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The Wyss Institute’s 2022-2023 Validation Projects

Meet the teams who are driving their technologies forward toward commercialization

By Lindsay Brownell

Every year, the Wyss Institute names a class of Validation Projects that receive funding, business development support, and a wide variety of resources to support them on every step towards commercializing their technologies. All of the project teams identified strong first use-cases with great potential impact, and will now validate these technologies. Over the course of the year, these projects will be de-risked through a combination of technical development, discussions with potential investors, and market research on their path to becoming viable products.

Please join us in celebrating this year’s teams, both first-year Validation Project teams and those who have won a second year of support to drive them toward commercialization.

Diagnostics

The Wyss Institute’s 2022-2023 Validation Projects
Isaac Han is leading a Validation Project to enable rapid and wash-free protein detection technologies using novel light-emitting amino acids. Credit: Wyss Institute at Harvard University

LymeSiTE: Rational genome fragmentation for ultra-sensitive Lyme disease diagnostics
Team lead: Soufiane Aboulhouda
Faculty lead: George Church
Contact: Alex Li 

Lyme disease is a growing problem in North America, and can cause chronic health problems. This team aims to develop a diagnostic for Lyme disease through a new workflow that isolates desired fragments of DNA from Borrelia bacteria, the source of the disease, in patient samples. The goal is to (1) detect Borrelia genomic DNA in early infection at much lower levels compared to existing techniques, especially when the patient doesn’t exhibit typical symptoms, and (2) determine if Borrelia is still present in patients exhibiting symptoms after completing antibiotic treatment.

Project Sparkle: Instant biosensors (second-year Validation Project)
Team leads: Helena de Puig, Isaac Han, Erkin Kuru
Faculty leads: George Church, Jim Collins
Contact: Bill Bedell

Project Sparkle enables rapid and wash-free protein detection technologies using novel fluorogenic (light-emitting) amino acids. Applications include instant immunostains for both research and clinical use that can significantly simplify and shorten existing pathology procedures, like tumor margin identification in breast cancer. In the future, these biosensors could have broad impact on research, diagnostic, and drug discovery applications of protein-based binders.

Drug Discovery Platforms

DNA nanoswitches for “lab-on-a-molecule” drug discovery
Team leads: Sylvie Bernier, Ken Carlson, Clinton Hanson, Mark Lipstein
Faculty lead: Wesley Wong
Contact: Bill Bedell

There is an urgent need for low-cost, high-throughput drug screening techniques. Using DNA nanotechnology, this team has developed a platform for logic-gated, high-throughput screening to identify novel therapeutic compounds. This technology can be used to find biologic or small molecule drug candidates that modulate the function of important drug targets with high specificity. For initial proof-of-concept studies, the team is using the platform to identify compounds against disease-related proteins, unlocking the potential to treat cancer, diabetes, obesity, and autoimmune diseases.

The Wyss Institute’s 2022-2023 Validation Projects
Girija Goyal, Ph.D. is leading a Validation Project to identify new immunotherapy treatments for pancreatic cancer using an Organ Chip model of Tertiary Lymphoid Organs. Credit: Wyss Institute at Harvard University

High-throughput single B cell selection for potent neutralizing antibody discovery
Team lead: Jingyi Luan
Faculty lead: Peng Yin
Contact: Sam Inverso

This team is developing a rapid, high-throughput, and low-cost isolation pipeline to identify potent antibodies against pathogens in a one-step screening of single memory B cells. This platform could facilitate the discovery of antibodies with broad therapeutic potential.

Novel immunotherapy for pancreatic cancer
Team lead: Girija Goyal
Faculty lead: Don Ingber
Contact: Paul Resnick

Some patients with cancerous tumors develop lymph-node-like clumps of immune cells called Tertiary Lymphoid Organs (TLOs) close to the tumor that seem to improve their response to therapy. This team has created an in vitro model of TLOs and is working on a second model of pancreatic cancer tumors with TLOs present. They plan to use these models to identify molecules that influence TLO function, as well as novel immunotherapy targets that leverage TLOs’ influence on tumors.

