Practice question

Adenosine deaminase deficiency autosomal recessive SCID became earliest successful gene therapy target due biological features favoring correction. Enzyme chromosome 20q13.12 deaminates adenosine to inosine and deoxyadenosine to deoxyinosine, deficiency leads accumulation deoxyadenosine converted deoxycytidine kinase to dATP elevated dATP allosterically inhibits ribonucleotide reductase essential dNTP synthesis DNA replication lymphocyte clonal expansion triggers apoptosis intrinsic pathway resulting absent T B NK cells. Lymphoid lineage provides selective advantage because corrected cells detoxify metabolite locally via metabolic cross-correction proliferate growth advantage while uncorrected die amplifying gene-marked population without myeloablation similar natural reversion mosaicism. HSC accessible bone marrow aspiration amenable retroviral transduction MoMLV vector carrying ADA cDNA under LTR promoter. First trial 1990 Anderson Blaese Rosenberg infused autologous transduced T lymphocytes demonstrating persistence partial enzyme activity. Later Strimvelis product autologous CD34 cells gamma retroviral vector achieved immune reconstitution and became first ex vivo gene therapy approved Europe highlighting importance long-term monitoring leukemia due insertional activation.