San Raffaele Telethon Institute for Gene Therapy

Mechanisms of inflammation in health and disease


Group leader

Alessandra Mortellaro


Inflammation is a vital process that the immune system executes to remove injurious stimuli and initiate the healing process. Failure to efficiently resolve inflammatory insults can have severe consequences for tissue maintenance and function, leading to chronic inflammatory diseases. The laboratory's overarching goal is to understand the inflammatory response pathways and molecular mechanisms that orchestrate immune dysfunction in autoinflammatory diseases and develop improved targeted therapies that positively impact the health outcomes of patients, often children, living with these conditions.


Alessandra Mortellaro received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement (No 841780) for the project entitled “Development of gene therapy and genome editing strategies to treat adenosine deaminase 2 deficiency”.

Research activity

Our research focuses on two areas:

  • Adenosine deaminase 2 deficiency (DADA2) is a newly identified autoinflammatory syndrome caused by autosomal recessive mutations in the ADA2 gene. The most common presentations of DADA2 are cutaneous and cerebral vasculopathy, stroke, systemic inflammation, hematological and immunological manifestations. If undiagnosed, patients with DADA2 can have a fatal outcome, and current treatments are unsatisfactory. Therefore, there is an urgent unmet medical need for this otherwise life-threatening disease. The clinical presentation suggests that immune dysregulation may be the primary cause of DADA2 pathophysiology, but currently, there is a complete lack of information on the role of ADA2 in immune regulation. Our group is working towards identifying the cellular and molecular mechanisms responsible for DADA2, with the final goal to initiate a first-in-human gene therapy clinical trial.
  • During homeostasis, the process of hematopoietic stem cell (HSC) renewal and the production of lineage-committed progenitors are tightly controlled to maintain daily blood cell production. Upon immunological stress, such as infection and inflammation, there is a high demand for leukocytes to replace cells and increase immune surveillance. HSCs can sense microbial components using innate cell receptors. NOD-like receptors (NLRs) are intracellular pattern recognition receptors, essential components of the innate immunity network. Although HSCs express these receptors, it is unclear whether NLRs could regulate hematopoiesis. Our group studies the role of NLRs in shaping HSC fate and blood output under physiological conditions and after inflammatory insults and in the context of chronic inflammatory diseases.

Our studies will collectively provide the molecular and cellular bases of inflammation, which can be exploited to pave the way for new strategies to hasten its resolution in patients affected by chronic inflammatory conditions.