Therapeutics

The Wyss Institute’s 2022-2023 Validation Projects
Kwasi Adu-Berchie is leading a Validation Project that allows adoptive T cell therapies to metabolically “tag” the surface of the T cells with cytokines to dramatically improve their persistence, anti-solid-tumor function, and ability to interact with and enhance host immune responses. Credit: Wyss Institute at Harvard University

Enhanced adoptive T cell therapy via metabolic labeling
Team leads: Kwasi Adu-Berchie, Michael Williams
Faculty lead: David Mooney
Contact: Paul Resnick

Adoptive T cell therapies (e.g., CAR-T cell therapy) have shown spectacular success in the treatment of blood cancers, but have not been similarly effective in solid tumors. This team has developed an elegant process that allows them to metabolically “tag” the surface of the T cells with cytokines, which dramatically improves T cells’ persistence, anti-solid-tumor function, and ability to interact with and enhance host immune responses. This strategy can be easily integrated into current T cell manufacturing processes, and could boost the efficacy of all forms of T cell therapy and other cellular therapies.

Broad-spectrum RNA therapeutic for fighting future viral pandemics
Team lead: Ken Carlson
Faculty lead: Don Ingber
Contact: Paul Resnick

The COVID-19 pandemic has highlighted the need for broad-spectrum antiviral treatments. This team has identified a new class of immunostimulatory short duplex RNAs that induce production of type I and type III interferon, and in so doing cause broad-spectrum inhibition of infection by many respiratory viruses with pandemic potential including SARS-CoV-2, SARS-CoV, MERS-CoV, and influenza A. This approach has already shown promise in cell lines, human Lung Chips, and animal models.

FeCILL: A targeted therapeutic for invasive fungal infections
Team leads: Michael Super, Alex Tatara
Faculty leads: Don Ingber, David Mooney
Contact: Paul Resnick

Invasive fungal infections have a high mortality rate despite the availability of anti-fungal treatments, and account for more than 1.6 million deaths globally per year. Current anti-fungal therapies lack specific targeting, and thus can cause significant systemic toxicity. This team has developed Fungicidal endovascular Controlled-release Iron-binding Lectin Liposomes (FeCILL) that specifically targets the fungal cell wall and concentrates drugs there. This platform therapy could increase efficacy while reducing toxicity and side effects in patients who take traditional anti-fungal drugs.

FASTeN: novel biologics for cancer therapeutics
Team leads: Raphael Ferreira, Chun-Ting Wu
Faculty leads: George Church
Contact: Alex Li

Certain limitations of CAR-T cell therapies have hindered their success in solid tumors, including their inability to home to solid tumors and their weak response in the immunosuppressive tumor microenvironment. This team’s novel biologic FASTeN can address these challenges by homing to tumors naturally and killing them efficiently using a novel tumor interaction mechanism.

The Wyss Institute’s 2022-2023 Validation Projects
Pam Silver and Jeffrey Way are leading a Validation project that aims to further develop their engineered protein treatment for pancreatitis. Pam is also leading a project with sustainability applications. Credit: Wyss Institute at Harvard University

A SPINK1-based fusion protein for treatment of pancreatitis
Team lead: Jeffrey Way
Faculty lead: Pam Silver
Contact: Alex Li

Pancreatitis, or inflammation of the pancreas, is a common and sometimes fatal disorder with no drug-based treatments. This team has developed an engineered protein treatment for pancreatitis that inhibits trypsin, the disease’s primary cause. The engineered protein is effective in a mouse model of acute pancreatitis, is easy to manufacture, and should be straightforward to commercially develop. The team aims to demonstrate their protein’s activity in a chronic mouse model of pancreatitis that more accurately represents human disease, and use the model to define a final molecule for human studies.

Ichor: Hematopoietic stem cell rejuvenation to increase health and lifespan
Team lead: Alex Plesa
Faculty lead: George Church
Contact: Bill Bedell

Aging is a major risk factor for chronic diseases, many of which arise from age-related dysfunctions in hematopoietic stem cells (HSC). This functional decline is evident in HSC transplantation (HSCT), where aged HSCs from older donors are linked to reduced recipient survival. This team is developing “transcriptomic reprogramming” techniques for HSC rejuvenation that can help patients undergoing allogeneic HSCT live longer and, in the future, could broadly improve human health and lifespan for a broader population.

