Project Summary Severe combined immunodeficiency (SCID) is a group of rare genetic disorders that result in profound defects in adaptive immunity. This disorder is treatable by bone marrow or blood transplantation with improved results if performed within the first few months of age and if a matched sibling donor is available. Unfortunately the majority of children do not have a sibling donor available, and the results of alternative donor transplant are non-optimal. SCID is now increasingly diagnosed at birth by universal newborn screening, which will soon spread to the entire 50 states. Determining the most efficacious and least toxic methods to cure SCID by transplantation in these newly identified newborns requires well designed prospective multi-institutional trials, which to date have never been performed. We have formed the Primary Immune Diseases Treatment Consortium (PIDTC) an NIAID funded group of >30 institutions dedicated to studying and advancing the treatment of immunodeficiency. The PIDTC is proposing to develop a trial to determine the optimal conditioning regimen for treatment of SCID, hypothesizing that a submyeloablative dose of busulfan will result in multilineage immune reconstitution. The trial is a phase I/II multi-institutional dose finding study that seeks to enroll 6 patients on each of 3 dose levels and 3 donor sources (haploidentical parent, matched unrelated donor, cord blood donor), a total of 54 patients with SCID. In Specific Aim 1 we describe the progress to date on trial development and detail how we would complete the protocol and obtain regulatory approval. In Specific Aim 2 we describe the current PIDTC structure and our plans to build the clinical trial infrastructure for this study.

Project Narrative Universal newborn screening targets genetic diseases where early identification impacts clinical outcome. We seek to improve the treatment of one such disorder, severe combined immunodeficiency (SCID), a rare disease of the immune system which is curable by bone marrow or blood transplantation. Because the best transplantation method for SCID is still not known, we propose a multi-institutional prospective trial to determine the method that will lead to the best immune reconstitution with the least toxicity.