# Lentiviral Gene Therapy and Genome Editing for X-linked Severe Combined Immunodeficiency

> **NIH NIH P01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2022 · $576,217

## Abstract

PROJECT SUMMARY – PROJECT 3 
The overall goal of this project is to determine if lentiviral gene therapy combined with subablative busulfan 
conditioning can be used to treat a broad spectrum of patients with severe combined immunodeficiency (XSCID). 
This catastrophic disease of childhood is caused by mutations in the IL2RG gene that lead to profound defects 
in T cell, NK cell, and B-cell mediated immunity. Allogeneic transplant is the standard therapy, but results in 
suboptimal outcomes in patients that lack matched sibling donors. While prior gene therapy trials with gamma- 
retroviral vectors showed clinical benefit, incomplete immune reconstitution and vector-related leukemia was 
seen in a significant number of cases. We propose a new approach using a safety-modified lentiviral vector and 
reduced intensity conditioning in order establish long-term correction via bone marrow engraftment of transduced 
hematopoietic stem cells. During the past funding period, we opened the first clinical lentiviral trials with 
subablative busulfan for XSCID and have obtained remarkable success in 12 cases treated thus far. The 
LVXSCID-OC trial at the NIH Clinical Center has enrolled eight XSCID patients who had waning immunity despite 
having undergone a prior allogeneic transplant. These cases have shown high levels of myeloid marking that 
are unprecedented in prior XSCID gene therapy trials and complete immune reconstitution in some cases. In 
particular, B cell function was restored in the first two cases leading to independence from gamma-globulin 
replacement therapy, which has not been obtained in prior gene therapy trials. We have also opened a newly 
diagnosed protocol (LVXSCID-ND) at St. Jude, UCSF, and Seattle and have treated four infants with transduced 
bone marrow cells following targeted subablative conditioning over the past seven months. Gene marking in 
blood and bone marrow myeloid cells has been very high and has been associated with rapid reconstitution of 
T and NK cell numbers and function. B cell marking levels have averaged 0.8 copies/cell and have been noted 
with preliminary evidence of endogenous gamma-globulin production in one case. Based on these results, we 
now seek support to complete both of these Phase I studies by validating more GMP-grade vector batches, 
completing enrollment on both protocols, and performing detailed, long term analyses of immune reconstitution, 
vector marking/clonality studies, and clinical safety in these cases. We anticipate that these studies will provide 
a new therapy for XSCID and leading to commercialization of this gene therapy approach so that this treatment 
can be made widely available.

## Key facts

- **NIH application ID:** 10453807
- **Project number:** 5P01HL053749-25
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Stephen Gottschalk
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $576,217
- **Award type:** 5
- **Project period:** 1997-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10453807

## Citation

> US National Institutes of Health, RePORTER application 10453807, Lentiviral Gene Therapy and Genome Editing for X-linked Severe Combined Immunodeficiency (5P01HL053749-25). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10453807. Licensed CC0.

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