Newborn Mice Offer Hope for Less Invasive Gene Therapy.

Gene therapy has made remarkable strides in treating genetic disorders, particularly through ex vivo methods where a patient’s stem cells are extracted, genetically altered, and reinfused. Although effective, this approach involves complex, invasive procedures and comes at a high cost—such as the $2.2 million price tag for the sickle cell treatment Casgevy.

To address these challenges, scientists at the San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget) have turned to a more direct and potentially less invasive alternative. Their research focused on delivering lentiviral vectors (LVs) straight into the bloodstream, eliminating the need to extract and reinfuse stem cells. The approach leverages a biological insight: newborn mice, during their first two weeks of life, have significantly higher levels of circulating hematopoietic stem and progenitor cells (HSPCs)—the primary targets for gene therapy.

Published in Nature, the study revealed that this early-life period offers a prime opportunity for in vivo gene transfer. When researchers administered gene therapy during this short window, they observed increased stem cell correction and therapeutic effects in mouse models of three inherited blood disorders. Intriguingly, similar patterns of elevated HSPCs were also detected in young human infants, hinting at a comparable therapeutic window for early-life intervention.

To pinpoint the optimal timing, the team monitored HSPC levels in mice from birth through adulthood. They confirmed that newborns held the highest stem cell concentrations. Next, they introduced LVs tagged with green fluorescent protein into these young mice. Clonal tracking confirmed that long-term stem cells had been successfully modified. Encouraged by the efficient gene transfer, researchers hypothesized that the vectors were effectively targeting the abundant circulating HSPCs in newborns.

Seeking to extend this window of opportunity, the team used granulocyte-colony stimulating factor and plerixafor—agents known to mobilize stem cells from the bone marrow and other tissues into the bloodstream. Additionally, the lentiviral vectors were modified with a phagocytosis shield to improve stability and cellular uptake.

This refined method was then tested on mouse models of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID), autosomal recessive osteopetrosis (ARO), and Fanconi anemia. In all three cases, gene therapy delivered during early life produced meaningful results. ADA-SCID mice experienced immune recovery through increased lymphocyte levels. ARO mice developed functional osteoclasts, critical for healthy bone remodeling. Meanwhile, Fanconi anemia mice showed progressive blood system repopulation and avoided bone marrow failure. Across the board, treated mice had improved survival rates compared to untreated groups.

Lead researcher Alessio Cantore emphasized the significance of these findings: “This study provides proof of concept that in vivo lentiviral gene delivery to blood stem cells is feasible during a short but accessible period early in life as a gene therapy strategy for blood disorders.”

To examine relevance in humans, the team evaluated HSPC levels in individuals ranging from birth to adulthood. As in mice, HSPCs were most abundant in early infancy. However, they noted that adult mice showed reduced gene transfer efficiency, suggesting that future strategies may require transduction enhancers—such as interferon-alpha blockers—to boost effectiveness.

Though current efficiency still lags behind ex vivo methods, Cantore believes the in vivo approach holds promise. “If replicated in human babies,” he noted, “this strategy could offer meaningful treatment options for genetic diseases like severe immunodeficiencies and Fanconi anemia.

Source:https://www.the-scientist.com/newborn-mice-may-hold-the-key-to-simpler-gene-therapy-73065

This is non-financial/medical advice and made using AI so could be wrong.