At Indiana University School of Medicine's Herman B Wells Center for Pediatric Research, the Gene and Cell Therapy program is researching gene and immunotherapies for hemophilia treatment. Through collaborations between researchers across disciplines, and with the added perspective of having a hemophilia patient on the program's research team, the Gene and Cell Therapy program is primed to develop safe and effective treatments for those with bleeding disorders.
PO1 Grant for Hemophilia Treatment
Contact Us
Administrative Assistant
Herman B Wells Center for Pediatric Research
Indiana University School of Medicine
1044 W. Walnut Street
Indianapolis, IN 46202
Toward Safer Gene Therapy for Hemophilia A
Gene therapy for the X-linked bleeding disorder hemophilia holds much promise to accomplish a lasting cure. Four clinical trials utilizing adeno-associated viral (AAV) gene transfer to the livers of males with severe hemophilia are currently being investigated in multiple Phase III clinical trials. Hemophilia A (deficiency in factor VIII, FVIII), the more common form of the disease (~80% of patients), has traditionally been more difficult to treat by gene therapy because FVIII is a large molecule and not efficiently expressed and secreted. Nonetheless, initial results demonstrated complete correction of the disease. However, FVIII levels declined substantially over time, raising worrying questions about durability, and patients also experienced prolonged mild hepatotoxicity despite steroid drug treatment during the first year of gene therapy. Multiple recent observations raise serious questions about the safety of hepatic gene therapy for hemophilia A. These urgently need to be addressed so that this promising approach can be safely applied to patients and to achieve sustained correction. For instance, the reasons for hepatotoxicity and for the decline in FVIII expression are unclear, highlighting critical gaps in our knowledge of the interactions between the vector and hepatocytes and between the FVIII expression and hepatocytes, as well as the role of the immune system in long-term outcome. There is also renewed concern about insertional mutagenesis.
This study will address these basic and mechanistic questions related to the biology of AAV and FVIII. The central hypothesis of this proposal is that multiple interconnected features of AAV and FVIII biology limit durability of therapeutic expression and pose serious safety concerns. Further, they postulate that unraveling these mechanisms will allow for design of vectors and protocols that minimize these problems, thus resulting in lasting therapy and enhanced safety.
The program combines expertise in FVIII biology, cellular stress responses, immunology, and AAV vector biology and is structured into three scientific projects, an administrative core and two scientific cores. Project 1 (Kaufman) seeks to overcome FVIII protein misfolding and cell toxicity. Project 2 (Xiao) will uncover the mechanisms that lead to formation of subgenomic AAV vector particles that form during vector production through nuclease and recombination activities. Project 3 (Herzog) will define the mechanisms of innate and adaptive immune responses to AAV-FVIII gene transfer. The objectives of the three projects will be supported by an administrative core (Core A), a core that provides human hepatocytes for in vitro and in vivo studies (Core B), and a core that performs development and molecular analysis of AAV vectors (Core C). Overall, this project applies the expertise of the individual investigators towards addressing major unanswered questions in FVIII biology, gene therapy for hemophilia, liver-directed gene transfer, and molecular and immunobiology of AAV vectors.

Funding provided by:
NIH, NHLBI, PO1 HL160472 - "Toward Safer Gene Therapy for Hemophilia A"

Video
Gene and Cell Therapy Program
Video
Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinoma
Video
Hemophilia A and immune response
CORES

Core B - Human Hepatocyte and Discovery Core

Core C - Molecular Virology Core
PROJECTS

Randal J. Kaufman, PhD
Director and Professor, Degenerative Diseases Program - Sanford Burnham Prebys

Roland W. Herzog, PhD
Riley Children's Foundation Professor of Immunology
Indiana University School of Medicine

Roland W. Herzog, PhD
Riley Children's Foundation Professor of Immunology
Program Director and Principal Investigator (Project 3)

Weidong Xiao, PhD
Professor of Pediatrics
Principal Investigator (Project 2) and Core Director (Molecular Virology)

Naro Biswas, MS, PhD
Assistant Professor of Pediatrics
Co-Investigator (Project 3)

