Wyss Institute-led collaboration awarded by ARPA-H PRINT program to engineer off-the-shelf, universal, transplant-ready graft for liver failure

(Press-News.org) (BOSTON) — The majority of human illnesses is caused by damage of a single organ like the liver whose failure accounts for 2M deaths worldwide every year. Orthotopic transplants are the only curative therapy available, but the severe shortage of donor organs, which are reserved for the most severe cases, leaves millions of patients without an accessible solution.

The liver is the central hub in our body for filtering blood, metabolizing nutrients and toxins, producing essential proteins and bile, storing vitamins and glucose, and a multitude of other processes. Accordingly, an excessive loss of liver function through various diseases poses an immediate risk to patients’ health and lives. Efforts to engineer liver tissue that could be implanted to restore liver function in these patients have been confronted with enormous technical challenges. The liver’s ability to function arises from its population of specialized cell types and their organization in a distinct 3D tissue architecture and interconnectedness with the rest of the body via vascular networks, all of which have been difficult to replicate in an engineered graft.

In a highly collaborative, cross-institutional ImPLANT project funded by the Advanced Research Projects Agency for Health (ARPA-H) Personalized Regenerative Immunocompetent Nanotechnology Tissue (PRINT)  program under a new contract of up to $25M over 5 years, world-leading researchers from the Wyss Institute at Harvard University, MIT, University of Colorado Boulder, and Columbia University join their expertise to create the multidisciplinary technological framework for building the first off-the-shelf engineered product that could address liver failure in many of the over 500M patients who suffer from the disease worldwide. In the ImPLANT project, the team, led by Wyss Institute Core Faculty member and Professor of Biomedical Engineering at Boston University Christopher Chen, M.D., Ph.D., will leverage cutting-edge technologies to install synthetic biology-based gene circuits in human induced pluripotent stem cells (iPSCs) that can drive cell differentiation into all required cell types of the liver. Those cells will then be immunoengineered to enable them to evade immune rejection in patients and be used to produce vascularized, functional tissue constructs at growing scales and ultimately organ scale in cost-effective bioreactors. The project team will engineer liver tissues by integrating bioreactors and 3D printing technologies and test them in small and large humanized animal models to assess and validate their immune tolerance, engraftment and function in vivo and plans to provide manufacturing standards for clinical application.

“I am thrilled to be working with this mission-driven dream team of pioneers to carve a new path toward the clinic, made possible by the timely confluence of foundational advances in regenerative medicine and tissue manufacturing. We all recognize the moonshot nature of the program and are thankful that ARPA-H is making it possible,” said Chen, the ImPLANT project’s Principal Investigator (PI) at the Wyss Institute. He is also the William Fairfield Warren Distinguished Professor at Boston University, Founding Director of the Biological Design Center at Boston University, a Paul G. Allen Distinguished Investigator. Chen was recently elected to the National Academy of Medicine.

Creating a path from cells to organs to patients

The liver ImPLANT project, short for Immunoshielded Printed Liver Assist NeoOrgan for Transplant, takes advantage of major breakthroughs made in multiple bioengineering disciplines in recent years, enabling them to synergize in unprecedented ways. Ron Weiss, Ph.D., with his group at the MIT, has pioneered the use of synthetic biology methods to program mammalian cell differentiation and behavior. In the ImPLANT poject, his group will design synthetic gene circuits around genes encoding liver specific transcriptional regulators that can initiate multi-step, branched differentiation programs to generate all relevant liver cell types from iPSCs. Weiss’ team aims to render the programmed liver cells universally compatible with recipient patients by editing their genomes to evade immune rejection in patients. He is Professor of Biological Engineering at MIT.

The differentiating liver cells will be grown into “liver organoids,” small mini-organs that already exhibit a spectrum of structural and functional features of the liver. Wyss Associate Faculty member Sangeeta Bhatia, M.D., Ph.D. pioneered methods to build and program multicellular tissues and is an expert in the engineering of human liver models for non-animal drug discovery and therapeutics. Her team will systematically evaluate the diverse liver functions of iPSC-derived cells, organoids, and implantable vascularized tissue constructs necessary to support life. Bhatia is also the John J. and Dorothy Wilson Professor of Health Science and Technology and of Electrical Engineering and Computer Science at MIT’s Koch Institute, a Howard Hughes Medical Institute investigator, and a member of the Broad Institute of MIT and Harvard.

To fabricate functional liver tissue at larger scale and complexity, the team will leverage Chen’s expertise in vascular biology and the engineering of vascularized tissues – larger engineered tissue constructs crucially depend on vascular networks that provide blood flow and thus the opportunity to filter blood and access glucose, vitamins, nutrients, and various of classes of toxic molecules that need to be metabolized by the liver to protect the body from their detrimental effects. Chen is also a co-leader of the Wyss Institute’s 3D Organ Engineering Initiative, which develops new approaches to engineer different replacement organs.

The team’s effort to achieve deep vascularization of larger engineered liver tissue constructs goes hand in hand with recently developed capabilities to 3D print living tissues, using engineered cell types, highly specialized engineered biomaterials and additive manufacturing techniques – a research front that has been significantly pioneered by Jason Burdick, Ph.D. and his group at the University of Colorado at Boulder. Burdick has innovated biomaterial approaches for the creation of large-scale biomaterial scaffolds that are able to template higher-order tissue organization and that work in concert with ongoing cell differentiation programs. Burdick is the Bowman Endowed Professor of Chemical and Biological Engineering and the BioFrontiers Institute at the University of Colorado Boulder.

