at Harvard Medical School

Benefactor Report

for the Dr. M. Lee Pearce Foundation
October 2025 (modified December 2025)

During the pre-proposal stage, Q-FASTR received 30 applications: 25 for Pilot Awards ($100,000 each) and 5 for Development Awards ($300,000 each). Of these, the Executive Steering Committee (ESC) invited 20 projects (17 Pilot and 3 Development) to advance to the full proposal stage.

After reviewing the applications, the ESC selected 12 projects for funding:

Pilot Awards:

1. 1. Andrew Kruse, PhD, Professor of Biological Chemistry and Molecular Pharmacology: “Melanocortin 1 Receptor Agonists for Preventing Skin Cancer”
      
      

   2. Bernardo Sabatini, MD, PhD, Alice and Rodman W. Moorhead III Professor of Neurobiology: “Brain-Specific Modulation of Thyroid Hormone Levels”
      
      

   3. Bruce Bean, PhD, Robert Winthrop Professor of Neurobiology: “Potassium-Channel Enhancers to Treat Pain and Epilepsy”
      
      

   4. Isaac Chiu, PhD, Assistant Professor of Immunology: “Targeting V8 Protease to Treat S. aureus Infection and Atopic Dermatitis”
      
      

   5. Josefina del Marmol, PhD, Assistant Professor of Biological Chemistry and Molecular Pharmacology: “Toward the Development of Improved Insect Repellents”
      
      

   6. Lee Rubin, PhD, Professor of Stem Cell and Regenerative Biology: “Targeting Bambi to Promote Remyelination”
      
      

   7. Norbert Perrimon, PhD, James Stillman Professor of Developmental Biology: “Targeting Ecdysone Importer for Control of Disease-Vector and Other Insects”
      
      

   8. Pamela Silver, PhD, Elliott T. and Onie H. Adams Professor of Biochemistry and Systems Biology: “Bacterial Siderophores for Accelerated Mineral Weathering and Carbon Sequestration in Seawater”
      
      

   9. Ruth Franklin, PhD, Assistant Professor of Stem Cell and Regenerative Biology: “Development of a Novel Therapeutic to Accelerate Epithelial Repair Following Viral Respiratory Infection”
      
      

   10. Ulrich von Andrian, MD, PhD, Edward Mallinckrodt Jr. Professor of Immunopathology: “Non-Invasive Theranostics for Endometriosis”
       
       

Development Awards:

1. 1. Arlene Sharpe, MD, PhD, Kolokotrones University Professor: “Enhancing Regulatory T-Cell Function for Adoptive CAR Treg Therapy to Treat Autoimmune Disease”
      
      
   2. David Corey, PhD, Bertarelli Professor of Translational Medical Science: “Enhanced Dual-AAV Gene Delivery to Treat Hereditary Deafness”
      
      

This year, the Q-FASTR leadership team also identified two extraordinary projects as potential candidates for Accelerator Awards. With the Pearce Foundation’s review and approval, the team awarded $400,000 Accelerator Awards to Amy Wagers and José Rivera-Feliciano, enabling them to advance promising concepts developed during early-stage research over the next two years. The following section introduces these investigators and their projects in detail, highlighting their efforts to close the gap between life span and health span for critical diseases.

Q-FASTR FISCAL YEAR 2026 RECIPIENTS

Project Summary

Heart failure with preserved ejection fraction (HFpEF) is the most common form of heart failure in humans and, due to its strong association with advanced age, grows more and more prevalent in developed countries like the United States as the population grows older. Older adults with HFpEF face a dismal prognosis, with no effective drug treatment options and high rates of repeated hospitalization and death. The mechanisms that underlie HFpEF pathology and its connection with age remain poorly defined, but researchers have implicated molecular pathways controlled by the ubiquitously expressed CISD2 protein, which plays an important role in regulating cellular calcium handling, energy production, protein quality control, and cell survival.

Experimenting with transgenic mice, Dr. Wagers and her team determined that turning off production of CISD2 (by “knocking out” the controlling gene, Cisd2) causes premature aging. In contrast, overexpression of the same gene increases healthy lifespan and protects against cardiac dysfunction, Alzheimer’s-like pathology, and fatty liver disease. The Wagers lab has developed a novel gene therapy system, DAEUS (Different AAVs Engineered for User-defined Systemic expression), which enables predictable, tunable delivery of genetic cargo across at least 15 different tissue types in the body. In a mouse model of the human progeroid syndrome Wolfram Syndrome II, Dr. Wagers and her team used DAEUS to rescue CISD2 production in mice lacking functional Cisd2 genes and observed marked therapeutic benefit. DAEUS-Cisd2 treatment reversed established pathology, leading to improvements in strength, activity, vision and other health metrics and an overall extension of lifespan, even in animals with already advanced disease.

