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		Search Text: Home/< Back ToThe Science/Regenerative Therapies for Inherited Blood Disorders
  Regenerative Therapies for Inherited Blood Disorders
    The Laboratory of Regenerative Therapies for Inherited Blood Disorders, led by Dr. Andre Larochelle, is investigating novel strategies and stem cell concepts that can help advance the translational regenerative field, with a focus on inherited disorders affecting blood-forming hematopoietic stem cells (HSCs).
    On This Page
    
          Andre Larochelle, M.D., Ph.D.
  Andre Larochelle, M.D., Ph.D.
          Senior Investigator
          Email
      Meet the Team
            Contact us
  Senior Investigator Research Interests
            
  Research Interests
              The research program focuses on pioneering regenerative therapies for inherited blood disorders, specifically Fanconi anemia (FA). FA is a complex condition characterized by bone marrow failure and a heightened risk of cancer. The program aims to harness the regenerative potential of hematopoietic stem cells (HSCs), which are the cornerstone of the body's blood-forming system. The ultimate goal is to provide permanent solutions for FA patients, for whom safe and effective treatments are currently lacking.Eltrombopag for the treatment of inherited bone marrow failureThe team has identified eltrombopag (EPAG) as a groundbreaking treatment for FA-associated bone marrow failure. EPAG is a small molecule that mimics thrombopoietin, a key regulator of HSC survival. Clinical trials have shown EPAG to be effective in stimulating residual HSCs, thereby improving blood counts across all cell lineages. The team's unique contribution lies in uncovering how EPAG overcomes HSC inhibition caused by inflammatory factors and improving DNA repair. His program has initiated a phase I/II clinical trial, with interim results showing promising outcomes, including improved blood counts in over 65% of patients. EPAG could be a game-changer, offering the first targeted drug therapy for FA patients.Gene Therapies for FAGene therapies offer a one-time curative approach, bypassing the need for long-term drug treatment or toxicities of allogeneic HSC transplant. However, due to the inherent hypersensitivity of FA HSPCs to DNA damage and inflammatory cytokines, gene therapy of FA presents unique challenges. In a comprehensive research program, the team is integrating three main strategies: Gene Correction Strategies, Engraftment of Gene-Edited HSPCs, and In Vivo Gene Therapy. For Gene Correction Strategies, the program is exploring foamy viral vectors for gene addition in HSCs from FA patients, offering advantages like shorter exposure time and reduced oncogenic risk. Concurrently, alternative CRISPR strategies are being developed to bypass FA cells' faulty DNA repair mechanisms, using chimeric proteins that combine CRISPR-Cas9 and DNA recombinase domains for targeted, DNA damage response-independent integration. For Engraftment of Gene-Edited HSPCs, the group is investigating safer, chemotherapy-free pre-transplant conditioning methods, including monoclonal antibodies and mobilizing agents. Strategies for ex vivo expansion of gene-edited HSPCs focus on promoting self-renewal, suppressing differentiation, and mitigating endoplasmic reticulum stress. Proteomic and transcriptomic screens are underway to identify innate immune pathways that may limit the efficacy of HSPC genetic manipulation. Lastly, under In Vivo Gene Therapy, a novel lipid nanoparticle (LNP) formulation is being optimized for in vivo delivery of CRISPR reagents to HSCs, with biodistribution studies planned to ensure specificity and safety, and proof-of-concept experiments underway in non-human primates to assess therapeutic applicability in FA. The aim is to make gene therapies safer, more efficient, and applicable to a broader range of FA patients.Cell Therapies for FAFor patients with depleted marrow HSPC reserves who may not respond well to EPAG treatment, de novo generation of HSPCs through induced pluripotent stem cells (iPSCs) offers a promising alternative. These iPSCs are generated from the patient's own cells, corrected for the genetic defect, and then differentiated into HSCs. The challenge lies in ensuring these lab-grown HSCs are as functional as natural ones. The group has developed and patented a scalable protocol, STEMdiffTM, for differentiating human iPSCs into HSPCs, although it currently lacks the ability to produce fully mature, engraftable HSPCs. To optimize this, they are exploring three avenues: 1) Ectopic activation of master transcription factors (TFs) identified through CHIP-seq and ATAC-seq methods to improve HSPC generation; 2) Pharmacologic inhibition of key epigenetic factors like EZH1 and EZH2 to accelerate cellular maturation; and 3) Ectopic expression of homing receptors like CXCR4 to enhance HSPC engraftment post-transplantation. These strategies will be tested in various stages of iPSC differentiation and their efficacy confirmed through xenotransplant assays. Concurrently, the team is generating genetically corrected FA-specific iPSCs for hematopoietic differentiation using this optimized approach, with the end goal of producing functionally corrected, engraftable HSPCs for therapeutic applications.In summary, the group is at the forefront of developing a multi-pronged approach to treat FA, leveraging the power of EPAG, gene therapies, and cell therapies. Each of these avenues holds the promise of revolutionizing the treatment landscape for FA and other inherited blood disorders.
  Images