Sean D. McCabe, PhD, MS
Assistant Professor of Biostatistics & Health Data Science
Co-Investigator (Biostatistics, Administrative Core)
April Maines Administrative Coordinator (Administrative Core)
Sreevani Arisa, BS Research Analyst
Dylan A. Frabutt, PhD Postdoctoral Fellow
Miguel Gonzalez, PhD Postdoctoral Fellow
Radek Kaczmarek, PhD Postdoctoral Fellow
Sandeep Kumar, PhD Assistant Research Professor
Anh K. Lam, PhD Postdoctoral Fellow
Xin Li, MS Research Associate
David M. Markusic, PhD Associate Research Professor
Patrick Mulcrone, PhD Postdoctoral Fellow
Maite Munoz, BS Research Technician
Jyoti Rana, PhD Postdoctoral Fellow
Kentaro Yamada, PhD Assistant Scientist
Junpig Zhang, PhD Research Associate
Weill Cornell University

Ype Peter de Jong, MD, PhD
Assistant Professor of Medicine, Weill Cornell Medicine
Co-Investigator (Project 3) and Core Director (Human Hepatocyte and Discovery Core)

Randal J. Kaufman, PhD
Director and Professor, Degenerative Diseases Program
Principal Investigator (Project 1)

Zhouji Chen, PhD
Research Associate Professor

Shakib Omari, PhD
Staff Scientist

Cynthia Lebeaupin, PhD
Senior Postdoctoral Fellow
Publications
-
Ectopic clotting factor VIII expression and misfolding in hepatocytes as a cause for hepatocellular carcinomaKapelanski-Lamoureux A, Chen Z, Gao ZH, Deng R, Lazaris A, Lebeaupin C, Giles L, Malhotra J, Yong J, Zou C, de Jong YP, Metrakos P, Herzog RW, Kaufman RJ.
Mol Ther. 2022 Dec 7;30(12):3542-3551. doi: 10.1016/j.ymthe.2022.10.004. Epub 2022 Oct 14.
PMID: 36242517; PMCID: PMC9734080. -
IL-15 Blockade and Rapamycin Multifactorial Loss of Factor VIII from AAV-Transduced Hepatocytes in Hemophilia A MiceButterfield JSS, Yamada K, Bertolini TB, Syed F, Kumar SRP, Li X, Arisa S, Piñeros AR, Tapia A, Rogers CA, Li N, Rana J, Biswas M, Terhorst C, Kaufman RJ, de Jong YP, Herzog RW.
Mol Ther. 2022 Jul 12:S1525-0016(22)00426-9. doi: 10.1016/j.ymthe.2022.07.005. Online ahead of print.
PMID: 35821634
-
Immune Complications and their Management in Inherited and Acquired Bleeding DisordersArruda VR, Lillicrap D, Herzog RW.
Blood. 2022 Jul 6:blood.2022016530. doi: 10.1182/blood.2022016530. Online ahead of print.
PMID: 35793465
-
Treatment-induced hemophilic thrombosis?Kaczmarek R, Herzog RW.
Mol Ther. 2022 Feb 2;30(2):505-506. doi: 10.1016/j.ymthe.2022.01.015. Epub 2022 Jan 20.
PMID: 35063080 No abstract available.
-
Coagulation factor IX gene transfer to non-human primates using engineered AAV3 capsid and hepatic optimized expression cassetteKumar SRP, Xie J, Hu S, Ko J, Huang Q, Brown HC, Srivastava A, Markusic DM, Doering CB, Spencer HT, Srivastava A, Gao G, Herzog RW.
Mol Ther Methods Clin Dev. 2021 Aug 26;23:98-107. doi: 10.1016/j.omtm.2021.08.001. eCollection 2021 Dec 10.
PMID: 34631930 Free PMC article.
-
Liver gene therapy and hepatocellular carcinoma: A complex webde Jong YP, Herzog RW.
Mol Ther. 2021 Apr 7;29(4):1353-1354. doi: 10.1016/j.ymthe.2021.03.009. Epub 2021 Mar 19.
PMID: 33743193 Free PMC article. No abstract available.
-
Endoplasmic reticulum stress in liver diseasesAjoolabady A, Kaplowitz N, Lebeaupin C, Kroemer G, Kaufman RJ, Malhi H, Ren J.
Hepatology. 2022 May 6. doi: 10.1002/hep.32562. Online ahead of print.
PMID: 35524448 Review.
-
Chop/Ddit3 depletion in beta cells alleviates ER stress and corrects hepatic steatosis in mice