With support from a Q-FASTR Accelerator Award, the Wagers lab will undertake two follow-on projects. First, Dr. Wagers and her team will leverage large-scale human data sets to analyze genetic variation in Cisd2 across the human population and correlate that variation to risk of cardiovascular disease and other age-related conditions. Identifying an association between heart failure and declining CISD2 levels in the cardiac tissue of aging humans would strengthen support for a causal relationship between CISD2 loss and elevated risk of heart disease in older adults, and could also help define the levels of Cisd2 expression necessary for healthy cardiovascular function.

 Second, Dr. Wagers and her team will determine the functional impact of rescuing Cisd2 gene function in preclinical models of HFpEF. Many pathological features of HFpEF in mice are reversible, even after the pathology is well-established, but scientists have yet to identify the molecular mediators and mechanisms involved in this functional rejuvenation. Dr. Wagers hypothesizes that rescuing Cisd2 expression and function, either body-wide or specifically within cardiac muscles, is key to this functional recovery. 

Together, these studies will establish the efficacy of Cisd2 therapy as a treatment or prevention modality in relevant preclinical models of HFpEF, clarify whether systemic or muscle-specific recovery of Cisd2 is required, and generate a mechanistic understanding of Cisd2 effects that could enable future development of small molecules with similar therapeutic activity.

Success in these studies will open the door to novel Cisd2-based therapies for heart failure in humans and chart a path for further exploration of such therapies for other age-related diseases, including Alzheimer’s, in which Cisd2 plays a role. More broadly, this work will establish AAV-based gene delivery (like DAEUS) as a powerful new modality in aging research. Once validated, this system could accelerate the discovery, translation, and clinical application of aging-relevant therapeutics across a broad spectrum of targets and conditions.

Project Summary

Over the past three decades, the advent of biologic medicines has reshaped the medical field, but diseases of the central nervous system (CNS) continue to pose challenges to the use of such drugs—the most systemically administered large molecules cannot efficiently cross the blood–brain barrier (BBB) and enter the CNS. Researchers are presently pursuing multiple strategies to overcome BBB impermeability, but each has limitations. The most promising approach uses conjugate drugs that target a surface receptor on CNS endothelial cells (ECs). After systemic administration, the conjugate drug engages the endothelial target, triggering receptor-mediated transport of a “payload” (the primary drug that will actually work on the CNS) across the BBB. Despite substantial investment in this approach, researchers have identified only a handful of suitable binding targets so far.

The primary target in clinical development is Transferrin Receptor 1 (Tfr1). However, Tfr1 has several shortcomings, including a limited capacity to mediate transcytosis (movement across the entire cell) of bound cargo and expression on many non-CNS cells exposed to flowing blood, such as reticulocytes, intestinal ECs, perivascular macrophages, and bone marrow cells. Many alternative targets likewise lack BBB specificity, resulting in potential on-target and off-tissue drug accumulation and reduced CNS bioavailability.

The von Andrian lab has recently generated a comprehensive atlas of endothelial gene expression across 20 different mouse model tissues, including four CNS regions (brain parenchyma, choroid plexus, pia mater, and dura mater). Dr. von Andrian and his team have identified several endothelial surface molecules that are uniquely expressed on CNS ECs, including Mfsd2a, a known BBB-associated lipid transporter. Preliminary experiments in an in vitro model of the human BBB indicate that a phycoerythrin-conjugated antibody against Mfsd2a is rapidly trancytosed across a tight monolayer of human brain microvascular ECs. This has motivated the team to produce novel nanobodies (NAbs) against a specific extracellular epitope of Mfsd2a that recognizes both mouse and human orthologues.

With support from a Q-FASTR Accelerator Award, the von Andrian lab will further characterize these NAbs in vitro and in vivo and demonstrate their potential utility as novel, tissue-specific vehicles for targeted drug delivery to the CNS. This work could create a new class of ligands for drug conjugation, generating novel therapies for a wide range of diseases.

As of December 2025, Dr. von Andrian’s project replaces an award originally made to Jose
Rivera-Feliciano, PhD , for his research into treating diabetes with the peptide hormone Atollin.