            Members of the lab in a meeting.Members of the lab in a meeting.Members of the lab in a meeting.Members of the lab in a meeting.Members of the lab in a meeting.Members of the lab in a meeting.Members of the lab in a meeting.Seven lab members standing under a tree.Three men in front of a poster.Group photo of ten members of the Regenerative Therapies for Inherited Blood Disorders lab.Group photo of members of PECASE.
Clinical Trials and Studies
Use of Granulocyte Colony Stimulating Factor (G-CSF) Mobilized Leukapheresis Collections from Healthy Volunteers to Develop Improved Methods of Stem Cell and Lymphocyte Selection for Allogeneic Transplantation
				Recruiting
											
											Adult
					
											All Genders
					
																		Accepting Healthy Volunteers

				Are a healthy adult who is interested in helping people who need a bone marrow transplant? This procedure is often associated with life-threatening reactions, such as graft-versus-host disease (GHVD). This study will test a technique that uses peripheral blood instead of bone marrow. With this technique, they can transplant donor stem cells and remove lymphocytes, which are the white blood cells from donor bone marrow that can cause GHVD. To participate, you must be between 18 and 60 years old. This study is located at the NIH Clinical Center in Bethesda, Maryland.Eltrombopag for Patients with Fanconi Anemia
				Recruiting
											
											All Ages
					
											All Genders
					
																		Not Accepting Healthy Volunteers

				Do you or your child have Fanconi anemia with lower blood cell counts? This study aims to see if a new drug called eltrombopag will help people with this condition. Participants must be at least 2 years old. The study is located at the NIH Clinical Center in Bethesda, Maryland.
Featured Publications
                Eltrombopag maintains human hematopoietic stem and progenitor cells under inflammatory conditions mediated by IFN-γ.
            Authors:Alvarado LJ, Huntsman HD, Cheng H, Townsley DM, Winkler T, Feng X, Dunbar CE, Young NS, Larochelle A.
                                                                                                                        
            Blood
      
                2019 May 09;133(19):2043-2055
        Read Publication
                      Eltrombopag promotes DNA repair in human hematopoietic stem and progenitor cells.
            Authors:Guenther KL, Cheruku PS, Cash A, Smith RH, Alvarado LJ, Burkett S, Townsley DM, Winkler T, Larochelle A.
                                                                                            
            Exp Hematol
      
                2019 Apr 13;73:1-6
        Read Publication
                      Eltrombopag Added to Standard Immunosuppression for Aplastic Anemia.
            Authors:Townsley DM, Scheinberg P, Winkler T, Desmond R, Dumitriu B, Rios O, Weinstein B, Valdez J, Lotter J, Feng X, Desierto M, Leuva H, Bevans M, Wu C, Larochelle A, Calvo KR, Dunbar CE, Young NS
                                                                                                                        
            N Engl J Med.
      
                2017 Apr 20;376(16):1540-1550
        Read Publication
                      CRISPR/Cas9-Mediated Homology Independent Targeted Integration in Human Hematopoietic Stem and Progenitor Cells
            Authors:Hanan Bloomer, Richard H. Smith, Waleed Hakami, and Andre Larochelle.
                                                                                                                        
            Mol Ther
      
                2021 Jan 01;29(4):1611-1624
        Read Publication
                      Modulation of WNT, Activin/Nodal, and MAPK Signaling Pathways Increases Arterial Hemogenic Endothelium and Hematopoietic Stem/Progenitor Cell Formation During Human iPSC Differentiation
            Authors:Yongqin Li, Jianyi Ding, Daisuke Araki, Jizhong Zou, and Andre Larochelle
                                                                                                                        
            Stem Cells
      
                2023 Jul 14;41(7):685-697
        Read Publication
                                View More Publications
  Meet the Team

