Modelling ADA-SCID neuropathology at scale using patient-derived organoids

Adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID) is a rare genetic disorder caused by the loss of ADA. ADA-SCID is widely known as an immunodeficiency which is fatal in early childhood if left untreated. However, in addition to the immunological impairment, ADA-SCID is characterized by the development of a spectrum of neurological deficits, including reduced verbal expression, learning disability, hyperactivity, attention deficits, structural abnormalities, and hearing loss. Despite the available ADA-SCID therapies, such as the correction of immune cells by gene therapy or the use of enzyme replacement therapy, children affected by ADA-SCID continue to present these neurological, cognitive and behavioural impairments throughout their lifetime.

How ADA genetic mutations lead to neurodevelopmental deficits and neurological symptoms in ADA-SCID patients remains unknown. This lack of knowledge further prohibits the development of new therapeutic strategies. In this project, we will use human stem cell-based three-dimensional models of the brain to further our knowledge of the neurological impairments in ADA-SCID patients and identify new therapeutic targets. Furthermore, starting from ADA-SCID patient blood cells, after their reprogramming into human stem cells, we will study how brain development is affected due to impaired ADA function. This study will represent an important step forward for our understanding of how ADA modulates brain development and function, and help identify therapeutic targets to design ADA-SCID neurological associated treatments, with the hope of improving the quality of life in ADA-SCID affected children.