An important barrier to overcome in transplant biology is the ever-present risk of immune rejection that newly introduced tissues are often confronted with in recipient patients. While immunosuppressants avoid some of these reactions, the complex interplay between newly introduced organs and patients’ immune systems in many cases still result in rejection, even if many immune features on donor and recipient cells have been deemed compatible by current immunogenicity tests. The immunoengineering approach taken by the ImPLANT project to allow transplanted liver tissue to evade the immune system more effectively and to create universal donor organs thus critically depends on a thorough analysis of the engineered liver cells and tissue constructs in immunologically active hosts.

 

The team’s two world-leading transplantation and transplant immunology experts, Megan Sykes, M.D. and David Sachs, M.D. will carry out this crucial validation. Sykes’ body of work has expanded the understanding of how the immune system responds to different types of transplants and the factors deciding over immune tolerance vs immune reaction. Vital to the ImPLANT project, her group also developed “human immune system mice” that will allow the team to study immune responses to the engineered liver cells and tissues and to assess the effectiveness of immune tolerance-enabling features in a living organism. As the founding Director of the Columbia Center for Translation Immunology, she also has established a large animal transplant program and closely collaborated with Sachs. Sachs discovered key molecular mechanisms that determine the recognition of cells and tissues as “self” vs. “non-self” and pioneered the first successful trial for inducing transplant tolerance in organ recipients, freeing them from the need for immunosuppressive drugs. His group developed the “miniature pig” as a large animal model for studies of human transplants, which will enable the ImPLANT project to take a crucial pre-clinical step in preparation for future patient studies. The analysis of engineered liver tissues in these different animal models will allow the team to comprehensively assess not only immune tolerance but also the metabolic functionality and viability of the constructs in the face of different disease-associated challenges. Sykes is the Michael J. Friedlander Professor of Medicine and Professor of Microbiology & Immunology and Surgical Sciences, and Sachs is Professor of Surgical Sciences and Professor of Medical Sciences at Columbia University’s Vagelos College of Physicians and Surgeons.

To develop the capabilities to fabricate liver cells, tissue and eventually entire organ constructs at scale, all engineering efforts of the liver ImPLANT project will be closely aligned with the tissue fabrication expertise of Gordana Vunjak-Novakovic, Ph.D. at Columbia University, Vunjak-Novakovic was the first researcher to introduce bioreactor technology into tissue engineering and to succeed in integrating the use of stem cells, biomaterial scaffolds, and bioreactors into complex processes for fabrication of tissues and organs. Her team will develop specialized bioreactors for manufacturing functional liver cells, organoids and tissues, with the quality and amounts necessary to conduct safety, immunogenicity, and efficacy testing in bioreactors and in animal models. In line with the key requirements, the bioreactors will be designed to enable precise control of cell/tissue environments and to also serve as transport containers with preservation of cell viability and function. These bioreactors will be integral to creating high-quality, functional liver tissue at scale, and enhancing their translation to clinical settings. Applied to the ImPLANT program, these capabilities will allow the production of large-scale liver tissues and organs for clinical use. The resulting suite of chemistry, manufacturing, and control (CMC) technologies will be the basis for future GMP facilities set up to fabricate off-the-shelf, universal liver tissues for implantation. Vunjak-Novakovic is the University Professor and Mikati Foundation Professor of Biomedical Engineering and Medical Sciences at Columbia University.

“The Wyss Institute is extremely excited to be part of ARPA-H’s PRINT program, and proud of Chris Chen’s leadership role in the ImPLANT project. The sheer visionary power of the project and impressive scientific expertise provided by this exceptional team have great potential for positively transforming the lives of patients whose livers fail by making science fiction a reality,” said Wyss Founding Director Donald Ingber, M.D., Ph.D., who is also the Judah Folkman Professor of Vascular Biology at Harvard Medical School and Boston Children’s Hospital, and the Hansjörg Wyss Professor of Biologically Inspired Engineering at Harvard John A. Paulson School of Engineering and Applied Sciences.

Research reported in this publication was supported by the Advanced Research Projects Agency for Health (ARPA-H) under Award Number D25AC00322-00. The content is solely the responsibility of the authors and does not necessarily represent the official views of the Advanced Research Projects Agency for Health.

PRESS CONTACT

Wyss Institute for Biologically Inspired Engineering at Harvard University
Benjamin Boettner, benjamin.boettner@wyss.harvard.edu

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The Wyss Institute for Biologically Inspired Engineering at Harvard University (www.wyss.harvard.edu) is a research and development engine for disruptive innovation powered by biologically-inspired engineering with visionary people at its heart. Our mission is to transform healthcare and the environment by developing ground-breaking technologies that emulate the way Nature builds and accelerate their translation into commercial products through formation of startups and corporate partnerships to bring about positive near-term impact in the world. We accomplish this by breaking down the traditional silos of academia and barriers with industry, enabling our world-leading faculty to collaborate creatively across our focus areas of diagnostics, therapeutics, medtech, and sustainability. Our consortium partners encompass the leading academic institutions and hospitals in the Boston area and throughout the world, including Harvard’s Schools of Medicine, Engineering, Arts & Sciences and Design, Beth Israel Deaconess Medical Center, Brigham and Women’s Hospital, Boston Children’s Hospital, Dana–Farber Cancer Institute, Massachusetts General Hospital, the University of Massachusetts Medical School, Spaulding Rehabilitation Hospital, Boston University, Tufts University, Charité – Universitätsmedizin Berlin, University of Zürich, and Massachusetts Institute of Technology.

 

 

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