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

Amsterdam University Medical Center (UMC), Radboud UMC, Leiden UMC, Netherlands


Gene Therapy

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.

Dr. Vandana Gupta

Brigham and Women’s Hospital, Boston, USA

NEB and KLHL40

Pathomechanism of NM / Gene Therapy

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.

Dr. Afrooz Rashnonejad

Nationwide Children’s Hospital, Ohio, USA

Gene Therapy

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. 

Alan Beggs, PhD

Boston Children’s Hospital and Harvard University, USA

Tissue Banking

Identifying and Correcting the Pathological Drivers of Nemaline Myopathy in Stem Cell-Derived Engineered Skeletal Muscle Tissues

A significant impediment to developing effective treatments is the creation and validation of suitable human models that recapitulate the disease phenotype with sufficient fidelity to predict whether a novel treatment will be successful in clinical trials. Dr. Mack’s research aims to create a derived human stem cell model of Nemaline Myopathy (NM) and test potential therapeutic methods to treat the disease.

In this project, they are differentiating stem cells from NM patients that have disease-causing mutations in the skeletal muscle actin gene (ACTA1) into skeletal muscle and then create 3D muscle bundles. These engineered muscle tissues (EMTs) are then suspended between two small posts—one stiff and one flexible. The deflection of the flexible post is used to calculate the force the muscle bundle can generate after electrical stimulation (the equivalent to a nerve impulse).

The research team has successfully generated 3D muscles from the ACTA1 mutant cells and 3D muscles from cells where the ACTA1 mutation was corrected. After electrical stimulation, they found that the ACTA1 mutant group produced impaired twitch force generation compared to the “rescued” 3D muscle, implying the 3D EMT could recreate the functional deficit of NM patients’ muscles in culture. They also performed immunofluorescent imaging of these 3D muscles and found that 3D EMT of ACTA1 mutant muscle has aggregated fluorescent puncta of alpha-actinin and titin, which are the major filament proteins known to comprise the nemaline bodies observed in NM patients.

After confirming and optimizing the accuracy of this experimental model the team will use it to test different potential therapeutic interventions. The planned interventions include 1) deleting the mutant copy of the ACTA1 gene, 2) introducing a small molecule that can help the misfolded actin protein assume a more normal shape, and 3) two strategies to increase the expression of cardiac actin to compensate for the ‘poison’ skeletal muscle actin.

Dr. David Mack

University of Washington

Patient-Derived Cell Models / Gene-Based Therapies / Small Molecule (Drug) Therapy

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.

Dr. Jonathan Realmuto

University of California, Riverside, USA


Completed Research Projects

Read about completed research projects and find additional resources for researchers below.

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.

Dr. Jenni Laitila and Dr. Julien Ochala

University of Copenhagen, Denmark

NEB (and possibly ACTA1)

Small Molecule (Drug) Therapy

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.

Dr. Vandana Gupta

Brigham and Women’s Hospital, Boston, USA

NEB and KLHL40

Pathomechanism of NM / Gene Therapy

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.

Dr. Jim Dowling

Hospital for Sick Children, Toronto, Canada

Greenwald Family Foundation

Gene Editing / Gene Therapy / Animal Model

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.

Dr. Hank Granzier and Dr. Johan Lindqvist

University of Arizona

NEB (likely transversal to other NM genotypes) and KLHL41

Antibody Therapy / Gene Therapy

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.

Rhonda Taylor, Joshua Clayton, Nigel Laing

Harry Perkins Institute of Medical Research, Western Australia

Patient-Derived Cell Models / Gene Editing

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.

Robert Bryson-Richardson

Monash University, Australia

Drug Repurposing

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.

Katarina Pelin, Jenni Laitila, Julien Ochala

Folkhalsan Research Center, Finland, and University of Copenhagen, Denmark


Pathomechanism of NM and Small Molecule (Drug) Therapy

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.