The NguyenLab, led by PI David Nguyen, is located within the Center for Translational Genomics at the Innovative Genomics Institute on the UC Berkeley Campus. 

Our research interests lie at the intersection of human immunology, infectious diseases, human genome engineering, and gene therapy. Our goal is to leverage the latest technologies in gene editing to understand how mutations cause human diseases of the immune system and to advance gene correction therapies to treat patients with a Primary Immunodeficiency (PID).

Background

Each year thousands of patients develop life-threatening infections, crippling autoimmunity, or other manifestations of an inborn error of immunity that are poorly understood and difficult to treat. Early PID diagnosis is paramount for prognosis, counseling, and treatment success. Sadly, a causative mutation remains elusive for many patients despite genome sequencing because of an inability to distinguish the truly damaging mutations from the numerous (often benign) genetic sequence variants of unknown significance (VUS). While mutations in over 430 different genes have been shown to cause some form of PID disease, each individual patient’s specific mutation is rare, unlikely to be previously investigated, and thus difficult to identify without further functional lab-based studies.

Instead of relying upon genetically dissimilar animal or cancerous cell lines, the NguyenLab leverages gene editing in primary human immune cells to create more pertinent models of disease. Recreating PID patient’s VUS mutations directly in primary human immune cells provides valuable insight into the genetic underpinnings of the human immune response, could uncover novel mechanisms of immune function, and helps us to ultimately develop curative cell and gene therapies.

Approach

The NguyenLab is founded upon continuous improvements in genome engineering technologies in primary human cells. As we build better gene-editing platforms, we are addressing unmet needs for helping patients with PID diseases:

1. Genome engineering in primary human cells to recreate, identify, and diagnose patient-specific PID mutations
2. Functional CRISPR screens to understand and predict how PID mutations impact immune cell behavior
3. Correcting pathogenic mutations in the immune and blood (hematopoietic) system – including PIDs and hemoglobinopathies

We are currently investigating three disease areas:

1. Severe combined immunodeficiency (SCID) and immune regulatory disorders (PIRDs) due to mutations in the interleukin receptor – JAK – STAT signal transduction pathways
2. Mutations causing familial hemophagocytic lymphohistiocytosis (HLH) syndromes.
3. Mutations pertinent to correcting hemoglobinopathies particularly sickle cell disease

Current Projects

‘Mutation Transfer’ to investigate highly suspicious variants of uncertain significance (VUS)

• In order to diagnose and treat a PID disease, it is ideal to understand with certainty that a patient’s mutations are disease-causing. This is particularly critical for developing a gene edited curative therapy.
• We are leveraging CRISPR gene editing to fulfill a ‘genetics Koch’s postulates’. We recreate VUS in primary human immune cells, then test how these mutations alter immune cell function.

Systematically mapping potentially pathogenic variants

• As genome sequencing is becomes cheaper and more accessible, it is emerging as a frontline test for patients with suspected PID but also uncovering highly suspicious VUS at a pace unmatched by laboratory studies. Waiting to study each patient’s mutation as they present to medical care is impractical for achieving a rapid diagnosis with certainty.
• The NguyenLab employs a pooled variant CRISPR knock-in screening approach (somewhat akin to saturation mutagenesis) using large libraries of single nucleotide variants overwriting a targeted portion of the most common PID genes. We can thus catalog potential disease-causing mutations a priori before they are found in a patient. This approach also builds more detailed fundamental knowledge of human genetic control of the immune system.

Drug delivery for therapeutic gene editing of primary human cells

• Virus-based gene insertion therapy strategies are difficult to reconfigure, limited in disease scope, and raise safety concerns due to semi-random genome integration without natural regulation of gene expression. Safer, cheaper gene editing for mutation correction in primary human cells (T, NK, B, HSCs) could vastly expand the number of patients who can access curative gene therapy globally.
• The NguyenLab collaborates with labs around the IGI and beyond to develop and apply novel tools for improved delivery of CRISPR gene editing reagents. We are studying peptide-mediated editing and molecular strategies for ‘gene patches’ to overwrite patient mutations with healthy code. Further, we are part of IGI-wide efforts to assess how various mutation correction strategies impact the diversity of cellular functions post-editing.

Recent Publications

See the full list of PI David Nguyen’s publications on Google Scholar

News

Recruiting

• We are actively seeking candidates for post-doctoral scientists, research assistants, and graduate students. If you are excited by our work and interested in joining the group, please reach out to David (PI): david[dot]n[dot]nguyen[at]berkeley.edu

Commitment to DEI

• The NguyenLab is eager to engage, support, and train the next generation of scientists and clinicians. All are welcome in our lab — regardless of race, ethnicity, gender identity, sexual orientation, socioeconomic background, or disability. We believe that diversity is a critical component of the educational experience, for maximizing innovative and translational science, and improving patient care and outcomes.
• We foster training programs and personal relationships to promote inclusion of all. We strive to ensure equity and access across all backgrounds and identities, and we are committed to recruiting, mentoring, and training people historically underrepresented in academia and the STEM fields.