HarborSite: Genome engineering via recombinase-mediated transgene integration into genomic safe harbors
Team leads: Erik Aznauryan, Tina Lebar
Faculty lead: George Church
Contact: Bill Bedell

Numerous gene and cell therapy applications require the ability to insert genes directly into the genome without causing damaging changes to neighboring genomic elements. This team is developing a platform to achieve safe and efficient targeted gene insertion in human cells using two key advances: i) identification and validation of “genomic safe harbor” sites that support safe and durable expression of genes of interest, and ii) characterization and engineering of site-specific recombinases that can insert large DNA sequences into precise locations in mammalian genomes without inducing double-stranded breaks. The combination of these two technologies could uncover a novel approach to human cell engineering, paving the way for a variety of clinical applications.

Vaccines

The Wyss Institute’s 2022-2023 Validation Projects
Kevin Emancipator and Yang Claire Zeng, Ph.D. from the DoriVac team won the first-ever Alnylam Bioventure Challenge based on their technology’s commercialization potential. Credit: Wyss Institute at Harvard University

DoriVac: A new vaccine for cancers and infectious diseases
Team lead: Yang Claire Zeng
Faculty lead: William Shih
Contact: Ally Chang

DoriVac, short for “DNA Origami Vaccine,” aims to leverage DNA origami nanotechnology and immune activators to stimulate stronger and long-lasting immune responses against both cancer and infectious diseases. Its off-the-shelf nanoparticle vaccine platform can be easily tailored by changing the specific antigens within it. DoriVac has been primarily verified in melanoma and lymphoma mouse models using cell lines that overexpress model tumor antigens, and in healthy mice against SARS-CoV-2, HIV and Ebola. The team has established a low-cost and large-scale manufacturing method for DoriVac, and aims to demonstrate its effects on a human lymph node model. They are also actively investigating DNA origami as a vector to deliver other adjuvants and antigens in different forms

Engineering macrophage vaccines with cellular backpacks for the treatment of primary brain tumors (second-year Validation Project)
Team leads: Michael Dunne, Charles Park
Faculty lead: Samir Mitragotri
Contact: Ally Chang

Glioblastoma multiforme (GBM) is the most common form of brain tumor, and less than 10% of patients survive for 5 years past diagnosis. Despite its severity, there have been no significant advancements in the treatment of GBM, in part because GBM tumors produce a highly immunosuppressive “cold” tumor microenvironment (TME) that limits immunotherapy approaches. The blood-brain barrier (BBB) further poses an additional hurdle to the delivery of therapeutics. This team aims to address this need by developing a macrophage-based neoantigen vaccine that can cross the BBB and initiate both systemic and regional immune responses. A core component of the technology is nanoparticle “backpacks” adhered to macrophages that keep them in a proinflammatory state, allowing them to convert the tumor microenvironment to a “hot” one that promotes cancer cell killing.

Sustainability

The Wyss Institute’s 2022-2023 Validation Projects
Vaskar Gnyawali, Ph.D. is leading a Validation Project to identify and evolve microbes that can digest different kinds of plastic to address the global plastic pollution problem. Credit: Wyss Institute at Harvard University

Accelerated evolution for sustainable plastic degradation (second-year Validation Project)
Team leads: Vaskar Gnyawali, Sukanya Punthambaker
Faculty leads: George Church, Donald Ingber
Contact: Bill Bedell

More than 360 million tons of plastic waste is generated globally every year, and about 75% of it persists for decades either in landfills or in the ocean. This team seeks to evolve microbes with the ability to break down complex mixtures of plastics into relatively harmless and ubiquitous substances: carbon dioxide, water, and decayed biomass. Using “bio-prospecting,” they have identified existing microbe strains that are able to decompose and assimilate multiple types of plastic. The next phase of development will apply analytical chemistry, genetics, and synthetic biology to evolve faster and more robust plastic-eating microbes that can help reduce plastic waste.

Design and engineering of intrinsically disordered proteins (IDPs) for enhancing desiccation tolerance in plant cells (second-year Validation Project)
Team lead: Samuel Lim
Faculty lead: Pam Silver
Contact: Alex Li or Paul Resnick

Drought is a major stressor that inhibits plant growth and limits worldwide crop production. This team is developing novel protein products that enhance the drought-resistance of plant cells. These products will be based on naturally occurring intrinsically disordered proteins (IDPs), which naturally occur in certain organisms including tardigrades. The team is currently focusing on completing the screening of synthetic IDP variants to select a final product design, and also expanding testing beyond plant cell cultures to verify end-user applications.

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