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Daedalus Fund Supports 15 Investigators

Fifteen winners (fourteen projects) have been selected for the fourth round of the Daedalus Fund for Innovation awards, a pioneering Weill Cornell Medicine program that helps advance promising applied and translational research projects and emerging technologies that have commercial potential.

In an expansion of the program, winners are now selected twice annually and are eligible for two levels of funding: $100,000 and $300,000 (the latter, subject to the satisfaction of certain specified pre-defined milestones).

The researchers — Drs. Francis Barany, Jochen Buck in collaboration with Lonny Levin, Ethel Cesarman, Shuibing Chen, David Cohen, Ronald Crystal, Lukas Dow, Katherine Hajjar, Samie Jaffrey, Gang Lin, David Lyden, Xiaojing Ma, John Pena, and Nicholas Schiff — have each won a Daedalus award to fund proof-of-concept studies that will enhance the data package, thereby helping to upgrade their technologies and translate their early-stage discoveries into new therapeutic modalities and hopefully more effective treatments for patients.

The fund’s independent external Scientific Advisory Committee, comprised of seasoned technology analysts from the biopharmaceutical and venture capital industries, selected the projects.

“The Daedalus Fund helps our investigators bridge the ‘development gap’ and accelerate their projects to the point at which they are strong candidates for business development and licensing,” said Larry Schlossman, managing director of BioPharma Alliances and Research Collaborations at Weill Cornell Medicine, who manages the Daedalus Fund. “By providing philanthropic support at this critical juncture, we are helping to advance early-stage research projects that have significant commercial potential.”

Dr. Francis Barany
Professor of Microbiology and Immunology

Self-Assembling Dimeric Drugs to Target Protein Destruction

Many proteins that are known to drive cancer growth lack the features that would make them good targets for small-molecule drugs or larger antibody-based therapeutics; that is, they are considered “undruggable.” These proteins reside within cells, unreachable by large antibodies, which cannot pass through the cell membrane, and lack a well-defined site to which a small molecule can bind.

Dr. Barany and collaborators have developed a platform of molecules, which they call “Coferons,” that are designed to easily pass through the cell membrane and then assemble into larger, two-component units upon binding to their target. This project’s goal is to expand the Coferon platform to take advantage of the cell’s natural ability to target proteins for degradation and recycling. Thus, one component will be designed to bind to the protein E3 ubiquitin ligase, which tags proteins for degradation. The other component will bind to the target to be destroyed. Upon assembly, the protein target will be tagged for destruction. Preliminary results show that this system can be used to achieve the degradation of the BRD4 protein, which is implicated in cancer and inflammatory disease.

Daedalus funding will allow Dr. Barany and his team to further develop the system, screen these molecular components for efficacy and characterize their activity in preclinical models. Taking advantage of the modular features of the platform, these new E3 ubiquitin ligase-binding components will be appropriate for use with many other targets, making this technology universally applicable. Dr. Barany believes his team’s demonstration of proof-of-concept will lead to the creation of a new family of drug molecules, with expansion potential for degrading other oncogenic proteins that have proven difficult to target by conventional pharmacological design.

Drs. Jochen Buck and Lonny Levin
Professors of Pharmacology

Development of “First of Their Kind” Activators of Soluble Adenylyl Cyclase for the Treatment of Glaucoma

Glaucoma is a potentially blinding condition caused by increased pressure in the eye, or intraocular pressure (IOP). Current treatment strategies work by reducing IOP, and because there is no cure, treatment must continue for life. Over time, these treatments can lose effectiveness or accrue intolerable side effects; therefore, there is ample need for novel therapeutic strategies to treat glaucoma.

Dr. Buck and Dr. Levin’s laboratory discovered that an enzyme called soluble adenylyl cyclase (sAC) regulates IOP. They have demonstrated that inhibitors that block this enzyme elevate IOP, and these are being developed into a first-of-its-kind treatment for the rare, but potentially blinding disease, ocular hypotony. They have also shown that a long-used class of drugs for treating glaucoma indirectly and transiently activates sAC, lowering IOP. They hypothesize that small molecules that directly activate sAC will be more effective in lowering IOP, and could thereby be the basis of a novel treatment for glaucoma.

