Exploiting ex vivo expansion and deep multiomics profiling to bring novel, efficient and safer hematopoietic stem cell gene therapies to clinical application

Introduction

Hematopoietic stem cells (HSC) are an elusive cell type, whose presence can only be inferred retrospectively from the outcome of time-consuming transplantation experiments. Since current state-of-the-art does not allow prospective HSC identification, today’s cell and gene therapy technology has been mostly optimized on surrogate progenitor cells, which differ biologically from HSC.

Technological Breakthrough

The technological breakthrough of this proposal is to capture HSC in the ex vivo culture, achieved by a combination of:

• Innovative expansion conditions
• Iterative cell sorting
• Multiomics single cell profiling

Rapid, quantitative, and qualitative in vitro HSC assessment predictive of in vivo function may become a sustainable alternative to mouse xenotransplantation experiments.

Application of Genetic Engineering Technologies

Applied to a state-of-the-art toolbox of genetic engineering technologies, including:

1. Clinically-proven lentiviral vectors
2. Established and emerging targeted genome editing approaches

Our in vitro HSC readout sets new standards in terms of throughput and turnaround time. This allows for efficient testing of a multitude of HSC engineering conditions and tailoring the most suitable technological approach to a specific disease or therapeutic application.

Precision-Based Approach

This new precision-based approach to ex vivo HSC gene therapy will be applied to:

• Inherited bone marrow failure syndromes
• Cancer

These serve as paradigmatic examples where gene therapy may be used to correct a cell-intrinsic genetic defect or turn hematopoietic progeny into therapeutic vehicles provided with novel functions.

Collaborative Expertise

Bringing together experts in:

• Cutting-edge gene editing technologies
• Ex vivo HSC manipulation
• Assessment of HSC responses to genetic engineering
• Bioinformatics analysis & integration of multi-dimensional single cell data

This collaboration will maximize the chances of delivering safer and more effective next-generation HSC-based gene therapy products. It will extend the reach of gene therapy to new disease contexts and make the outcome after gene therapy more predictable.