# Targeted Genetic Therapy for Artemis-Deficient SCID

> **NIH NIH R21** · UNIVERSITY OF MINNESOTA · 2020 · $229,226

## Abstract

ABSTRACT SCID-A (T-B-NK+ severe combined immunodeficiency of Athabascan-speaking Native
Americans) is a primary immunodeficiency disease (PID) resulting from absence of Artemis protein, required
for nonhomologous end-joining in V(D)J gene rearrangement. The only effective therapy for SCID-A is
allogeneic hematopoietic stem cell (HSC) transplant, for which there is a significant risk of morbidity and
mortality. We recently demonstrated that ex vivo lentiviral correction of Artemis deficiency in a mouse model of
SCID-A was most effectively accomplished using the endogenous human Artemis promoter to regulate Artemis
expression, forming the basis for a clinical trial of this approach to be initiated in early 2018. However,
integrative gene transfer has been associated with adverse oncogenic reactions in clinical trials for X-linked
SCID. As a superior genetic therapy to maintain regulated Artemis gene expression and avoid the risk of
genotoxicity, we propose to develop site-directed correction of the Y192X mutation in the Artemis gene that
underlies SCID-A that occurs at a higher frequency in Athabascan-speaking Native Americans in the
southwest United States.
 To this end, we have been using the CRISPR/Cas9 system for targeted modifications and the Artemis
locus and genetic correction of Artemis deficiency. In preliminary studies, we have achieved highly efficient
targeting of Artemis codon 192 using the CRISPR/Cas9 nuclease system for site directed double-strand break
and initiation of homology-directed recombination (HDR). In an even more elegant strategy, we have acquired
the Adenosine Base Editor (ABE) system from the laboratory of Dr. David Liu for introduction of site directed
single base changes without the need of making a double strand break. For correction of the Artemis gene, we
will first determine effectiveness of the ABE system for targeting the Athabascan exon 8 stop codon in patient-
derived fibroblasts (Aim 1). Either the base editor (if effective) or Cas9 mediated HDR will then be used for
correction of the exon 8 Athascan stop codon in patient-derived human hematopoietic stem cells (Aim 2). The
overall goal of this study therefore is to generate definitive proof-of-concept results supporting clinical testing of
HSC genetically corrected at the Artemis locus for restoration of immunity in SCID-A. After these studies are
complete, HSC from SCID-A patients will then be developed for cGMP manufacturing and clinical testing as a
lead condition, with subsequent application to the treatment of other primary immune deficiencies and diseases
treatable by gene editing of human hematopoietic stem cells.

## Key facts

- **NIH application ID:** 9870871
- **Project number:** 5R21AI144311-02
- **Recipient organization:** UNIVERSITY OF MINNESOTA
- **Principal Investigator:** R. Scott McIvor
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $229,226
- **Award type:** 5
- **Project period:** 2019-02-12 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9870871

## Citation

> US National Institutes of Health, RePORTER application 9870871, Targeted Genetic Therapy for Artemis-Deficient SCID (5R21AI144311-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9870871. Licensed CC0.

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