With Daedalus funding, they will use high-throughput screening, a method to rapidly and efficiently test a large number of small molecule compounds for activity against a target, to identify “first-of-their-kind” small molecule activators of sAC. To maximize the likelihood for success, they have developed two robust and reproducible complementary screening strategies. They anticipate identifying small molecule activators of sAC that are safe, work in cell culture and animals, and are selective for sAC over related forms of the enzyme, thereby limiting toxic side effects. These will define lead compounds for a novel therapeutic strategy to treat glaucoma.

Dr. Ethel Cesarman
Professor of Pathology and Laboratory Medicine

Development of Nucleoside Analogue Selectively Activated Adenosine Kinase to Treat ADK-expressing Adenocarcinomas

Lung, colorectal and pancreatic cancers take an enormous toll on populations worldwide. Currently available treatments for these malignancies, particularly in more advanced stages, have serious side effects and often fail to keep the disease in check for a significant amount of time. Dr. Cesarman’s lab has discovered a promising avenue for developing more effective therapies for these malignancies.   

Nucleoside analogues are chemically similar to the building blocks of DNA, RNA and ATP, but they are nonfunctional and therefore can inhibit cell functions when they compete with these molecules in binding to key cellular enzymes. Dr. Cesarman recently discovered a nucleoside analogue, 6-ETI, and two derivatives that selectively block growth of cancerous cells that express adenosine kinase (ADK), an enzyme that plays a fundamental role in cellular metabolism. These malignancies include the blood cancers multiple myeloma and primary effusion lymphoma. She has tested 6-ETI in mouse models of these diseases, with remarkable responses and no obvious toxicity.

Dr. Cesarman has more recently discovered that ADK is expressed in pancreatic, colon and lung adenocarcinomas. She was encouraged to find that pancreatic and colon cancer cell lines are sensitive to her nucleoside analogues, two of which are part of a patent application.

Now, with Daedalus funding, she will document the effectiveness of these compounds in mouse models of pancreatic and colon adenocarcinoma. Through these studies, she will also investigate the effectiveness of ADK as a biomarker of response to identify patients most likely to benefit from this new cancer drug. The major research objective of this project is to complete the necessary pre-clinical steps to make the compounds attractive for licensing.

Dr. Shuibing Chen
Associate Professor of Chemical Biology in Surgery
Associate Professor of Chemical Biology in Biochemistry

Evaluation of Anti-Zika Virus Drug Candidates

Zika virus (ZIKV) infects fetal and adult human brains, and is associated with serious neurological complications, including microcephaly and Guillain-Barré Syndrome. To date, no therapeutic treatment is available to treat ZIKV infection. Although an antibody-based treatment of ZIKV infection was recently reported to prevent ZIKV replication in mice, the high cost of antibody-based therapy limits its broad application.

In preliminary studies, Dr. Chen tested the contents of a chemical library containing FDA-approved drugs or drug candidates for their ability to inhibit ZIKV infection in both human neural progenitor cells (hNPCs), which are stem cell-like cells that generate neurons and other nervous system cell types, and human fetal-like forebrain organoids, mini-organs that are derived from pluripotent stem cells. She identified two drug candidates that inhibit ZIKV infection, induce increased cell death and decrease cell proliferation of infected cells, and block virus propagation. More important, the drug candidates eliminate the virus from the ZIKV-infected cells. Finally, both drug candidates suppress ZIKV infection in vivo.

With Daedalus funding, Dr. Chen will focus on determining the therapeutic potential of the drug candidates. To optimize the lead compound, she will synthesize a group of related molecules and systematically evaluate each one’s ability to eliminate the infection of different ZIKV strains in hNPCs, brain organoids and mouse models. She will then conduct tests to assess pharmacological properties of the lead compounds. This study will identify drug candidates that provide long-term in vivo control of ZIKV infection in both fetal and adult brains, and can be used to develop broadly effective clinical therapies for ZIKV infection.