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

            Andre Larochelle, M.D., Ph.D.
                Senior Investigator
                With a career spanning over three decades, Dr. Larochelle brings a unique blend of expertise in both fundamental hematopoiesis and clinical hematology. His journey began in 1992 when he delved into the intricacies of hematopoietic stem and progenitor cell (HSPC) regulation, culminating in a Ph.D. from the University of Toronto in 1996. Recognizing the transformative potential of bridging basic science with clinical practice, he accelerated his medical education, completing a three-year MD program at McMaster University in 1999. His medical training continued at the Mayo Clinic, followed by a Clinical Hematology Fellowship at the NIH, where he became a board-certified clinical hematologist and stem cell transplant specialist. Dr. Larochelle chose to extend his tenure at the NIH, initially as a post-doctoral trainee and later as a Staff Clinician and Associate Clinical Investigator within the Hematology Branch of the NHLBI. During this period, he spearheaded pivotal projects focused on the mobilization, genetic modification, and expansion of HSPCs for clinical applications in cell and gene therapy. In 2016, he was appointed as a tenure-track investigator, a role in which he continues to pioneer innovative strategies, including gene therapy and editing, to advance regenerative therapies for inherited disorders affecting HSPCs. His contributions to the field have been widely recognized, both through numerous peer-reviewed publications and invitations to speak at prestigious events. He is an active member of the American Society of Hematology and the American Society of Gene and Cell Therapy. He was honored with the 2016 Presidential Early Career Awards for Scientists and Engineers (PECASE), the U.S. Government's highest accolade for early-stage science and engineering professionals.
    
          Contact the lab
    10 Center DrRM 5-5132Bethesda, MD 20814United States
        Phone:
                    301-451-7139
                Fax:
            301-496-8396
  Fariba Chinian
    
            Fariba Chinian, M.Sc.
        

    Biologist

        chinianff@mail.nih.gov
            smith
    
            Richard Smith, Ph.D.
        

    Staff Scientist

        smithr@nhlbi.nih.gov
            headshot
    
            Daisuke Araki, M.D.
        

    Staff Clinician

        daisuke.araki@nih.gov
            Ruf
    
            Christi  Salisbury-Ruf, Ph.D.
        

    Postdoctoral Fellow

        christi.gurniak@nih.gov
            Ding
    
            Jianyi  Ding, Ph.D.
        

    Postdoctoral Fellow

        jianyi.ding@nih.gov
            Bretagne Cowling
    
            Bretagne Cowling, RN
        

    Research Nurse

        bretagne.cowling@nih.gov
            Sadia Perveen, M.Sc.
    
            Sadia Perveen, M.Sc.
        

    Graduate student

        sadia.perveen@nih.gov
            Emily Clark
    
            Emily Clark, B.Sc.
        

    Postbaccalaureate Trainee

        emily.clark4@nih.gov
                    Load more members
  
  Alumni
        

Patali Shikhi Cheruku, M.D.
        

    Postbaccalaureate Trainee
                                        2014

      -
            2016
      Hai Cheng, M.D.
        

    Postdoctoral Trainee
                                        2014

      -
            2016
      Luigi Alvarado, Ph.D.
        

    Postdoctoral Trainee
                                        2014

      -
            2018
      Fatima Sancheznieto (previously Juan Pablo Ruiz), Ph.D.
        

    Pre-Doc Graduate Student
                                        2014

      -
            2018
      Heather Huntsman, Ph.D.
        

    Postdoctoral Trainee
                                        2014

      -
            2018
      Jianfei Fu, M.D., Ph.D.
        

    Postdoctoral Trainee
                                        2014

      -
            2019
      Joseph Panos, M.D.
        

    Summer Trainee
                                        2015

      -
            2015
      Kevin Bachrach, M.D.
        

    Summer Trainee
                                        2015

      -
            2015
      Neranjan DeSilva, M.Sc.
        

    Summer Trainee
                                        2015

      -
            2015
      Ishan Asokan, M.D.
        

    MRSP Medical Student
                                        2015

      -
            2016
      Roop Dutta, M.D.
        

    MRSP Medical Student
                                        2015

      -
            2016
      Michael Drakopoulos, M.D.
        

    Summer Trainee
                                        2016

      -
            2016
      Noah Zachary Laird, Ph.D.
        

    Summer Trainee
                                        2015

      -
            2016
      Kacey Bui Gunther, B.Sc.
        

    Postbaccalaureate Trainee
                                        2016

      -
            2018
      Daisuke Araki, M.D.
        

    Clinical Trainee
                                        2017

      -
            2019
      Beth Staskal, B.Sc.
        

    Summer Trainee
                                        2017

      -
            2017
      Husam Qanash, Ph.D.
        

    Pre-Doc Graduate Student
                                        2017

      -
            2020
      Hanan Bloomer, B.Sc.
        

    Postbaccalaureate Trainee
                                        2018

      -
            2020
      Waleed Hakami, Ph.D.
        

    Pre-Doc Graduate Student
                                        2018

      -
            2022
      Yongqin Li, Ph.D.
        

    Postdoctoral Trainee
                                        2018

      -
            2023
      Nebojša Skorupan, M.D.
        

    Clinical Trainee
                                        2019

      -
            2021
      Shing Gao
        

    Summer Trainee
                                        2022

      -
            2022
      Anirudh Rao, B.Sc.
        

    MRSP Medical Student
                                        2022

      -
            2023
      Emily Pollack
        

    Summer Trainee
                                        2023

      -
            2023

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