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I – Gene & Cell Therapy Trials in Progress -> Gene & Cell Therapy Trials in Progress

Long Term Lineage Commitment is Modulated by the Underlying Disease in Hematopoietic Stem Cell Gene Therapy Patients

Type: Oral Abstract Session

Presentation Details
Session Title: Late-breaking Abstracts 2
Location: Concourse Hall 152 & 153
Start Time: 5/19/2023 11:00
End Time: 5/19/2023 11:15

Hematopoietic Stem and Progenitor Cells (HSPCs) can self-renew, produce all blood cell types during the entire lifespan. In HSPC gene therapy, patients’ HSPCs are purified, genetically modified in vitro with gene therapy vectors to restore the defective function, and then reinfused into the patient to allow the reconstitution of the hematopoietic system and provide therapeutic benefit. Although this approach has been successful for the treatment of diverse genetic disorders such as immunodeficiencies, hemoglobinopathies and metabolic diseases, how the underlying genetic disease, age of treatment and other factors may impact hematopoietic reconstitution, lineage specification, and efficacy in different each different context is not well understood. Here we compared the clonal repertoire and dynamics of hematopoietic reconstitution by tracking >4 million vector integration sites, a surrogate of clonal identity, from purified myeloid, lymphoid, erythroid cell lineages and HSPCs from 53 patients treated by lentiviral-based HSPC-GT for metachromatic leukodystrophy (MLD) - a neurodegenerative lysosomal storage disorder, Wiskott-Aldrich syndrome (WAS) - an immunodeficiency with thrombocytopenia and β-thalassemia (β-Thal) - a hemoglobinopathy (up to 8 years of follow-up). All patients, regardless the disease, showed neutral long-term polyclonal and multi-lineage reconstitution. The number of repopulating HSPCs in vivo long-term ranged from 770 to 35,000, with a direct proportionality to the total number of infused HSPCs. A large fraction of clones estimated in the early phase were exhausted within 12 months and were replaced by a smaller, yet substantial, number of long-term IS stably sustaining steady-state hematopoiesis. About 50% of clones were found to have multilineage output (thus present in multiple lineages, such as in lymphoid and myeloid or erythroid lineages) while most of the remaining 50% of clones showed disease-specific lineage-biases. In MLD patients, HSPCs output was skewed towards the myeloid lineage, while in WAS patients was skewed towards T and B cells, and in β-Thal patients towards erythroid cells. Adult β-Thal patients (>30 years old at the time of treatment), showed a strong bias towards the erythroid linage compared to pediatric, potentially indicating the effect of functional impairment of the bone marrow niche and HSPCs. Intriguingly, the impact of the disease condition has a long-term effect on the commitment of HSPCs even after gene therapy has successfully treated the disease manifestations. Indeed, MLD patients showed a long-term commitment of their HSPC towards myeloid lineages, while patients treated for WAS had a preferential output and commitment towards lymphoid lineages and patients treated for β-Thal towards the erythroid lineage, especially in adult patients. Therefore, our data suggest that HSPCs acquire and retain a memory of the preexisting clinical condition, resulting in a permanent biased commitment to differentiate toward specific lineages. In summary, our results show that in HSPC gene therapy patients, the hematopoietic reconstitution, lineage output, and long-term lineage commitment, are regulated by the underlying disease and and and that HSPCs adapt to better respond to the pathological condition.

Andrea Calabria1, Giulio Spinozzi1, Daniela Cesana1, Fabrizio Benedicenti1, Giulia Pais1, Serena Scala1, Maria Rosa Lidonnici1, Samantha Scaramuzza1, Sarah Marktel1, Bernhard Rudolf Gentner1, Fabio Ciceri2, Luigi M. Naldini1, Giuliana Ferrari1, Alessandro Aiuti1, Eugenio Montini1

1San Raffaele Telethon Institute for Gene Therapy, IRCCS San Raffaele Scientific Institute, Milan, Italy,2Pediatric Immunohematology and BMT, San Raffaele Hospital, Milan, Italy
 E. Montini: None.

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