Title:
What we learnt from the gene therapy for ADA deficiency

Masafumi Onodera, MD, Ph.D
Chief, Department of Human Genetics, Research Institute, National Center for Child Health and Development

Abstract:
An accumulation of the toxic metabolites of purine nucleotides, dATXP, due to an inherent deficiency of adenosine deaminase ( ADA ) causes one form of severe combined immunodeficiencies (SCID) by impairing proliferation of immature T lymphocytes in the thymus severely. In addition, ADA-SCID is also categorized as an inherent metabolic disease because the toxic metabolites are accumulated in the whole body resulting in serious organ failure of the brain, liver, or gastrointestinal tract, so on. Therefore, contrary to other primary immunodeficiencies in which the curative treatments are limited to HLA-identical stem cell transplantation or stem cell gene therapy, ADA-SCID is an disorder capable of being treated with the enzyme replacement therapy (ERT) using the polyethylene glycol-conjugated ADA (PEG-ADA) as the third therapeutic option. More than 160 patients with ADA-SCID have received PEG-ADA as the cumulative total number and approximately 90 are still being treated with the ERT. On the other hand, the stem cell gene therapy has been done for 36 patients all over the world and most of the cases have shown curative effects without any severe adverse effects. In Europe , stem cell gene therapy is one of the effective therapeutic options for ADA-SCID without suitable donors.
We have had various experiments and learnt important lessons on gene therapy through the care for two ADA-SCID patients since 1995 when gene therapy targeting the peripheral lymphocytes was performed for the patient as the first clinical trial in Japan . In particular, stem cells gene therapy that we performed under the non-myeloablative condition in 2004 was obvious proofs of importance of bone marrow niche in stem cell gene therapy and yielded the partial recovery of their clinical symptoms, resulting in a requirement of the restart of ERT at 6 years after gene therapy. In this seminar, I would like to introduce what we learnt from the gene therapy for ADA-SCID and think about the directional movement of stem cell gene therapy together.