Alessandra Mortellaro (Italy)
IRCCS San Raffaele Scientific Institute
San Raffaele Telethon Institute for Gene Therapy (SR-Tiget)
Alessandra received a Ph.D. in Cellular and Molecular Biology from the Open University (UK) and the Vita-Salute San Raffaele University. During her Ph.D. studies at San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), she investigated the efficacy and safety of lentiviral vector-mediated gene therapy in the mouse model of ADA-SCID. Alessandra actively contributed to the clinical development of gene therapy mediated by the infusion of genetically corrected hematopoietic stem cells for ADA-SCID. She continued her postdoctoral studies in the laboratory of Prof. Paola Castagnoli at the Department of Biotechnology and Biosciences, University of Milano-Bicocca, where she investigated the role of dendritic cells in the inflammatory process induced by pathogens and danger signals alerting the immune system. In 2008, Alessandra moved to the Singapore Immunology Network (SIgN-A*ASTAR, Singapore), a new and vibrant international research institute, and became a Principal Investigator in 2011. She studied the innate mechanisms driving inflammation, particularly the role of the NLRP3 inflammasome. Her work also significantly contributed toward filing a patent for IL-1b-neutralizing human monoclonal antibodies following functional studies in a mouse model of gout. She is currently a Group Leader at SR-Tiget. The research activity of her group focuses on understanding the immunological mechanisms regulating the inflammatory processes to identify new therapeutic targets. In addition, her team is developing advanced therapies based on genetically corrected hematopoietic stem cells to treat autoinflammatory diseases. Alessandra published more than 50 peer-reviewed original papers and reviews. She received the Young Investigator Award from the League Associations of Rheumatology (2011) and the prestigious Marie Skłodowska-Curie Individual Fellowship funded under the Horizon 2020 program by the European Commission (2019).

Presenter of 1 Presentation

 Conference Calendar

CHARACTERIZATION OF HEMATOPOIETIC STEM CELL FUNCTIONS IN PATIENTS WITH ADENOSINE DEAMINASE 2 DEFICIENCY

Session Type
Parallel Sessions
Session Name
0930 - Parallel Session 11: IEI and Hematological Disease/BM Failure (ID 74)
Date
Fri, 14.10.2022
Session Time
14:00 - 15:30
Room
Session Hall 01
Lecture Time
15:02 - 15:12
Presenter

Abstract

Background and Aims

The deficiency of adenosine deaminase 2 (DADA2) is an inborn error of immunity caused by loss-of-function mutations in the ADA2 gene. Manifestations include vasculopathy and immunological and hematological abnormalities. It is unknown how ADA2 loss causes bone marrow (BM) failure, and understanding these mechanisms is essential for developing new targeted therapies.

Methods

We analyzed the BM composition in patients and evaluated the toxicity and efficacy of ADA2 gene transfer in patients’ hematopoietic stem-progenitor cells (HSPCs).

Results

HSPCs and the primitive compartment were significantly reduced in patients’ BM compared with healthy donors (HDs). Although reduced in number, patients’ HSPCs showed normal clonogenic and differentiation potential. We also characterized patients’ mesenchymal stromal cells (MSCs), critical elements interacting with HSPCs in the BM. They exhibited a reduced clonogenic capacity and low levels of primitive marker expression, while senescence markers increased compared with HDs. To assess whether gene therapy could represent a potent treatment for DADA2, we developed a lentiviral vector (LV) to restore constitutively ADA2 expression in patients’ HSPCs. HSPCs transduction allowed efficient delivery of the functional ADA2 enzyme in patients’ CD34-derived cells without signs of toxicity. Transduced HSPCs infused into immunocompromised mice demonstrated that ADA2-modified cells supported a multilineage reconstitution with a polyclonal integration pattern.

Conclusions

Our results indicate that the loss of ADA2 leads to a reduced number of primitive progenitors in the HSPC pool and an exhausted MSC phenotype. LV-mediated ADA2 reconstitution seems a promising approach to re-establish stable ADA2 activity and correct the hematological manifestations in patients with DADA2.

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