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

Hematopoietic Stem Cell and Gene Therapy

Andre Larochelle
Andre Larochelle, M.D., Ph.D.
Investigator
Hematopoietic Stem Cell and Gene Therapy
Building 10-CRC Room 5E-5130 (access via 5E-5140)
Bethesda, MD 20892
P: +1 (301) 451-7139
F: +1 (301) 496-8396
larochea@nhlbi.nih.gov

Background

Andre Larochelle earned a B.Sc. and M.Sc. in biochemistry from the University of Sherbrooke in 1990 and 1992, respectively, a Ph.D. in molecular and medical genetics from University of Toronto in 1996, and a M.D. from McMaster University in 1999. He subsequently completed his internal medicine internship and residency at the Mayo Clinic in 2002, and his hematology fellowship training at the NHLBI in 2004. Dr. Larochelle then carried out post-doctoral training at the NHLBI with Dr. Cynthia Dunbar. He was then promoted to staff clinician in the NHLBI Hematology Branch in 2007 and tenure track Investigator in 2012. Dr. Larochelle also serves as an attending physician in the hematopoietic stem cell transplant inpatient service at the NIH Clinical Center. Dr. Larochelle has authored numerous peer-reviewed scientific and review articles, book chapters, and has given several invited lectures and presentations about his work. He is a member of the American Society of Hematology.

Research Interests

Hematopoietic stem cells (HSCs) offer tremendous therapeutic promise, but remain shrouded in a great deal of mystery that limits use of their full potential. Dr. Larochelle is interested in three fundamental and clinically-relevant HSC processes: 1) the mechanisms by which stem cells expand and mobilize from bone marrow niches when needed, 2) the mechanisms by which they home in on and engraft in the bone marrow after transplantation, and 3) the mechanisms by which HSCs develop from pluripotent stem cells. By identifying the key molecular players in these events, clinicians will be better equipped to manipulate HSCs for gene therapy or other clinical applications.

Dr. Larochelle’s group has already made several inroads in this area. They have shown that quiescent HSCs, but not actively cycling stem cells, display a polarized membrane domain enriched in tetraspanins; this domain may mediate homing and engraftment, providing a potential new therapeutic target to enhance engraftment of highly active stem cells. In studies using human CD34+ cells, they have also found that silencing PTEN (phosphatase and tensin homologue deleted on chromosome 10) enhances cell proliferation and the ability to engraft in mice, suggesting this protein promotes human stem cell quiescence just as it does in mouse stem cells.

Dr. Larochelle’s research group also looks to exploit knowledge gained from these mechanistic studies to improve the delivery and effectiveness of gene therapy interventions for these blood-related disorders. His group is currently carrying out translational approaches to genetically modify HSCs and pluripotent stem cells derived from patients with blood disorders (e.g. bone marrow failure) These studies are conducted using both healthy and patient cell samples in preclinical animal models, including rhesus macaques and immune-deficient mice.

Among the gene therapy projects being conducted are studies using the mobilizing agent AMD3100 as both a preparative regimen for HSC transplantation and as a way to improve gene transfer. They are also examining the use of hypoxia as a way to improve the efficiency of viral transduction in HSCs, by mimicking the low-oxygen microenvironment that may contribute to stem cell longevity. While treating blood-related disorders is a principal goal, the lessons learned from these studies might be applied to pluripotent stem cells, opening up gene therapy avenues for many other diseases.

Selected Publications

Bone marrow homing and engraftment of human hematopoietic stem and progenitor cells is mediated by a polarized membrane domain.
Larochelle A, Gillette JM, Desmond R, Ichwan B, Cantilena A, Cerf A, Barrett AJ, Wayne AS, Lippincott-Schwartz J, Dunbar CE
Blood 2012 Feb 23;119(8):1848-55.
Human and rhesus macaque hematopoietic stem cells cannot be purified based only on SLAM family markers.
Larochelle A, Savona M, Wiggins M, Anderson S, Ichwan B, Keyvanfar K, Morrison SJ, Dunbar CE
Blood 2011 Feb 3;117(5):1550-4.
In vivo selection of hematopoietic progenitor cells and temozolomide dose intensification in rhesus macaques through lentiviral transduction with a drug resistance gene.
Larochelle A, Choi U, Shou Y, Naumann N, Loktionova NA, Clevenger JR, Krouse A, Metzger M, Donahue RE, Kang E, Stewart C, Persons D, Malech HL, Dunbar CE, Sorrentino BP
J. Clin. Invest. 2009 Jul;119(7):1952-63.
Intercellular transfer to signalling endosomes regulates an ex vivo bone marrow niche.
Gillette JM, Larochelle A, Dunbar CE, Lippincott-Schwartz J
Nat. Cell Biol. 2009 Mar;11(3):303-11.
Identification of primitive human hematopoietic cells capable of repopulating NOD/SCID mouse bone marrow: implications for gene therapy.
Larochelle A, Vormoor J, Hanenberg H, Wang JC, Bhatia M, Lapidot T, Moritz T, Murdoch B, Xiao XL, Kato I, Williams DA, Dick JE
Nat. Med. 1996 Dec;2(12):1329-37.
Andre Larochelle's Full List of Publications