Dr. David Cohen 
Vincent Astor Distinguished Professor of Medicine
Chief, Division of Gastroenterology and Hepatology

Them1 Inhibitors for the Management of Obesity-Related Disorders

Obesity is closely associated with many disorders, including atherosclerosis and type 2 diabetes. The prevalence of obesity-related disorders continues to increase, but current management options remain limited.

Brown adipose tissue (BAT), a type of fat tissue, is rich in mitochondria, the energy generators of the cell, and plays a key role in human energy expenditure by increasing cellular metabolism to generate heat. Dr. Cohen hypothesizes that interventions that increase BAT activity will mitigate obesity. Thioesterase superfamily member 1 (Them1) is an enzyme that is highly expressed in BAT and strongly suppresses energy expenditure as part of a feedback mechanism to turn down the system when enough energy has been released.

With Daedalus funding, Dr. Cohen will test a large number of small molecule compounds for their ability to block the activity of Them1. Because he has already produced pure Them1 protein to use in the screen and optimized the assay, the potential for success is high. After he obtains candidate drug compounds, he will optimize the activity of the most promising ones and determine how they are inhibiting Them1 using in vitro and in cell-culture systems. Lead compounds should prove attractive for optimization and for in vivo testing, with the objective of commercialization.

Dr. Ronald G. Crystal
Bruce Webster Professor of Internal Medicine
Chairman, Department of Genetic Medicine

A Human Embryonic Stem Cell-Based Platform for Directed Evolution of Viral Tropism to Generate Cell-Type Specific Vectors for Gene Therapy

Gene therapy has the potential to cure a vast number of human diseases. Recent therapeutic breakthroughs are rekindling commercial interest in the field. Despite this, gene delivery remains a critical roadblock. Currently it is only possible to deliver genes to a handful of cell types, limiting therapeutic scope.

With support from the Daedalus Fund, Dr. Crystal – together with Gustav Cederquist, an MD-PhD student at Weill Cornell Medicine and Dr. Lorenz Studer, director of the Center for Stem Cell Biology at Memorial Sloan Kettering Cancer Center – proposes to develop a human embryonic stem cell (hESC)-based platform to engineer benign viral vectors (i.e., viruses that can deliver therapeutic genes) targeted to any desired human cell type. Human embroyonic stem cells have the remarkable ability to differentiate into any cell type in the body. By controlling the differentiation process, it is now possible to generate over 40 human cell types in cell culture. These hESCs will be used as a tool to select for viruses that specifically infect a particular cell type.

He will use an iterative process known as directed evolution to arrive at a virus that is highly selective for infecting the desired cell type. In directed evolution, a pool of viruses is created, each bearing a different set of mutations in the gene that encodes a protein on the surface of the virus. This protein is key to determining the virus’ infection selectivity. After infecting cells with these viruses, the virus that is most selective for the desired cell type is chosen for use in the next round of infection. Eventually, a virus that is highly specific to the desired cell type will emerge.

As proof of principle, the investigators aim to engineer a viral vector that can specifically target cardiac cells and deliver therapeutic genes to cardiac tissue. These gene-therapy vectors could be readily applied to widespread cardiac diseases, including congestive heart failure and cardiomyopathies. Daedalus funding would help achieve (1) a licensable viral gene-therapy vector for cardiac indications and (2) proof-of-concept data that his hESC-based platform could be applied to generate gene-therapy vectors for a number of disease indications.

Dr. Lukas Dow
Assistant Professor of Biochemistry in Medicine

Selective TNKS2 Inhibition as a Collateral Vulnerability in Colorectal Cancer

Colorectal cancer (CRC) accounts for more than 600,000 deaths annually worldwide, making it the second leading cause of cancer-related deaths and a major public health problem. Despite a thorough characterization of the genetic alterations driving CRC, there are still no safe and effective therapies to treat advanced tumors.

Dr. Dow has designed an approach that takes advantage of the chromosome breakage that is a hallmark of advanced CRC. Approximately 50 percent of these cancers involve the loss of the TNKS gene, a gene that helps drive cancer growth. In its absence, the cancerous cells sustain themselves by becoming more reliant on a related protein encoded by the TNKS2 gene.

