Andre Larochelle, M.D., Ph.D.

The Larochelle laboratory develops regenerative therapies for inherited blood disorders, especially Fanconi anemia (FA). Hematopoietic stem cells (HSCs) replenish blood throughout life. Defects in the FA-BRCA DNA-repair pathway make HSCs vulnerable to DNA damage and inflammatory stress; their progressive loss causes bone marrow failure and increases cancer risk. The program integrates clinical research, stem-cell biology, genome editing, and transplantation to preserve remaining HSCs, correct mutations, generate replacement HSCs, and improve engraftment.

Eltrombopag for FA-associated bone marrow failure
Eltrombopag is an oral drug that activates cMPL, the thrombopoietin receptor supporting HSC survival and function. In preclinical studies of primary human blood stem and progenitor cells, the team showed that eltrombopag protects against suppression by interferon-gamma and promotes repair of DNA double-strand breaks, improving genome stability and function. These findings motivated an NIH phase 2 trial. Enrollment and primary-endpoint follow-up are complete; most evaluable participants improved one or more blood counts, often with expansion of stem and progenitor cells in the marrow. Long-term follow-up assesses durability, dosing, liver safety, and changes in blood-cell clones and chromosomes.

Gene correction and lipid nanoparticle delivery
Correcting a patient's own HSCs could provide durable treatment for FA-associated blood disease and reduce reliance on donor transplantation. FA HSCs are scarce, lose function in culture, and tolerate DNA double-strand breaks poorly. Adenine base editing can correct selected single-letter mutations without creating such breaks. Lipid nanoparticles, also used in messenger RNA vaccines, transiently deliver the editor's messenger RNA and guide RNA. A lead formulation edited human blood stem and progenitor cells in the presence of human serum; nonhuman primate studies showed preliminary delivery of nanoparticle-encoded reporter RNA to bone marrow cells. Current work improves blood stability, cell uptake, and cargo release and adds cMPL-binding molecules to target HSCs for efficient correction directly in the body.

Blood stem cells from induced pluripotent stem cells
When too few native HSCs remain, induced pluripotent stem cells (iPSCs) could provide a renewable source. Patient cells can be reprogrammed, corrected, expanded, and guided to form blood stem cells. Using a published, developmentally guided embryoid-body method, the laboratory recreates key stages from mesoderm through arterial endothelium to blood formation. Healthy-donor products achieved durable, multilineage engraftment in primary and secondary immunodeficient mice. This benchmarks the approach for patient-specific FA iPSCs. FANCA correction improved blood-cell colony formation and increased cells with HSC-associated markers; ongoing studies assess durable function.

Safer conditioning and engraftment
Corrected or replacement HSCs need space in the bone marrow for durable blood production. Chemotherapy or radiation creates this space through broad tissue damage, which is especially hazardous in FA. The laboratory identified high cMPL expression as a feature of long-term human HSCs and developed an immunotoxin that preferentially depletes these cells in preclinical models. Mobilizing drugs are also being tested to create temporary niche access and expose more HSCs to circulating nanoparticles. The team also showed that post-transplant granulocyte colony-stimulating factor can intensify the p53-mediated DNA-damage response and reduce engraftment of Cas9-edited HSCs in preclinical models. These findings guide safer conditioning and transplantation.

Dr. Larochelle is a Senior Investigator at the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health (NIH). A physician-scientist and board-certified hematologist, he combines expertise in blood stem cell biology and transplantation to develop regenerative therapies for inherited blood disorders, particularly Fanconi anemia. His research connects fundamental questions about stem cell survival, DNA repair, and blood formation with the challenges of treating patients.

Dr. Larochelle earned his Ph.D. from the University of Toronto in 1996 and his M.D. from McMaster University in 1999. He completed postgraduate medical training at the Mayo Clinic, followed by a clinical hematology fellowship and postdoctoral research training at the NIH. He subsequently served as a Staff Clinician and Associate Clinical Investigator in the NHLBI Hematology Branch, studying the mobilization, genetic modification, and expansion of blood stem cells for therapeutic applications. He was appointed a tenure-track investigator in 2016 and promoted to Senior Investigator in 2024.

His laboratory integrates clinical investigation with stem cell biology, gene editing, and transplantation research. The program develops complementary approaches to preserve patients’ remaining blood stem cells, correct disease-causing mutations, generate replacement stem cells, and reduce the toxicity of transplantation. His clinical and laboratory experience informs a shared goal: translating discoveries in stem cell biology into durable treatments for inherited blood disorders.

Dr. Larochelle is a member of the American Society of Hematology and the American Society of Gene and Cell Therapy. In 2016, he received the Presidential Early Career Award for Scientists and Engineers (PECASE), the U.S. government’s highest honor for scientists and engineers in the early stages of their research careers.