Prof. Marisa Jaconi, University of Geneva

Abstract

Human mesoangioblasts (hMABs) constitute a new potential stem cell type for regenerative medicine; they are indeed mesenchymal-like cells retaining endothelial and mesodermal differentiation potential, present in the large-vessel niche. Many recent publications point out how mesoangioblasts, derived from skeletal muscle associated large vessels, can actively migrate after systemic injection and participate to the regeneration of skeletal muscle in diseased animals, such as mdx/SCID mice 1,2 and dystrophic mice and dogs 3,4.  Recently, a clinical trial in five paediatric patients affected by Duchenne muscular dystrophy is under completion at San Raffaele Research Institute in Milan (Italy) under the direction of Prof. Giulio Cossu.

The aim of this project is a preclinical trial in limb-girdle muscular dystrophy type 2D (LGMD-2D) immunodeficient mice (Scga null/SCID/beige) with a novel optimized cell therapy protocol based on intra-muscular (i.m.) and intra-arterial (i.a.) delivery of hMABs that are produced in clinically-compliant GMP conditions. This project aims to find a therapy for muscular dystrophy. It aims at correcting the genetic lesion, through fusion of normal stem cells with regenerating dystrophic muscle fibers to which they will contribute a wild type copy of α‐sarcoglycan. Human α‐sarcoglycan expression should lead to molecular rescue of the regenerated fibers.

The primary end-points of the study are:  1) The evaluation of the engraftment under immunosuppressive conditions (SCID/beige mice) of HLA-characterized donor hMABs directly injected in bilateral tibialis anterior muscles of mice. We will evaluate the ability of hMABs to give rise to human α-sarcoglycan-positive muscle fibers within murine dystrophic muscle; 2) The evaluation of safety of hMAB intra-arterial injection, both at short-term and long-term times in dystrophic mice.

The secondary end-points are: 1) The evaluation of efficacy of hMAB intra-arterial injection (i.e. complete assessment of muscle strength and motor ability and presence of donor-derived dystrophin). We will perform micro-PET analysis to assess muscle function post transplantation; 2) The evaluation of immunization against HLA-characterized donor hMABs in groups A and B.

The final outcome will depend on the total number of fibers that will be reconstituted with donor α-sarcoglycan and on the amount and distribution of the expressed protein. Even though it is not realistic to expect a complete rescue of the clinical pathology, a significant amelioration with stabilization of muscular force would represent a milestone in the field and set the stage for future trials, combining cell and pharmacological therapies, leading in time to a real “cure”.

In summary, this project is expected to 1) provide further information on safety and efficacy of transplanting HLA-characterized hMAB isolated using GMP-certified clinically-compliant Standard Operating Procedures (SOPs),and 2) prepare all the regulatory assets for producing clinical-grade hMABto ensure a rapid translation into future clinical trials.