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.
NEM6: From Pathophysiology to Therapy
This research builds upon two decades of remarkable progress in understanding Nemaline Myopathy. In 2002, the same team identified a large Dutch family with the characteristic muscle weakness and slowness of NM. By 2010, they had pinpointed the culprit gene: KBTBD13 (NEM6). Then, in 2020, a major breakthrough! Using the first-ever NEM6 mouse model, they unraveled how NEM6 mutations stiffen muscle fibers, leading to the hallmark slowness.
Now, they’re ready for the next giant leap: therapy. This project will explore knocking down the mutant KBTBD13 protein to prevent and potentially reverse disease progression. They’ll utilize two cutting-edge gene therapy approaches:
- RNA interference (RNAi): Delivering molecules that silence the NEM6 gene, reducing its protein production. They’ll test both intramuscular and systemic delivery methods in the NEM6 mouse model.
- Gene editing: Permanently removing the NEM6 gene using sophisticated gene-editing tools.
The ultimate goal? Achieve proof-of-concept for gene therapy in NEM6 patients, paving the way for clinical trials. This research holds immense promise for individuals living with Nemaline Myopathy, offering hope for a future free from its limitations.
This project is being co-funded with Prinses Beatrix Spierfonds.
Dr. Coen Ottenheijm, Dr. Tyler Kirby, Dr. Nicol Voermans, Dr. Annemieke Aartsma-Rus
Developing Therapies for Nemaline Myopathy
Nemaline myopathy (NM) is a genetic disorder caused by mutations in 12 genes that regulate the function of skeletal muscle. The common link between all the known NM genes is that they affect actin-thin filaments crucial for skeletal muscle strength and function. Mutations in three members of the Kelch gene family, KLHL40, KLHL41 and KBTBD13, result in rare forms of NM.
Dr. Gupta’s work has led to the development of mouse and zebrafish models of NM-causing Kelch genes. Now, Dr. Gupta’s studies are focused on developing therapies for these rare forms of myopathies by (a) a gene replacement approach, in which a normal copy of the disease-causing gene is added back to patients to restore the muscle function, and (b) testing several hundred FDA approved drugs in animal models of NM to potentially repurpose those having a positive effect in muscle function.
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.
Nemaline Myopathy Biobanking Program
Functioning as a secure repository for tissue samples obtained through various medical procedures, including surgeries, fetal sampling, autopsies, and muscle biopsies, the Beggs Lab lab aims to advance scientific understanding and therapeutic development for Nemaline Myopathy. With a mission to support patients and families in their contributions to medical research without financial burdens, the biobank welcomes tissue donations from individuals with NM of all ages and genetic subtypes. The centralized human tissue samples and medical data are critical to advancing research, aiding clinical trial planning and follow-up, and fostering collaborative advancements in the field.
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.
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. The team aims to test potential inhibitors of NRAP in mammalian cells and animal models in the future.
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.