With the award for up to $27M from the Advanced Research
Projects Agency for Health (ARPA-H), a collaborative research
project at the Wyss Institute for Biologically Inspired
Engineering at Harvard University will advance a
disease-agnostic novel RNA therapeutic with the potential to treat
diverse diseases, and to be effectively and rapidly deployable. By
safely and naturally stimulating the “innate immune” system — the
body’s first line of defense against disease-causing tumor cells
and pathogens — this approach has the potential to stimulate the
immune system as a whole, including its more cancer cell and
pathogen-specific “adaptive immune” responses. Its therapeutic
effects in the body can significantly outlast the presence of the
RNA drug itself, and potently synergize with other immunotherapies
in patients suffering from various types of cancer and infectious
diseases.
“We are excited by the opportunity afforded by the
ARPA-H award to develop new RNA-based therapeutics, advanced
delivery vehicles, and manufacturing capabilities to provide
patients with cancer and infectious diseases with new treatment
opportunities. We have assembled an exceptional team that is eager
to realize the potential of our proposed program,” said Wyss Core
Faculty member Natalie Artzi, Ph.D., who is the
lead-investigator on the project with co-principal investigator and
Wyss founding director, Don Ingber, M.D., Ph.D. Artzi also is
Associate Professor of Medicine at Harvard Medical School (HMS)
and Brigham and Women’s Hospital and a Principal Research
Scientist at MIT.
ARPA-H is a federal funding
agency established by the Biden Administration, which
funds transformative biomedical and health research breakthroughs,
rapidly translating research from the lab to applications in the
marketplace. The ARPA-H award will allow the Wyss team to
significantly accelerate and expand their efforts in order to
advance the therapy towards an Investigational New Drug (IND)
submission to the Federal Food and Drug Administration (FDA).
With its first focus on cancer as a disease
target, the multidisciplinary Wyss team combines critical and
highly complementary expertise in the areas of drug discovery,
advanced in vitro and in vivo models for
preclinical drug testing, innovative drug delivery, RNA
nanotechnology, and next-generation RNA synthesis and
manufacturing. After having significantly de-risked their
disease-agnostic immunotherapeutic RNA therapy as a cancer
treatment, the team will also validate its use for
difficult-to-treat infectious diseases.
The ARPA-H project builds on a Duplex
RNA technology pioneered by Ingber's team and leverages
innovative drug delivery approaches that Artzi’s group developed
with a particular focus on programming the immune system, as well
as an expansive array of human “Organ Chip” tissue culture
systems advanced by Ingber’s group that enable preclinical
human drug testing. Artzi and Ingber are joined on the project by
additional key investigators, including Wyss Director of
Translational R&D Kenneth Carlson, Ph.D., a drug discovery
and development specialist with extensive industry experience, who
drove the development of the Duplex RNA, and Wyss Core Faculty
member William Shih, Ph.D., who has developed DoriVac, a
DNA origami platform that allows the precise and highly effective
presentation of RNA drugs, cancer and pathogen-derived antigens,
and immune activating adjuvants to the immune system.
Shih and his team will provide their DNA nanotechnology approach as
an additional drug delivery component to the project. Finally, the
researchers will collaborate with Wyss start-up EnPlusOne
Biosciences to harness the RNA solution company’s
novel enzymatic RNA synthesis and manufacturing
capabilities that overcome key limitations of commonly used
chemical RNA synthesis methods.
“The Wyss Institute’s ambition and ability to take
on extraordinarily difficult challenges, and to mature promising
early research discoveries all the way to real-world solutions that
are prime for clinical stages, resonates well with ARPA-H’s
mission. We are excited and confident that our accomplished, highly
multidisciplinary team will have a significant impact on future
immune therapies and patients’ lives with ARPA-H's tremendous
support,” said Ingber, who
isalso 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 the Harvard John A. Paulson School of
Engineering and Applied Sciences.
Origins and validation
The project began in the middle of the COVID-19
pandemic, when Ingber’s group identified a novel,
structurally distinct double stranded RNA molecule (Duplex RNA)
that they showed prevents the replication of various potential
pandemic respiratory viruses, including SARS-CoV-2 in an animal
model as well as MERS-CoV, and various influenza viruses in human
lung tissues engineered in Organ Chips. It did so by stimulating an
innate immune response involving a family of protective cytokines
known as interferons (IFNs) without triggering potentially
dangerous inflammation that occurs when the innate immune system is
overactivated. As the molecular target for the Duplex RNA, the
researchers identified the RIG-I protein, which normally responds
to viral RNA molecules by inducing tissue-protective immune
responses through the balanced activation of several
gene-activating IFN pathways.
