Creation of a GLP bank of immune-privileged, immortal mesoangioblasts to treat monogenic, recessive diseases of muscle and connective tissue

Introduction

Stem cells led to effective cures for diseases of blood and epithelia. However, in the case of diseases affecting muscles, connective tissue, or the brain, significant challenges persist for the expansion of a sufficient number of corrected cells, delivery, and engraftment. Even when these problems are solved, the prospective per-patient cost of the treatment (up to $2M) will make such therapies unsustainable for the NHS.

Current Research

We developed protocols for cell therapy using mesoangioblasts (Mabs), vessel-associated progenitors that, despite promising results in animal models, showed modest efficacy in patients. To address this, we transplanted autologous dystrophic Mabs expressing a small nuclear RNA engineered to skip dystrophin exon 51. This RNA enters and corrects neighboring nuclei of the multinucleated muscle fiber, thus bringing dystrophic production to therapeutic levels. A Phase I/IIa trial is currently running. Even in the case of success, the cost would remain prohibitive.

Future Directions

Through the ongoing ERC ADG 884952-UniMab, we are completing the development of immortal, immune-privileged Mabs from dystrophic patients thanks to genome editing of HLA and the expression of tolerogenic proteins.

Proof of Concept Project

In this PoC project, we will:

1. Produce universal Mabs from healthy donors.
2. Study the feasibility of producing and storing a large amount of universal Mabs through a bank of universal donor Mabs from healthy patients.
3. Prepare these cells to be corrected for the specific genetic mutation and injected into the patient, following the motto "one serve many."

Available cells, a GMP-grade lentivector expressing the wild-type cDNA of the mutated gene, and a mouse model for pre-clinical tests would be sufficient to start a trial even for extremely rare diseases that currently lack any hope of therapy.

Business Exploitation

This work will enable the business exploitation of the MABANK technology by creating a company with a GMP biobank that may operate internally and make cells available to clinicians and biotech companies.