With limited resources and low interest for rare diseases, research funded by A Foundation Building Strength (AFBS) is designed to make the most impact in the shortest period of time. With strategic funding, AFBS supports breakthrough research projects to bring us closer to life-changing treatments and cures for Nemaline Myopathy. Let’s take a closer look at the research progress made this year.

CORRECTING MUSCLE FUNCTION IN NEMALINE MYOPATHY BY MUTATION INDEPENDENT APPROACHES
– DR. GUPTA, BRIGHAM & WOMEN’S HOSPITAL

Dr. Gupta has identified the abnormal accumulation of the protein NRAP in NM- affected muscles. Now she is testing genetic manipulations and small molecules (drugs) to downregulate that protein aiming at improving muscle structure and motor function. Most recently, she has broadened her research by including specific work on a severe form of Nemaline Myopathy caused by mutations in the KLHL40 gene where she is testing a classical gene therapy (gene replacement) approach.

DRUG REPURPOSING FOR THE TREATMENT OF NEB NEMALINE MYOPATHY 
-DR. BRYSON RICHARDSON, MONASH UNIVERSITY

From an exhaustive screening of nearly 1,500 FDA-approved drugs on an NM zebrafish model, the team selected the best 5 drugs showing improvement in the swimming function of the NM-affected fish model. They finished optimizing the beneficial dose range and they are entering the next phase which will explore the impact of these drugs on pathology and long-term muscle function.

PRE-CLINICAL TESTING OF CRISPR/CAS9 BASED THERAPY
-DR. DOWLING, SICKKIDS CHILDREN’S HOSPITAL

In a previous AFBS research funding cycle, this team explored for the first time the potential application of the Nobel Prize- winning CRISPR/Cas9 gene-editing technology to Nemaline Myopathy (NM) therapeutics. They successfully created the specific guides and templates to edit and correct the most frequent recessive mutation in NM, deletion of exon 55 of the Nebulin (NEB) gene. They tested these tools on isolated cells with encouraging results.

Now they will work on a critical step for the clinical translation of this novel strategy. They will test the specific CRISPR/Cas9 tools, in vivo, in exon 55 deletion carrier mice and exon 55 deletion patient-derived myotubes. If successful, this project will provide the proof of concept required for the advancement of this strategy to patients. Watch Dr. Dowling’s full presentation on the latest research here.

UNCOVERING THE MECHANISM OF MYOSIN DYSFUNCTION IN NEMALINE MYOPATHY
-KATARINA PELIN, FOLKHALSAN RESEARCH CENTER

The team has discovered positive preliminary results through testing specific small molecule drugs in NM patient samples. This discovery has sparked the interest of Edgewise Therapeutics (ET), a growing pharmaceutical company developing clinical stage drugs for Duchenne Muscular Dystrophy, among other neuromuscular indications. In general, there is a lack of interest by the pharma industry in rare diseases, but this research project has set the conversation table between the top management team at ET with AFBS. The two teams met to discuss the current state of NM research, the dynamics of our strong AFBS community, and “a day in the life” of families affected by NM. The company was enthusiastic about the potential of some of their drugs aiding in the unmet medical needs we face and the dialogue channel is now open.

EFFECT OF MYOSTATIN INHIBITION ON MUSCLE SIZE AND MUSCLE FUNCTION IN A NOVEL MOUSE MODEL OF TYPICAL NEMALINE MYOPATHY
-DR. GRANZIER, UNIVERSITY OF ARIZONA

Testing myostatin inhibitor compounds (safe in humans) on NM mouse models, the team observed a 20% increase in body weight and muscle size. Now they are assessing the effect of the myostatin inhibitor on muscle mechanics, force, size and strength. They are also testing a classical gene therapy (gene replacement) approach on another severe form of Nemaline Myopathy caused by mutations in the KLHL41 gene.

TESTING NOVEL GENETIC THERAPIES FOR ACTA1 NEMALINE MYOPATHY (NEM3) – HARNESSING PATIENT CELLS
-N. LAING & R. TAYLOR, UNIVERSITY OF WESTERN AUSTRALIA

Using blood cells obtained from four ACTA1 myopathy patients, they created multiple induced pluripotent stem cell (iPSC) lines that they’ve converted into muscle cells. This is an important step towards being able to use these cells to test new treatments. As such, they started testing new gene-editing treatments that they developed: 1) a selective deactivation of the dominant mutant copy of the gene using the CRISPR/Cas9 system, and 2) Inducing ‘genetic compensation’ as a therapy for both dominant and recessive cases of ACTA1 NM. By using another feature of the CRISPR/Cas system, they will try to ‘turn on’ an alternative version of the faulty ACTA1 gene, the endogenous heart actin gene, to recover skeletal muscle function. The novel ACTA1 patient-derived iPSCs have been presented in two scientific publications and they can be shared with the NM research community at large to further studies on pathology and treatments for NM.