Yong J, Parekh VS, Reilly SM, Nayak J, Chen Z, Lebeaupin C, Jang I, Zhang J, Prakash TP, Sun H, Murray S, Guo S, Ayala JE, Satin LS, Saltiel AR, Kaufman RJ. Sci Transl Med. 2021 Jul 28;13(604):eaba9796. doi: 10.1126/scitranslmed.aba9796.
PMID: 34321322 Free PMC article. -
Defects in Protein Folding and/or Quality Control Cause Protein Aggregation in the Endoplasmic ReticulumPoothong J, Jang I, Kaufman RJ. Prog Mol Subcell Biol. 2021;59:115-143. doi: 10.1007/978-3-030-67696-4_6.
PMID: 34050864 Free PMC article. -
Effect of CpG Depletion of Vector Genome on CD8+ T Cell Responses in AAV Gene TherapyBertolini TB, Shirley JL, Zolotukhin I, Li X, Kaisho T, Xiao W, Kumar SRP, Herzog RW.
Front Immunol. 2021 May 31;12:672449. doi: 10.3389/fimmu.2021.672449. eCollection 2021.
PMID: 34135899 Free PMC article.
-
Recombinant Adeno-Associated Virus Production, the Beginning of the End of UncertaintyXiao W, Samulski RJ.
Hum Gene Ther. 2022 Apr;33(7-8):355-357. doi: 10.1089/hum.2022.29207.wxi.
PMID: 35442070 No abstract available. -
Chemical Modifications of the Capsid for Redirecting and Improving the Efficacy of Adeno-Associated Virus Vectors
Lam AK, Frabutt D, Li L, Xiao W. Hum Gene Ther. 2021 Dec;32(23-24):1433-1438. doi: 10.1089/hum.2021.124. Epub 2021 Aug 17.
PMID: 34254844 -
Flies in the ointment: AAV vector preparations and tumor riskZhang J, Yu X, Herzog RW, Samulski RJ, Xiao W.
Mol Ther. 2021 Sep 1;29(9):2637-2639. doi: 10.1016/j.ymthe.2021.08.016. Epub 2021 Aug 26.
PMID: 34450107 No abstract available. -
"D" matters in recombinant AAV DNA packagingZhang J, Guo P, Xu Y, Mulcrone PL, Samulski RJ, Xiao W.
Mol Ther. 2021 Jun 2;29(6):1937-1939. doi: 10.1016/j.ymthe.2021.05.002. Epub 2021 May 19.
PMID: 34010593 Free PMC article. No abstract available.
-
Influence of N-glycosylation in the A and C domains on the immunogenicity of factor VIIIVander Kooi A, Wang S, Fan MN, Chen A, Zhang J, Chen CY, Cai X, Konkle BA, Xiao W, Li L, Miao CH.
Blood Adv. 2022 Jul 26;6(14):4271-4282. doi: 10.1182/bloodadvances.2021005758.
PMID: 35511725 -
Ultrasound-mediated gene delivery of factor VIII plasmids for hemophilia A gene therapy in miceSong S, Lyle MJ, Noble-Vranish ML, Min-Tran DM, Harrang J, Xiao W, Unger EC, Miao CH.
Mol Ther Nucleic Acids. 2022 Jan 10;27:916-926. doi: 10.1016/j.omtn.2022.01.006. eCollection 2022 Mar 8.
PMID: 35141050 Free PMC article. -
Mouse characteristics that affect establishing xenografts from hepatocellular carcinoma patient biopsies in the United StatesZou C, El Dika I, Vercauteren KOA, Capanu M, Chou J, Shia J, Pilet J, Quirk C, Lalazar G, Andrus L, Kabbani M, Yaqubie A, Khalil D, Mergoub T, Chiriboga L, Rice CM, Abou-Alfa GK, de Jong YP.
Cancer Med. 2022 Feb;11(3):602-617. doi: 10.1002/cam4.4375. Epub 2021 Dec 24.
PMID: 34951132 Free PMC article. -
Primary human hepatocyte gene editing: Prometheus' chains are looseningMichailidis E, de Jong YP.
Mol Ther. 2021 May 5;29(5):1666-1667. doi: 10.1016/j.ymthe.2021.04.014. Epub 2021 Apr 22.
PMID: 33891863 Free PMC article. No abstract available.
Scientific Advisory Board

Kenneth G. Cornetta, MD
Professor of Clinical Medical & Molecular Genetics
Indiana University

Reuben Kapur, PhD
Director, Herman B Wells Center for Pediatric Research
Indiana University