB-mFc in an effort to correct myofiber smallness in an animal model of X-linked myotubular myopathy (XLMTM). Unfortunately, while ActRIIB-mFc produced hypertrophy and increased strength in healthy animals, the conduction abnormalities found in XLMTM severely limited the efficacy of this agent in XLMTM mice. In the present study, we propose to test ActRIIB-mFc therapy in the nebulin-deficient NebEx55 KO mouse model of NM. NebEx55 KO show severe weakness and muscle fiber smallness, and do not possess the conduction abnormalities that limited the efficacy of this therapeutic strategy in XLMTM mice. We will also investigate the muscle fiber growth pathways in treated and untreated mice, in an effort to understand the molecular events that lead to insufficient muscle fiber growth in NM. Success in this project will identify the degree to which muscle fiber smallness contributes to weakness in NM, while also testing an effective treatment for NM using agents that are already in the FDA clinical trial process.

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