Lentiviral Gene Therapy for Artemis-Deficient SCID.

BACKGROUND: The DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation. METHODS: We carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months. RESULTS: Marrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor ß chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report. CONCLUSIONS: Infusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).

Pediatric specialists' beliefs about gastroesophageal reflux disease in premature infants.

BACKGROUND: Wide variation exists in the treatment of suspected gastroesophageal reflux disease (GERD) in premature infants; it is unknown to what degree diagnosis and treatment are affected by the treating physician's medical specialty or interpretation of the medical literature. METHODS: This study involved an online survey of board-certified neonatologists, pediatric pulmonologists, and pediatric gastroenterologists about their beliefs regarding the symptoms, diagnosis, and treatment of GERD in premature infants in the NICU on the basis of both clinical impression and interpretation of the literature. RESULTS: A total of 1021 neonatologists, 232 pediatric pulmonologists, and 222 pediatric gastroenterologists participated in the study (47.5% response rate). There was disagreement among specialists in nearly all aspects of the survey. Pulmonologists were most likely to report that respiratory symptoms are caused by GERD (P < .001). Neonatologists were least likely to report that a therapeutic trial of pharmacologic agents would be useful for diagnosing GERD (P < .001) or that lansoprazole, ranitidine, or cimetidine are safe or effective (P < .001). No pharmacologic therapy had >50% of respondents supporting its effectiveness. There was moderate correlation between physician belief based on the medical literature and belief based on clinical impression (Spearman rank correlation: 0.47-0.75). For therapies supported by multiple meta-analyses in infants versus therapies with few infant trials, physicians rated the evidence for effectiveness similarly. CONCLUSIONS: There is wide variation among pediatric specialists regarding beliefs about GERD in premature infants, as well as about the weight of evidence in the medical literature for this patient population. Physician beliefs do not seem to be driven by the degree of evidence in the neonatal literature. With no agreed-on standard of care in the setting of widespread use of antireflux medications, greater understanding is needed about the ways physicians form clinical impressions, access and process medical evidence, and apply it to patient care.