IFN protein therapeutics have made their way into
the clinic for the treatment of infectious diseases as well as
certain cancers, and they also have been used to sensitize cancer
cells to other forms of therapy, including chemo- and radiation
therapy, as well as newer immunotherapies. However, “past
therapeutic approaches, which administered a single concentrated
dose of an individual manufactured IFN
protein via injection, have often been unbalanced, as
they strongly and selectively activate only one of many downstream
pathways, and they had highly variable effects across patients and
cancer types,” said Carlson. “Our Duplex RNA approach induces the
body’s own innate immune response, resulting in a more balanced,
highly beneficial activation of multiple types of protective IFNs
with a significantly larger therapeutic window that we aim to
broadly harness in this project.”
The Duplex RNA project was named a Wyss Validation
Project in 2022, during which time the Wyss team further de-risked
their novel approach as an infectious disease therapeutic by
showing potent efficacy in a mouse model of COVID-19. Then, in a
second Wyss Validation Project awarded in 2023 and coordinated by
Ingber and Carlson, which also includes Artzi and Shih as
investigators, they successfully pursued it as a potential cancer
therapeutic. In the new ARPA-H project, they will leverage the
powerful RNA delivery capabilities of Artzi’s and Shih’s groups
along with the groundbreaking enzymatic RNA synthesis capabilities
of EnPlusOne to optimize the Duplex RNA’s stability and efficacy.
They also will utilize human Organ Chip culture technology and
preclinical animal models as highly relevant test beds.
Importantly, findings obtained in human Organ Chip models,
according of the 2022 FDA Modernization Act, can now be
included in an IND submission to the FDA.
Delivery is key
Key for the project’s success will be the team’s
ability to deliver an optimized Duplex RNA to the body’s
tumor-bearing or infected tissues. Artzi has pioneered multiple
drug delivery systems that can be used to target therapies to
specific sites and cells in the body, or effectively distribute
them broadly. For example, her group’s polymeric
nanoparticles can increase the stability and loading of drugs,
as well as drug uptake by cells, when compared to other delivery
methods, and release their cargo in response to specific cellular
cues. This enabled her team to create an immunotherapy that
accumulates in immune and cancer cells, with the latter functioning
as a depot – releasing the nanoparticles to innate immune cells in
their vicinity, and activating them to generate a long-lasting
anti-tumor immune response.
While these nanoparticles are administered
intravenously, another material-based delivery strategy developed
in Artzi’s group consists of polymeric microneedles that,
applied as a patch, can be used to deliver drugs into subcutaneous
layers of the skin. The team used these microneedle patches to
administer a melanoma therapy in a mouse model, and to monitor
local immune responses based on skin biomarkers collected by the
patch. The utility of microneedles, including their safe and
painless administration, also makes them an important future avenue
to treat many more patients in clinically underdeveloped settings,
allowing them to benefit from otherwise inaccessible
therapies.
“We will pursue both delivery routes for the
disease-agnostic Duplex RNA therapy and, together with William
Shih’s group, also explore their integration with DNA origami
technology, which can function as a precision instrument to
fine-tune and enhance the presentation of the Duplex RNA to RIG-I
sensor proteins within cells,” said Artzi. “Our ultimate goal is a
disease-agnostic innate immune therapeutic platform that
effectively synergizes with other immunotherapies, enabling a much
larger proportion of patients to be treated with them across a much
larger range of cancer and infectious diseases.”
PRESS CONTACTS
Wyss Institute for Biologically Inspired
Engineering at Harvard UniversityBenjamin
Boettner, benjamin.boettner@wyss.harvard.edu
Conway Communications for EnPlusOne
BiosciencesMary T. Conway, mtconway@conwaycommsir.com
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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.
EnPlusOne
BioSciences (www.enplusonebio.com) is enabling the future
of RNA therapeutics. Its ezRNA™ platform is a revolutionary
innovation that harnesses the power of enzymes to synthesize RNA
and can incorporate a diverse array of natural and modified
nucleotides. Their enzymatic, water-based approach promises to
unlock sustainable and scalable commercial manufacturing of RNA
therapeutics.
Seth Kroll
Wyss Institute at Harvard University
seth.kroll@wyss.harvard.edu