Stem cells can tailor their role in gene therapy based on the underlying disease, study suggests

RCCS San Raffaele Scientific Institute in Milan researchers have discovered that hematopoietic stem cells (HSCs) adapt their lineage commitment during gene therapy based on the underlying genetic disease.

Hematopoietic stem cell gene therapy (HSC-GT) represents a cutting-edge treatment strategy for multiple genetic disorders. By correcting genetic defects within hematopoietic stem cells (HSCs), this therapy aims to reestablish normal blood cell function.

A comprehensive understanding of the long-term behavior and adaptation of these stem cells, particularly in relation to various disease contexts, is vital for optimizing therapeutic outcomes and ensuring sustained patient benefits.

In the study “Long-term lineage commitment in hematopoietic stem cell gene therapy,” published in Nature, the team investigated how stem cells used in gene therapy behave differently depending on the genetic disease they’re treating, offering new insights into the dynamics of hematopoietic reconstitution in patients with inherited disorders.

Researchers analyzed 53 patients treated with lentiviral HSC-GT for metachromatic leukodystrophy, Wiskott-Aldrich syndrome, or β-thalassemia. Patients were followed for up to eight years, allowing for a comprehensive examination of long-term hematopoietic reconstitution. By tracking vector integration sites as unique markers of clonal identity, the team assessed how transplanted HSCs contributed to blood cell production over time.

Findings revealed that long-term hematopoietic reconstitution was supported by 770 to 35,000 active HSCs. Approximately 50% of the transplanted clones showed multilineage potential, contributing to multiple blood cell types across all conditions.

The remaining clones exhibited disease-specific lineage preferences. In patients with a disorder affecting red blood cells (like β-thalassemia), the stem cells primarily produced more red blood cells. They produced more immune cells in conditions affecting immune cells (like Wiskott-Aldrich syndrome). Similarly, stem cells produced more myeloid cells in patients with metachromatic leukodystrophy, a disorder affecting myeloid cells.

This means that stem cells can adjust their development to better address the particular problems caused by each disease during treatment.

These observations suggest that the underlying genetic disease influences HSC behavior, affecting both lineage output and long-term commitment. Factors such as patient age at therapy, the extent of genetic correction, and disease-induced hematopoietic stress were found to modulate HSC activity and somatic mutation rates.

The detailed insights the findings provide have potential implications for optimizing HSC-GT protocols and improving long-term outcomes for patients with inherited blood disorders.

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