Our goal is to find treatment by funding targeted research and support studies that pave the way for regulatory approval.
Active Research Projects
Learn more about our active research projects or read about our completed research projects below.
Novel Gene-Based Therapy
This team has previously used a “cut and repair” strategy with CRISPR/Cas9 to show that they can replace exon 55 in cells from patients with NEB exon 55 deletion. They have successfully generated a new model which should have a phenotype more comparable with human NEB-related NM by exon 55 deletion. Using this new mouse model they will repeat the Gene Editing (CRISPR/Cas9) strategy. They will also pilot testing an alternative repair methodology called PASTE, and a gene therapy approach using a “miniNEB” type of gene.
Correcting Muscle Function in Nemaline Myopathy by Mutation Independent Approaches
This study found that removing the NEB-chaperone protein, NRAP, totally and partially, in an NEB deficiency model of zebrafish, modestly but significantly improved survival, swimming distance, myofiber and sarcomere organization while reducing protein aggregates.
They showed that NRAP downregulation results in an improvement in skeletal muscle function and survival, making attractive the idea of developing an NRAP inhibitor as a potential therapy, at least for NEB patients but probably also transversal to other NM genotypes.
They also succeeded in establishing a KLHL40 Knock Out mice colony. They will test AAV-mediated gene replacement therapy. This is an extended project thanks to new donor funding. The team also aims to test inhibitors of NRAP in mammalian cells and animal models in the future.
Identifying and Correcting the Pathological Drivers of Nemaline Myopathy in Stem Cell-Derived Engineered Skeletal Muscle Tissues
In this newly funded study, the team will use patient-derived cells to create 3D muscles to test different therapeutic modalities.
Inhibitor Molecule to Myostatin; Gene Replacements for KLHL41
This active study is administering an inhibitor molecule (antibody) to the protein Myostatin, eliciting an improvement in muscle function and size in a mouse model of typical nemaline myopathy with compound heterozygous nebulin mutations. They are also testing a gene replacement strategy for KLHL41 mutants. They have encountered mixed results and additional studies are ongoing.
Soft Robotic Garments for Assisting Lower-Limb Function in Children with Nemaline Myopathy
Exoskeletons and suits are an emerging technology for mobility impairment, but no such technology is commercially available for children. Motivated by this missing gap in technology, our goal is to amplify the functional independence of children with NM through the development of soft robotic garments that physically assist the lower extremities. The singular goal of the research is to actualize and demonstrate a lower limb exosuit prototype (soft robotic garment) that can provide physical assistance to a pediatric user during sit-to-stand, maintenance of balance, and stand-to-sit actions. Long-term we envision our results to provide foundational technology to realize comfortable, low-cost, high power wearable robots that seamlessly interface with human users, adapting in synchrony to provide continuous ambulation assistance.
Exploring the Potential of Mavacamten as a Treatment for Nemaline Myopathy
In a previous AFBS-funded study, the team discovered that the conformation of myosin heads was abnormal in isolated muscle fibers from NM patients with NEB and ACTA1 mutations. This dysregulated state of myosin is known to consume five times more energy (ATP) than normal and is thus likely to negatively affect muscle metabolism. Adding a small compound, Mavacamten, targeting the altered myosin heads conformation was able to decrease the energy consumption to normal levels.
In this extended study, the researchers will test Mavacamten, a recently FDA-approved drug, in a NEB (and potentially in an ACTA1) mouse model and will further characterize the beneficial effects of this drug on the metabolic signature of the muscle fiber.
Completed Research Projects
Read about completed research projects and find additional resources for researchers below.
Testing Novel Genetic Therapies for ACTA1 Nemaline Myopathy (NEM3) – Harnessing Patient Cells
This completed study produced 4 ACTA1 patient-derived cell lines to use as a sharable “Therapy Discovery Platform”. The 4 cell lines are induced pluripotent stem cells, iPSCs from 4 different patients with different ACTA1 mutations. They started to test gene editing tools (CRISPR/Cas9) to calibrate future potential therapeutics. AFBS promoted a collaboration with Dr. David Mack (University of Washington), a new grantee who will use those cells to create 3D muscles to test different therapeutic modalities.
Drug Repurposing for the Treatment of NEB Nemaline Myopathy
This completed study screened a large FDA-approved chemical library to identify compounds that improve swimming performance in a zebrafish nemaline myopathy model (NEB). They found one drug increasing swimming performance in the zebrafish model. However, whilst the swimming performance was improved, the drug had deleterious effects on other aspects of the phenotype, requiring further investigation to determine if the drug may be suitable for the treatment of nemaline myopathy.
Uncovering the Mechanism of Myosin Dysfunction in Nemaline Myopathy – A Potential Target for Therapy
This completed study aimed to uncover how myosin is dysregulated in nemaline myopathy. The team observed that the conformation of myosin heads was abnormal in isolated muscle fibers from NM patients with NEB and ACTA1 mutations (but not from TPM2 and TPM3) when compared to control healthy subjects. This dysregulated state of myosin is known to consume five times more energy (ATP) than normal and is thus likely to negatively affect muscle metabolism. These encouraging results originated a new proposal submission whose aim is to test a recently FDA-approved drug, in a NEB (and potentially in an ACTA1) mouse model.
Research Partners
With strategic funding, we invest in scientific experts and world renowned research institutions can focus on their research, making breakthroughs and bringing us closer to life-changing treatments and cures.
Additional Resources
We have provided significant funding for and have connections to multiple NM experts. Through their research, available resources include numerous publications as well as murine models with phenotypes typical of moderate human disease.