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Resources for Scientists

NDF continues to be the world leader in funding diverse and groundbreaking research projects devoted to GNE Myopathy. Our team of new scientific investigators are growing at an impressive rate, and their dedication to data-sharing and genuine collaboration is keeping with NDF’s grant awards and proving to be of great value. Please see see our list of past and present grantees here. 

We are always on the lookout for promising research projects that will directly impact the lives of GNE Myopathy patients. 

If you are a researcher interested in applying for funding from NDF, please contact us. 

 

Ongoing Scientific Studies and Collaborations

The following laboratories and scientists are currently the key players in the field of GNE Myopathy research.

Current Status of Therapy Development

Several factors contribute to the successful development of an effective therapy to HIBM

  • Identification and optimization of a therapeutic approach (AAV-mediated gene therapy; gene correction strategies; drug replacement/development  therapy)
  • Development of outcome measures (critically important in diseases characterized by slow progression like HIBM)
  • Identification of biomarkers to be used to validate efficacy as well as identify new drugs that can slow down disease progression.
  • Establishing a patient registry to use for clinical trials.
  • Generation of animal models to validate therapy efficacy.
  • Repositories of data and biological specimens to identify biomarkers/outcome measures.

 

SUMMARY OF CURRENT STUDIES SUPPORTED BY NDF in 2020

Project 1. Development of animal models for GNE myopathy (Hadassah Medical Center/Dr. Stella Rosenbaum)

The goal of the project is to develop a mouse and a zebrafish models lacking expression of GNE. Progress reports submitted to the NDF show that both projects are on their way. Animal models are necessary to assess efficacy of any therapy and establish dose needed to achieve an effect. Furthermore, these models will enable to stimulate the interest and gain the attention of pharmaceutical companies interested in developing and marketing a cure for HIBM. The NDF has been aggressively pursuing the development of multiple models for the disease with the aim of obtaining at least one that shows the phenotype and the characteristics needed to be a useful model. Sofar, the only models available either don’t show a consistent phenotype or they die too young to be able to evaluate possible outcomes. The results obtained so far, although still at an early stage, are very encouraging and demonstrate that at least one of the model (zebrafish) has been generated. Currently the NDF is promoting and is helping establishing collaborations among different scientists to ensure that the model becomes a valuable shared resource for the HIBM field.

 

Project 2. Biobank (Yale University- Lek Lab/Dr. Monkol Lek & Dr. Angela Lek)

The goal of this project is to establish a repository of cells from patients, family members and eventually animal models as a resource for the HIBM community of scientists and pharmaceutical companies for research purposes (including identification of biomarkers and to validate therapeutic applications). To date, the Lek lab was able to establish and bank 40 cell lines. All are available as fibroblasts (skin cells) as well as myoblasts (muscle cells). DNA and RNA have been collected and stored for upcoming sequencing and samples have been already shared with other investigators in the HIBM field (Noah Weisleder -Ohio State University, Kelly Crowe -Mount St. Joseph University). Future plans include further collection and storage of samples that contain different mutations from so as to obtain a good representation of all HIBM patients worldwide.

 

Project 3. Whole Genome Sequencing (WGS) (Dr. Monkol Lek & PerkinElmer)

Of the 100 samples originally contracted with PerkinElmer (PE), a total of 40 samples have been collected and WGS has been carried out accordingly.  Samples were obtained from NIH (8 samples, 2 families), India (18 samples), Israel (27 samples), Philadelphia (26 samples). One family (5 samples) overlap with NIH samples. Sequencing of 40 samples completed and raw data was shared by PE. Raw data is currently being processed and analyzed in the Lek lab.

 

Project 4.  Identification of Biomarker (NHGRI-NIH/Dr. Marjan Huizing)

The study is focused on identify biomarkers and gene modifiers that could play a role in disease progression. Analyses could identify new players in the disease as well as new potential outcome measures to use in clinical trials to validate the efficacy of the therapy. Currently, there are 22 GNE-M patients from the Phase 1-ManNAc trial and 12 patients from the Phase 2-ManNAc trial, whose blood has been tested for differences in free Neu5Ac from baseline levels.

Quantitative lectin analysis on muscle biopsy slides at baseline and after 30 days of ManNAc therapy in 12 patients in the NIH Phase2-ManNAc trial show significant differences in hyposialylation of GNE-M muscle tissue after 30 days ManNAc therapy compared to baseline suggesting that this assay could be used as possible outcome measure although it requires invasive procedures like collection of muscle biopsies. Current studies are now focused on identify additional biomarkers which require less invasive procedures (Sialylated Blood Glycans, Plasma T-ST Ratios).

