Gene therapy in newborn mice targets blood stem cells directly

Blood stem cells can be targeted directly with gene therapy to improve survival of newborn mice with rare disorders.

Ex vivo gene therapies targeting blood stem cells have been successful in clinical trials in recent years (see BioNews 1095, 1118, 1272). In these cases, the stem cells were extracted from the body, a lentiviral vector used to insert the necessary DNA, and then the cells were reinfused following chemotherapy. Although successful, this approach can be invasive and costly. Now, researchers in Italy have shown that in newborn mice, blood stem cells inside the body can be targeted directly, which led to improved therapeutic outcomes and prolonged lifespan.

'After birth, blood stem cells need to move from the liver, where they have resided throughout the last months of pregnancy to their definitive home in the bone marrow,' said Dr Michela Milani from San Raffaele Hospital in Milan, who is lead author of the study published in Nature. 'We found that as they so travel in the circulation they can be more easily accessed by intravenous delivered vectors and thus be genetically modified without the need to harvest and process them outside of the body.'

Dr Milani and colleagues identified a short window in the first two weeks after birth, where a high number of blood stem and progenitor cells are circulating in the blood stream. In vivo gene therapy at this point resulted in a greater number of modified stem cells – compared to treating adult mice – that remained detectable for one year after the initial treatment.

The gene therapy was tested in three mouse models of genetic conditions: one was adenosine deaminase-deficient severe combined immunodeficiency which affects lymphocytes – white blood cells crucial to immune function – leading to a severely compromised immune system. The other two conditions both affect bone marrow: autosomal recessive osteopetrosis which is typically fatal in infancy, and Fanconi anemia which affects DNA repair, particularly in stem cells.

The approach significantly improved survival across all three conditions, and in the Fanconi anemia model, the modified stem cells gradually increased in the bloodstream over a period of one year and successfully prevented bone marrow failure in the treated mice.

Although the research was conducted in mice, the authors noted that similar circulating blood stem cells are present in human newborns in the first months after birth.

'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,' said Dr Alessio Cantore from Vita-Salute San Raffaele University in Milan, who supervised the research. 'While the efficiency currently remains limited as compared to established ex vivo treatments, it may suffice, if replicated in human babies, to benefit some genetic diseases.'

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The availability of genetic and genomic testing for people and families affected by rare disease will be discussed at the free-to-attend online event Rare Disease Genomic Testing: How Do We Make Access Equitable and Timely?, taking place online on Wednesday 22 October 2025.

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