Because this reliance is specific to these CRC tumors, Dr. Dow hypothesizes that inhibitors of TNKS2 will not exhibit the same profound intestinal toxicity that caused TNKS inhibitors to stall in clinical testing. With Daedalus funding, he will apply both genetic and new pharmacologic tools to validate the therapeutic potential of selective TNKS2 targeting in CRCs missing the chromosome region with the TNKS gene.

Dr. Dow’s lab’s approach represents a significant departure from current strategies for targeting the molecular pathway driving CRC, and could represent a new precision- medicine approach to treating a specific subset of CRC patients. Completion of his studies would provide key proof-of-concept of this approach, and create value for future commercialization or industry partnership, through the development and validation of novel TNKS2-specific small molecule inhibitors.

Dr. Katherine Hajjar
Brine Family Professor of Cell and Developmental Biology
Professor of Pediatrics
Professor of Pediatrics in Medicine

Development of Novel Annexin A2 Antibodies as First-in-Class Therapeutic for Diabetic Retinopathy

By the year 2050, it is expected that there will be more than 15 million individuals with diabetic retinopathy (DR) in the United States. DR is the leading cause of blindness in industrialized countries, and at least 10 percent of those with DR will have vision-threatening disease. Current treatments are beneficial in only about 50 percent of patients, and there are no preventive measures available.

In DR, proliferation of abnormal microvessels and leakage of the vessels within the retina contribute to hemorrhage, scarring and detachment, as well as edema, or fluid buildup, around the macula, the area of high acuity vision. Thus, strategies to treat DR are based on blocking the growth of these abnormal vessels in the eye.

Studies have shown that a protein called annexin A2 (A2) is overexpressed in the retinas of diabetic mice and in the retinas of human eyes from diabetic donors. Mice lacking the gene that encodes A2 have impaired new blood vessel growth in a “gold-standard” model of DR. Based on these findings, Dr. Hajjar hypothesized that antibody blockade of A2 would prevent the destructive proliferation of microvessels in the model of DR, and she generated a panel of five anti-A2 antibodies.

Encouraged by preliminary results, with Daedalus funding, she will generate increased quantities of these antibodies to characterize their ability to bind and inhibit the activity of A2 in vitro and to test their effectiveness, either alone or in combination with conventional therapy. She anticipates that this work will determine whether it is feasible to target A2 in DR, by blocking a molecule whose mechanism of action is separate and distinct from the current therapeutic target.

Dr. Samie Jaffrey
Greenberg-Starr Professor
Professor of Pharmacology

Platform and Rapid Discovery of Small Molecules That Bind and Modulate Disease-Associated RNA Targets

Most small molecule therapeutics bind and modulate the function of specific proteins inside the cell. However, in addition to proteins, there are a large number of highly structured RNA sequences that are also associated with disease. These RNAs fold into specific configurations that can be recognized by small molecules. However, other than antibiotics that target ribosomal RNA, there are very few small molecules that bind and modulate the function of RNA. A major reason for this is that platforms for the discovery of small molecules that bind RNAs are lacking.

Dr. Jaffrey has developed a way to visualize RNA by creating a specially designed RNA molecule, called “Spinach” RNA, which emits a fluorescent greenish glow. With Daedalus funding, he will use this technology to develop RNA sensors composed of high-value target RNAs linked to the "Spinach" RNA. These in vitro sensors will fluoresce when incubated with small molecules that bind to the target RNA sequences. His initial work will focus on a highly structured RNA sequence that is essential for hepatitis B infection.

He will screen 250,000 compounds to discover lead compounds for the treatment of hepatitis B. This work will result in a robust platform to discover RNA-binding small molecules, as well as potential new therapies for hepatitis B infection.

Dr. Gang Lin
Associate Professor of Research in Microbiology and Immunology

Conversion of Novel Pathogen-Selective Proteasome Inhibitors to Human Proteasome Inhibitors
 
There are more than 80 types of autoimmune and inflammatory disorders that result from aberrant immune responses of the body against itself. These diseases are chronic and presently incurable. Some can be alleviated; others, like scleroderma, have no effective treatment. The chronic nature of such diseases necessitates long-term treatment, which, in turn, prioritizes safer drugs than those currently available. In addition, an increased number of organ transplant patients calls for better management of immune-mediated graft rejection.
 
