# Gene therapy for SCID-X1 with low dose busulfan and a SIN-lentiviral vector

> **NIH NIH U01** · BOSTON CHILDREN'S HOSPITAL · 2020 · $982,311

## Abstract

Project Summary
 Gene therapy using autologous CD34+ cells is a promising treatment for primary immunodeficiency,
particularly for individuals without optimal allogeneic donors. SCID-X1 is caused by mutations in IL2RG, which
encodes the common gamma chain (γc) of multiple cytokine receptors. Boys with SCID-X1 lack T and NK
cells, and their B cells fail to produce antibodies due to the lack of IL-7, IL-15 and IL-21 function respectively.
This project seeks to test the efficacy and safety of a new self-inactivating lentiviral (LV) vector to treat SCID-
X1. We hypothesize that this trial will improve immune reconstitution through the introduction of low dose
busulfan conditioning (Aim 1) and improve safety through the change from a gammaretroviral (γRV) vector
used in previous trials to the LV vector in this trial (Aim 2).
 Previous trials of gene therapy for SCID-X1 have infused cells without chemotherapy conditioning, which
resulted in robust T cell recovery and gene marking, but negligible gene marking in B cells and failure of
humoral immune reconstitution. Initial development and marking in NK cells was not sustained. In Aim 1 we will
examine the impact of low dose busulfan conditioning on 1) cell type specific engraftment and gene marking,
2) in vivo T cell reconstitution, T cell phenotype and TRB repertoire by deep sequencing, 3) in vivo humoral
immune reconstitution, B cell number, phenotype, IL-21 dependent function and IGH repertoire by deep
sequencing, 4) NK cell number, phenotype and function.
 Previous trials of gene therapy for SCID-X1 have used a γRV vector with intact viral promoters/enhancers,
which resulted in 5/20 patients developing T cell leukemia due to insertional oncogenesis. Gene therapy using
a self-inactivating γRV vector in which viral enhancers have been deleted shows encouraging evidence of
reduced insertion sites near lymphoid oncogenes, but an initial insertion site pattern that is still risky. The
proposed trial in this application will further improve safety by using a self-inactivating LV vector. In Aim 2 we
will investigate the initial insertion site pattern in the patients’ CD34+ transduced cells and compare samples
from the proposed trial to historical trials using γRV, analyze insertion site profile in peripheral blood after gene
therapy to perform lineage tracing and compare clustering with samples from previous trials.

## Key facts

- **NIH application ID:** 9977108
- **Project number:** 5U01AI125051-05
- **Recipient organization:** BOSTON CHILDREN'S HOSPITAL
- **Principal Investigator:** DAVID A WILLIAMS
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $982,311
- **Award type:** 5
- **Project period:** 2016-07-07 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9977108

## Citation

> US National Institutes of Health, RePORTER application 9977108, Gene therapy for SCID-X1 with low dose busulfan and a SIN-lentiviral vector (5U01AI125051-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9977108. Licensed CC0.

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