 

Project 5. CRISPR gene editing approaches to GNE (Dr. Angela Lek)

The project is focused at conducting proof-of-concept studies in cells in vitro and at correcting the M743T mutation in patient fibroblasts. According to the most recent progress report, the cell lines and constructs needed to carry on the project have been successfully generated and results on the feasibility of using CRSPR-mediated gene editing approaches should be obtained by the end of the funded project.

 

Project 6. Lectin Staining Biomarker for GNE Myopathy (Mt. St. Joseph University /Dr. Kelly Crowe & NIH)

The goal of this study is to test levels of GNEM biomarkers in patient cells in vitro before and following gene therapy. Studies will then be extended to patient muscle biopsies as well as zebrafish models for the disease currently being established in the laboratory of Dr. Stella Mitrani-Rosenbaum and sponsored by the NDF. The results obtained are particularly important because, if successful, will enable to establish outcome measure to be used in clinical trials and are required by the FDA in order to receive approval of the therapeutic approach being tested.

 

Project 7. Compromised membrane repair as a potential pathologic mechanism in GNEM patients (Ohio State University/Dr. Noah Weisleder)

Exiting preliminary studies provided by Dr. Weisleider suggest that muscle cells isolated from GNE myopathy patients and obtained through the Lek lab) show to be more susceptible to damage than cells isolated from non-affected individual. This finding is particularly important because could explain the slow deterioration of muscles in patients. Furthermore, the studies will help establish important biomarkers and outcome measures to be used in future clinical trials which are critically needed at this stage of clinical development for HIBM. The assays being developed in the Weisleider lab could in fact become integral part of clinical practices in human trials and to identify different stages of the disease. In addition, the assay could be used to prove the efficacy of the gene therapy application being tested thus becoming a valuable tool to ensure FDA approval.

 

Project 8. Development of FDA-compliant gene therapy assays for GNE myopathy (Nationwide Children's Hospital/Dr. Paul Martin)

The project is focused on developing a gene therapy clinical development plan to be used to demonstrate activity of AAV-mediated delivery of GNE into cells and muscles of mice. In particular, the project will establish a potency assay that effectively describes the biological activity of the AAV vector to be used, in this case a AAV.GNE gene therapy vector. This assay must be done annually on clinical lots of AAV to demonstrate that potency has not been lost, and it must also be done to demonstrate that the AAV to be used in patients has the necessary biological activity when it is administered. Dose-response study in wild type (C57Bl/6J) mice with AAV.GNE vector will be used to assess the dose and level of vector genome transduction needed to provide a one-fold elevation in GNE enzyme activity (i.e., functional gene replacement). These studies will provide data needed to determine levels of functional GNE over expression required for gene replacement in all organs and the number of vector genomes that must be transduce to accomplish such changes.

 

Project 9. Activation of endogenous mutated GNE product by small compound (NCNP/Dr. Ichizo Nishino/Dr. Wakako Yoshioka)

Dr. Yoshioka will undertake a drug discovery project aimed at identify compounds capable of activating the GNE/MNK kinase. In silico, computerized models will be used to identify drugs that are already available on the market and that could therefore be repurposed for HIBM patients. The goal is to identify drugs that activate GNE/MNK kinase and therefore elevates supply of sialic acid (SA) to the whole body, including muscles. The use of drugs that are already approved for the use in patients for other diseases may be subjected to less stringed regulatory issues and has the potential to reach the bed side in a shorter period of time compare to new compounds. If proven safe and effective, the drug could be used alone or in combination with gene therapy- mediated approaches to HIBM thus increasing the efficacy of the clinical approach.

 

In 2019 NDF Funded the Following Studies:

 

1.      Hadassah. Dr. Stella Rosenbaum

 Knock-in Mouse Model and zebra fish study.

If successful, this grant will expedite approval at the FDA level and solve a long-standing obstacle in this area.

 

2.     Yale. Lek lab. Drs. Monkol & Angela Lek

 If successful, this grant will provide new biomarkers useful in tracking therapies, including gene therapy. The other study, the CRISPR study, provides an alternative form of gene therapy that may be more successful.

 

3.     National Institutes of Health (NIH). Dr. Nuria Carrillo & Marjan Huizing

SAC considers this funding (in the form of a grant) critical to the continuation of support for the GNEM studies at NIH and aid in additional human resource to further their studies in this area.

 

 Mount St. Joseph/Nationwide Children’s Hospital. Dr. Kelly Crowe

This project proposes to use sialylation-sensitive lectins in GNEM patient myoblast cells with a variety of GNE mutations to identify biomarkers of disease which can then be used to assess the therapeutic potential of therapies such as gene therapy.

             Click the image below for a detailed and comprehensive explanation of GNEM (HIBM)