Our goal is to find treatment for Nemaline Myopathy 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.
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.
Development of Gene Therapy for ACTA1-based Nemaline Myopathy
Accumulation of defective ACTA1 protein in muscle cells causes muscle weakness, leading to Nemaline Myopathy (NEM3). Thus, a potential therapeutic strategy could be reducing defective ACTA1 protein and replacing it with healthy ACTA1 protein. This strategy is called “knockdown and replace.” To accomplish this, the team will use gene therapy to deliver an ACTA1-reducing molecule called an RNA interference (RNAi), microRNA (miRNA), along with a healthy copy of the ACTA1 gene, to the skeletal muscles of NEM3 models. They will test different molecular designs trying to obtain the best efficiency to restore normal actin formation in cultured muscle cells and then later to improve symptoms of NEM3 in ACTA1 mouse models of the disease. Upon completion of the aims of this study, Dr. Rashnonejad expects to produce pre-clinical data to support translating an ACTA1 “knockdown and replace” strategy toward clinical trials.
NEM6: From Pathophysiology to Therapy
The title expresses a full circle of great research performed by this research team over 20 years. In 2002, they described a large Dutch family with nemaline myopathy and a peculiar kind of muscle slowness, that severely hampers daily-life activities. In 2010, in an international consortium, they identified the implicated gene: KBTBD13 (referred to as NEM6). In 2020, they discovered that muscle slowness is caused by the binding of mutant KBTBD13 to actin, thereby stiffening the actin filaments in sarcomeres. This finding was made possible by the generation of the first NEM6 mouse model. The stage is set now to take the next step toward therapy.
The team will use the therapeutic approach of Knocking-down the mutant KBTBD13 hoping to prevent and reverse disease development in NEM6. To accomplish this, they will use gene therapy to deliver a KBTBD13-reducing molecule called RNA interference (RNAi). They will test the efficacy of intramuscular and systemic delivery of this gene therapy on the NEM6 mouse model. They will also work on developing a gene-editing approach to delete KBTBD13 permanently. This research aims at obtaining the proof-of-concept that will enable the testing of this Gene Therapy approach in NEM6 patients.
Dr. Coen Ottenheijm, Dr. Tyler Kirby, Dr. Nicol Voermans, Dr. Annemieke Aartsma-Rus
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.
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.
Novel Gene-Based Therapy
This team 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. When testing the strategy in the Mouse model they discovered a flaw in the model and 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 are designing the strategy to 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.
Inhibitor Molecule to Myostatin; Gene Replacements for KLHL41
This study tested an inhibitory molecule (antibody) to the protein Myostatin. They observed a modest improvement in muscle function and size in a mouse model of typical nemaline myopathy with compound heterozygous nebulin mutations. These results suggest that inhibition of myostatin could be of therapeutic value in non-severe forms of NM warranting further studies. They have also tested how increased protein levels of KLHL41 affected muscle function in their nebulin-based NM mouse model. Unfortunately, decreasing protein levels of KLHL41 appeared to have no effect on muscle function so this approach doesn’t seem to offer therapeutic potential.
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.