Dr. Lin’s laboratory has been working with a class of drugs called proteasome inhibitors. These drugs are broadly applicable, because they affect the proteasome, a critical cell component common to many species. Proteasomes degrade proteins, either to rapidly change a cell’s responses or to discard damaged proteins and recycle their parts. Specialized proteasomes, called immunoproteasomes, predominate in cells of the immune system and affect inflammatory responses.

In a project with the Tri-Institutional Therapeutics Discovery Institute (TDI), TDI medicinal chemists have developed four new kinds of proteasome inhibitors for Mycobacterium tuberculosis and the malarial parasite Plasmodium falciparum. Many compounds in these classes are highly potent and selective against mycobacterium or plasmodium proteasomes over human proteasomes, and several members of each class displayed reasonable oral bioavailability; that is, they can reach the bloodstream after being taken orally. Additionally, several members of each class displayed potent human proteasome inhibitory activities.
 
With Daedalus funding, Dr. Lin proposes to convert these new, highly potent inhibitors to compounds that can inhibit human proteasomes, and to optimize the leading candidates for studies in animal models. Working closely with the Office of Biopharma Alliances and Research Collaborations, he is actively pursuing options to commercialize immunoproteasome inhibitors.

Dr. David Lyden
Stavros S. Niarchos Professor in Pediatric Cardiology 

Development of Exosome Protein Blocking Strategies for the Prevention and Treatment of Brain Metastasis

Despite our increasing understanding of the molecules that drive metastasis in general, our knowledge of how metastatic cells enter and adapt to the environment of specific organs remains severely impaired. In particular, the brain, as a site protected from substances in the bloodstream by the unique properties of the blood-brain barrier (BBB), remains a challenge, and brain metastasis remains one of the deadliest complications of treatment failure, affecting 10 to 40 percent of all cancer patients.

Dr. Lyden has shown that tumor cell-derived “packages” called exosomes carry proteins and nucleic acids such as RNA or DNA through the bloodstream and can prepare a specific target organ (e.g., lung, liver or brain) for metastasis. Furthermore, he has found a hyaluron-binding protein that is associated with metastasis to the brain.

This protein was over-represented in exosomes from cell models with brain metastatic ability and exosomes from patients with brain metastasis, establishing it as a candidate biomarker for brain metastatic disease. Dr. Lyden developed several models to study the role of tumor-derived exosomes in laying the groundwork for metastasis to the brain, and demonstrated that the hyaluron-binding protein promotes blood vessel growth needed to sustain a tumor and promotes cancer cell association with the brain vasculature.

Daedalus funding will enable him to develop and validate antibody-based strategies for blocking the hyaluron-binding protein, to prevent and treat primary and recurrent brain metastases. If successful, this study will be a breakthrough in the detection and treatment of brain metastasis that can be readily commercialized, and would lead to significant changes in standard of care for patients with brain metastases.

Dr. Xiaojing Ma
Professor of Microbiology and Immunology
Professor of Microbiology and Immunology in Pediatrics

In Search of an Inhibitor of the E3 Ubiquitin Ligase UBR5 for Cancer Therapy

Patients with the highly aggressive triple negative breast cancers (TNBC) are at high risks for recurrence and metastasis soon after treatment, because standard chemotherapeutic treatment is often not as effective as therapies that target specific molecules. There is a great need for better therapies based on new targets.

Ubiquitin ligases are a family of proteins that attach a destruction tag called “ubiquitin” to a protein, which signals the cell’s protein-destruction apparatus, the proteasome, to eliminate the ubiquitin-marked protein. UBR5 is a little-studied member of the family that is amplified in about 25 percent of prostate cancer, about 23 percent of breast and ovarian cancers, close to 20 percent of bladder, liver, uterine and stomach cancers, and in about 10 percent of many other types of solid tumors. Dr. Ma’s recent experimental work in animal models of breast cancer demonstrates that genetically targeting UBR5 has profound effects on tumor growth and metastasis.

