1. Global FKRP Patient Registry

    • Dr. Volker Straub at Newcastle upon Tyne University in Newcastle, UK
    • Since 2012
    • Description

      This grant pays for the coordinator of the registry. The registry is part of Treat-NMD, a network with the mission of ensuring that the most promising new neuromuscular therapies reach patients as quickly as possible.

    • Outcome

      As of April 2017, 527 patients from 35 countries had registered since 2011. The proportion of patients with a genetically confirmed diagnosis is 45%.

    • Articles:

      1. Natural History, Trial Readiness and Gene Discovery: Advances in Patient Registries for Neuromuscular Disease. Thompson R, Robertson A, Lochmüller H. Adv Exp Med Biol. 2017 1031:97-124.
  2. Patient Sequencing Project

    • Dr. Madhuri Hegde at the Emory Genetics Laboratory in Atlanta, GA
    • Since 2012
    • Description

      The LGMD2i Research Fund has a dedicated account with the Emory Genetics Laboratory to fund the genetic testing of patients that have a high probability of LGMD2I based on clinical symptoms and family history.

  3. The Rare Disease Awareness Project or MYO-SEQ Project: Application of next generation sequencing technologies to a large cohort of patients affected by unexplained limb-girdle muscular weakness

    • Dr. Volker Straub at the Newcastle Upon Tyne University in Newcastle Upon Tyne, UK
    • 2014-2016; 2017-2019
    • Description

      The goal of the project is to provide centralized genetic diagnosis at a global scale. Individuals with elevated serum CK activity in combination with unexplained limb-girdle muscle weakness were selected for the study; biological samples were prepared and sent to the project team in Newcastle Upon Tyne, UK. DNA was extracted and sent to the Broad Institute (MIT, Cambridge MA USA) for whole exome sequencing.

    • Outcome

      The first 1,000 DNA samples from 41 centers (mainly in Europe) have been sequenced. Of the 1,000 patients, 48.5% had likely causal mutations. Eight out of 1,000 were found to have a mutation in FKRP and were diagnosed with LGMD2I.

    • Articles:

      1. Identification of GAA variants through whole exome sequencing targeted to a cohort of 606 patients with unexplained limb-girdle muscle weakness. Johnson K, Töpf A, Bertoli M et al. 2017 Orphanet Journal of Rare Diseases 12:173-184.
      2. Limb girdle muscular dystrophy due to mutations in POMT2. Østergaard ST, Johnson K, Stojkovic T et al. J Neurol Neurosurg Psychiatry. 2017 88(11):
      3. Novel recessive TTN founder variant is a common cause of distal myopathy in the Serbian population. Peric S, Nikodinovic Glumac J, Töpf A et al. European Journal of Human Genetics 2017 25:572–581.
      4. Homozygous DPM3 mutation in a patient with alpha-dystroglycan-related limb girdle muscular dystrophy. Van den Bergh PYK, Sznajer Y, Van Parys V, et al. Neuromuscular Disorders. 2017 27(11):1043–1046.
  4. Dystroglycanopathies: Patient and Family Conference

    • Dr. Katherine Mathews at the University of Iowa, Carver College of Medicine in Iowa City, IA
    • Since 2012
    • Description

      The “Patient and Family Conference” provides an opportunity for individuals with a dystroglycanopathy (which includes LGMD2I) and their families to receive up to date information about research and clinical developments, and about various issues related to living with dystrophy including public policy, reimbursement, psychology, etc. It also helps individuals with a dystroglycanopathy to meet other people with a similar diagnosis. Importantly, it facilitates the enrollment in the longest running natural history study in individuals with LGMD2I.

  5. Wellness and Quality of Life Survey on Patients with LGMD2I

    • Dr. Masa Sasagawa at Bastyr University in Seattle, WA
    • Since 2017
    • Description

      The goals of this project are to gather information on natural remedies that improve quality of life; analyze, organize, and share the collected information with the LGMD2I community.

    • Outcome

      Ongoing

  6. Determination of the Dose Effect in FKRP Gene Transfer (gene therapy)

    • Dr. Isabelle Richard at the Généthon at Evry, France
    • Since 2015
    • Description

      Based on promising results of past experiments on genetic correction by transfer of the wild type FKRP gene, this project focuses on studying the effects of variable therapeutic doses of adeno-associated virus (AAV) vector containing the FKRP gene in an appropriate mouse model.

    • Outcome

      Ongoing

    • Articles:

      1. AAV-mediated transfer of FKRP shows therapeutic efficacy in a murine model but requires control of gene expression. Gicquel E, Maizonnier N, Foltz SJ, et al. Human Molecular Genetics 2017 26(10):1952–1965.
      2. Xenograft models of FKRP muscular dystrophy for AAVA (gene) therapy
  7. Xenograft Models of FKRP Muscular Dystrophy for AAV (gene) therapy

    • Dr. Charles P. Emerson, Jr. at the University of Massachusetts Medical School in Worcester, MA
    • Since 2015
    • Description

      During this project, a humanized mouse model of FKRP will be developed and validated. In this model, a group of the leg muscles will be destroyed and replaced by human muscles. A mouse with human muscles may provide a more suitable (and cost effective) disease model for the testing of gene therapies in a human muscle without falling under the FDA regulation for the use of human subjects.

    • Outcome

      Ongoing

  8. A Phase 1b/2, Open-Label, Multiple Ascending Dose Study to Evaluate the Safety, Tolerability, Efficacy, Pharmacokinetics and Pharmacodynamics of PF-06252616 in Ambulatory Participants with LGMD2I

    • Dr. Kathryn Wagner at the Kennedy Krieger Institute in Baltimore, MD
    • Since 2015
    • Description

      This study provides the initial clinical assessment of PF-06252616, a novel myostatin inhibitor, following repeat IV doses in adult ambulatory participants with LGMD2I. Reduction in myostatin has been found to improve muscle regeneration and decrease fibrosis in a variety of animal models. This study is a Phase 1b/2, open-label multiple ascending dose escalation study to evaluate the safety, tolerability, efficacy, PK and PD of PF-06252616 in 20 ambulatory adults with LGMD2I.

    • Outcome

      Ongoing

  9. Application of Rosetta to Elucidate and Correct FKRP Structure-Function

    • Dr. David Baker at the University of Washington in Seattle, WA
    • Since 2016
    • Description

      The project focuses on computationally designing peptides that will serve as chaperones for mutant forms of FKRP and help fold FKRP so that it is stabilized and its function restored. Chaperones, specific to mutated FKRP, may represent perfect candidates to stop the progression of the disease.

    • Outcome

      Ongoing

  10. Effects of Simvastatin on Systemic Muscle Function in P448L Mice

    • Dr. Bert Tanner at Washington State University in Spokane, WA
    • 2017-2018
    • Description

      The aim of this project was to determine if simvastatin could improve systemic muscle function in the P448L (LGMD2I) mouse. Because this drug was demonstrated to reduce inflammation, oxidative stress and fibrosis, and improve some muscle function in the mdx (Duchenne) mouse, long-term simvastatin supplementation in P448L mice was tested.

    • Outcome

      Ongoing