Personal Regenerative Medicine Program for NMDs

Neuromuscular disorders (NMDs) constitute a large and heterogeneous group of diseases which impair the function of muscles and/or their nervous control that lead to movement problems. These affect 160 in 100,000 individuals, making them weak, exhausting their financial resources, and often leading to death. These possibilities are what make them of great concerns in terms of public health.

The Sheba Medical Center Neuromuscular clinic is a large tertiary referral center that serve patients from all around Israel. More than 4000 patients across the country visit the clinic every year. It also provides leading diagnostic tools for NMDs like EMG (electromyography)/NCS (nerve conduction studies), biopsies of muscles, nerves and skin, nerve and muscle ultrasound, and MRI to name a few. The three full-time clinic staff, who are trained neurologists, are involved in various clinical studies and basic research projects in the field.

A dedicated Neurogenetic clinic was established in the Danek Gertner Institute of Human Genetics at Sheba Medical Center in 2016. It is the only one in Israel devoted to provide the full spectrum of genetic services (including WES/WGS), and it serves more than 100 new NMD patients every year who were referred from the Neuromuscular clinic.

Another division at Sheba Medical Center, The Wohl Institute for Translational Medicine, was inaugurated in 2017. It is equipped with cutting-edge core labs in the fields of genetics, sequencing and bioinformatics (including a clinical genomic unit for WES/WGS analysis), proteomics, metabolomics, stem cells, chemical synthesis, microscopy and high-throughput screening platforms, along with new Good Manufacturing Practice (GMP) labs that enable development of new medical treatments in the fields of cellular and genetic therapies, as well as tissue engineering.

This campaign aims to raise funds so that Sheba Medical Center can establish a personalized regenerative medicine program for NMDs, which will be the first of its kind in Israel. We envision a hub that will bring together the neuromuscular clinic, the neurogenetic clinic, and the scientific infrastructure and knowledge of the Wohl Institute for Personalized Medicine whose main activities include genetic diagnosis, iPSC-based disease modeling, multi-omics profiling, proof-of-concept genetic therapy/RNA therapy and drug screening.

The program will focus on myopathies (such as congenital muscular dystrophy, limb-girdle muscular dystrophy, distal myopathies and congenital myopathies) and genetic forms of axonal neuropathies (such as Charcot-Marie-Tooth and distal hereditary motor neuropathies). It will have the following functions, building on expertise already in place: 

1. Comprehensive genetic characterization of NMD patients based on whole exome/genome sequencing and advanced in-house bioinformatics to identify disease-causing defects and modifiers. 

2.  Generation of individual patient iPSCs, and differentiated tissue thereof, to form a national biorepository for research and disease modeling. 

3.  Multi-omics (DNA, RNA, protein) profiling of patient/healthy iPSCs and differentiated tissue.

4.  Confirmation of the genetic basis of disease and proof-of-concept CRISPR/Cas-based genome editing by two complementary approaches: isogenic control cell lines will be generated by introducing patient-identified mutations into WT iPSCs, and mutations in patient-derived iPSCs will be corrected by CRISPR/Cas. Molecular and functional assays will be developed and used for confirmation. 

5.   RNA therapy (ASO, RNAi etc.) and gene replacement as alternative/complementary approaches to genome editing, depending also on the individual nature of the molecular defect. 

6.  Development of high content assays for HTS/HCA of small molecule libraries and scaling-up of one assay with a number of small molecule libraries using 1-2 iPSC lines.

Our team has the infrastructure, capacity and scientific knowledge to deliver these ambitious goals. We find ourselves at a unique juncture where we have the power to integrate multi-dimensional clinical, biological, imaging and genetic datasets of our patient cohorts with characteristics of the patients’ own cell towards identification of precision therapies. <b> </b>

The resources and data generated will help develop a personalized patient-centric therapy discovery pipeline. The combination of these aims will form the infrastructure for personalized genomic medicine for NMDs in Israel.

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