# GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2021 · $784,972

## Abstract

NK cell deficiency (NKD) is a subset of primary immunodeficiency diseases/inborn errors of immunity (IEI) in
which the NK cell abnormality represents the main clinical immunodeficiency. Patients with abnormal NK cells
are susceptible to lethal virus infections and certain cancers, offering us a unique window into how these
critical immune cells work. For over 15 years we have cared for and investigated these complex patients,
applying genomic techniques to discover causative genes and illuminate NK cell biology. With this application,
we aspire to renew our coordinated NKD discovery program, with the ultimate goals of understanding how to
care for these patients as well as how to best use NK cells therapeutically. Over the past 5 years of our
program, we have defined 2 new genetic causes of NKD and 8 new causes of IEI that affect NK cells. We
established and grew an international referral network for NKD patients, honed methods to clinically and
immunologically define these rare patients, matured our genomic evaluation/discovery pathways, and
optimized patient-focused functional genomics and NK cell biological techniques, all to advance progress in
understanding NKD. At present, we have 156 patients enrolled in our NK cell evaluation and research (NEAR)
program at Columbia: of these, 70 have undergone exome sequencing (ES) at Baylor College of Medicine, 13
have found genetic solutions for their disease, 11 have a promising gene identified, and 36 remain unsolved.
During this renewal period, we will build on our successful momentum, adding new NKD patients to our
pipeline, clinically and immunologically defining their disease through the use of databases, advanced
biostatistical techniques and research level phenotypic and functional assessments (Aim 1), adding new
genomic discovery and analytic techniques like whole genome sequencing and RNA sequencing to bring
clarity to the patients whose NKD genes remain “unsolved” (Aim 2), and applying cutting-edge functional
genomics and NK cell biological techniques to demonstrate the impact and relevance of the gene mutations we
discover (Aim 3). We capitalize on strong, long-standing collaborations both within and beyond the field of
Immunodeficiency in order to best define how the gene mutations we identify impact how NK cells function in
human health. In so doing, we aim to not only better diagnose and care for these complex patients, but to
better understand how NK cells protect humans from viruses and cancer.

## Key facts

- **NIH application ID:** 10363767
- **Project number:** 2R01AI120989-07
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Jordan Scott Orange
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $784,972
- **Award type:** 2
- **Project period:** 2016-01-19 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10363767

## Citation

> US National Institutes of Health, RePORTER application 10363767, GENETIC, IMMUNOLOGIC AND MECHANISTIC BASIS OF HUMAN NK CELL DEFICIENCY (2R01AI120989-07). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10363767. Licensed CC0.

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