Encouraged by these results, he will use Daedalus funding to initiate a screen of chemical libraries containing about 290,000 compounds, at The Rockefeller University’s High-Throughput Screening Facility, for small molecule inhibitors of UBR5. He will use a new fluorescence-based probe called UbFluor to detect changes in the activity of UBR5 in response to small molecules. These lead compounds will be coupled with technology to induce the degradation of UBR5 via the proteasome.

The initial hits will be confirmed in cell-based functional assays and potentially in mice. Patent application will be filed to protect the validated hits. Strong commercial interests will be attracted, due to UBR5’s vital importance in the growth and metastasis of a variety of aggressive tumors that often fail conventional therapies.

Dr. John Pena
Assistant Professor of Ophthalmology

In Vivo Application of a Vitreous Vesicle Vector for Delivering Recombinant and Small Molecule Drug Delivery to Ocular Tissues

The molecular basis of many eye diseases has been well characterized, yet the bench-to-bedside translational applications have encountered a major obstacle: an inability to deliver therapeutics to ocular tissue targets.

The vitreous humor of the eye is a clear, gel-like structure that is composed of collagen and water and fills the back of the eye between the lens and the retina. Though it was long considered biologically inert, our laboratory has demonstrated that the vitreous humor has a structured network of vitreous extracellular vesicles (EVs), or membrane-wrapped “packages,” that naturally deliver cargo from one cell to another. Dr. Pena’s goal is to harness this system to safely and efficaciously deliver therapeutics to target ocular tissues. His preliminary studies have demonstrated that vitreous vesicles can deliver an exogenous (i.e., drug) cargo of nucleic acids, proteins and small molecules to cells, in vitro, where the cargo then exerts its biological function.

With Daedalus funding, he aims to demonstrate and characterize this vitreous vesicle drug-delivery platform in vivo. He will examine whether EV vectors from the vitreous humor of cows can target the ocular tissue in mice, establish the dose and incubation time, and evaluate the safety and efficacy. This proof-of-concept study will show that the EV vector can be loaded with protein and then administered to the eye through a common, office-based procedure for intraocular injection (intravitreal injection) to achieve effective delivery of functional protein to the retina. The long-term goal is broad clinical application of vitreous vesicles for the delivery of a diversity of therapies for a broad range of eye diseases.

Dr. Nicholas Schiff
Jerold B. Katz Professor of Neurology and Neuroscience

Dynamic Multi-Lead Deep Brain Stimulation of the Central Thalamus to Treat Chronic Cognitive Deficits in Severe-to-Moderate Traumatic Brain Injured Patients

Severe-to-moderate traumatic brain injury (smTBI) annually encumbers an estimated 125,000 people in the U.S. (estimated prevalence of about 3.3 to 5.3 million), with lifelong cognitive deficits in attention, memory and motivation, as well as mental fatigue. Despite efforts to develop rehabilitation and medication-based therapies, currently there are no effective therapies for these patients.

Deep brain stimulation (DBS) is a safe, well-established and rapidly expanding therapy that seeks to alter brain function through the use of electrical, magnetic and radiowave stimulation, or focally targeted pharmacological injection. Based on extensive clinical and preclinical studies, Dr. Schiff has identified a brain region called the central thalamus (CT) as the optimal DBS target to provide an effective therapy for smTBI patients. He is conducting the first-in-man, FDA-approved CT-DBS study in these patients through the NIH Brain Initiative, with the explicit goal of developing a next-generation DBS device. The BRAIN Initiative study uses a conventional DBS system with electrical stimulation that is targeted to a single site through an electrode, also known as a lead.

His lab’s new “Multi-Lead Field Shaping CT-DBS” (fsCT-DBS) device and method is designed to overcome constraints in stimulating multiple sites to provide a more flexible and personalized therapy that can be tailored around unique injury profiles of smTBI patients. Daedalus funding will provide Weill Cornell Medicine with sole rights to new IP that he expects to generate from his experiments, which will substantially strengthen his existing IP portfolio. Importantly, these experiments, if successful, will broaden the potential applications of his new DBS device platform.