# CRISPR Editing of Primary Human Cells to Model and Correct Primary Immunodeficiency Mutations

> **NIH NIH K08** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $198,735

## Abstract

PROJECT SUMMARY / ABSTRACT
 The goal of this application is to train Dr. David Nguyen PhD MD, an infectious disease clinician and
medical engineer, with the skills necessary to become an independently-funded investigator studying,
diagnosing, and eventually curing genetic diseases of the immune system. Primary immunodeficiency (PID)
disease is commonly recognized as an inability of the immune system to develop, self-regulate, or fight infection
due to a genetic defect in some aspect of the normal immune response. Gene therapy is a possibility to cure
PID disease once a patient's mutation can be identified, but there is incomplete knowledge of the genetic
underpinnings of PID. PID-causative mutations often remain undiagnosed despite state-of-the-art genomic
sequencing efforts because of an inability to separate benign sequence variations from the truly pathologic
mutations. This research plan addresses key limitations in the ability to provide a molecular diagnosis and cure
for PID patients. Dr. Nguyen will utilize recently developed advanced CRISPR-gene editing tools in innovative
ways to study PID-associated mutations and understand how they lead to clinical disease. He will then develop
novel strategies for replacing PID mutations in a patient's own hematopoietic stem progenitor cells (HSPCs). He
aims to 1) accurately recreate and functionally test PID patient sequencing variants by replacing wild-type alleles
in (otherwise healthy) primary human immune cells, 2) utilize high-throughput functional genomics to catalogue
all possible mutations in key PID-associated genes that could lead to immune dysfunction, 3) improve site-
specific gene correction in primary HSPCS.
 The proposed a 5-year career development and training plan incorporates didactic lecture-based
learning, mentored practical training, and career advising to complement Dr. Nguyen's expertise in ways that are
critical to completion of his research and career goals. He will receive instruction in advanced human T cell and
HSPC biology, functional genomics methods in particular next-generation sequencing techniques and
manipulation of large datasets, and pre-clinical development of cell and gene therapies. He will be training at
UCSF, a center for both basic and translational research that provides an excellent environment supporting
physician-scientists with local experts in all aspects the proposed research and training goals. He will be closely
mentored by Dr. Alexander Marson, a leading expert in using CRISPR gene editing to understand the genetic
basis of human immune function, and Dr. Jennifer Puck, a world-leader in the diagnostics, genetics, clinical care,
and gene therapy of severe combined immunodeficiency. The long-term goal of this study is to provide Dr.
Nguyen with the skills required to become a R01-funded faculty member leading efforts to identify, functionally
validate, and correct immunodeficiency patient mutations.

## Key facts

- **NIH application ID:** 10433980
- **Project number:** 5K08AI153767-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** David-Huy Nhu Nguyen
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $198,735
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10433980

## Citation

> US National Institutes of Health, RePORTER application 10433980, CRISPR Editing of Primary Human Cells to Model and Correct Primary Immunodeficiency Mutations (5K08AI153767-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10433980. Licensed CC0.

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