# Clinical and mechanistic studies defining optimal preparative approaches to infants with IL2RG/JAK3/RAG1/RAG2 SCID: a randomized trial of busulfan dosage

> **NIH NIH U01** · NATIONAL MARROW DONOR PROGRAM · 2024 · $1,072,951

## Abstract

Project Summary
 Severe combined immunodeficiency (SCID) is a group of genetic disorders that abrogate T cell development
and function. Allogeneic hematopoietic cell transplantation (HCT) is the standard treatment for the disease and
can be performed successfully in SCID patients without the high dose pre-HCT busulfan conditioning due to the
unique capacity for progenitors to engraft in the empty thymus and reconstitute T cell development. Without
conditioning, lineages other than T cells remain of host origin. The CSIDE protocol was funded with an earlier
grant to test the efficacy and safety of a regimen of low dose, individualized targeted busulfan compared to
moderate dose in SCID patients at risk of poor humoral outcome undergoing non-matched sibling donor HCT.
We hypothesize that patients randomized to receive low dose busulfan will achieve similar outcomes compared
to those receiving moderate dose (myeloablative) busulfan, achieving both T and B cell immune reconstitution.
Due to COVID and competition with gene therapy, accrual slowed, but with 50 centers open and a redesigned
approach, additional enrollment facilitated by this grant will ensure that the trial reaches meaningful conclusions.
 In Aim 1, patients have been randomized to cumulative area-under-the-curve (cAUC) exposure of busulfan
of 30 mg*h/L versus 60 mg*h/L. IL2RG/JAK3 patients also receive rATG, while RAG1/2 patients receive rATG,
fludarabine, and thiotepa. Stem cell sources include unrelated and haploidentical related donor products that
have been TCRαβ+/CD19+ depleted with no post-HCT GVHD prophylaxis. The safety profile of the trial has
been excellent to date. The original primary endpoint was protective antibody response to tetanus by 2 years
post-HCT. Because of enrollment challenges, we redesigned the primary endpoint into an ordinal ranked win
comparison, which allows higher power even if we cannot fully enroll. The primary outcome will center around
the IL2RG/JAK3 cohort, which should achieve full accrual, randomizing 32 patients. The RAG1/2 cohort will
close once the IL2RG/JAK3 cohort closes, likely accruing up 18-20 patients which we will analyze descriptively.
 In Aim 2, We hypothesize that donor HSC engraftment measured by the surrogate of myeloid donor
chimerism will be associated with superior quality of T cell reconstitution and improved adaptive immune
responses to vaccination. We hypothesize that T cell exhaustion and poor T cell receptor (TRB) diversity seen
in patients undergoing HCT in the absence of conditioning will be diminished or absent in CSIDE participants
due to improvements in thymic output associated with engraftment of donor-derived HSC. We hypothesize that
IL2RG/JAK3 patients receiving moderate dose busulfan and/or with high level donor chimerism will exhibit
multiple in vitro biomarkers of IL-21 response, as this cytokine signals via IL2RG/JAK3. We hypothesize that
vaccine response will correlate with normalization of IGH CDR3 diversity in ...

## Key facts

- **NIH application ID:** 10928997
- **Project number:** 1U01AI184132-01
- **Recipient organization:** NATIONAL MARROW DONOR PROGRAM
- **Principal Investigator:** JEFFERY J AULETTA
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,072,951
- **Award type:** 1
- **Project period:** 2024-08-13 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10928997

## Citation

> US National Institutes of Health, RePORTER application 10928997, Clinical and mechanistic studies defining optimal preparative approaches to infants with IL2RG/JAK3/RAG1/RAG2 SCID: a randomized trial of busulfan dosage (1U01AI184132-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10928997. Licensed CC0.

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