Numerous clinical trials in amyloidosis have failed as a result of misdirected focus on amyloid states of disease-causing proteins. Pangolin Therapeutics’ (PTx) small-molecule platform, termed Pangomers™, was developed to address this deficiency. The Pangomer™ core structure enables selective targeting of pre-amyloid, toxic oligomers (PAOs). Here, we seek to address Multiple System Atrophy (MSA), an aggressive, orphan-indicated form of Parkinson's for which there are no approved therapeutics. Our pilot efforts have identified and validated a strategy for development of Pangomer™ analogues that neutralize PAOs from MSA. Additional funding will allow execution of this strategy delivering a lead molecule for pre-clinical advancement.
Pearl Bio is an early-stage venture pioneering design and production of next-generation therapeutics and biomaterials for medical applications and beyond. Biology is constrained to the 20 natural amino acids, limiting the ability to site-specifically modify therapeutic proteins to improve half-life, tissue targeting, or assembly. In contrast, chemical synthesis of therapeutics enables access to greater functional diversity, but template-directed synthesis is challenging. Pearl Bio unites the precision of biology with the unlimited diversity of chemistry in a transformative platform that produces therapeutics and biomaterials with tunable properties for applications in oncology, immunology, and rare disease.
The team has developed a first in class family of molecules that target a membrane receptor present in the most common metastatic brain tumors (breast, colon, melanoma, lung and others), as well as in primary glioblastoma. These molecules are: 1) conjugated to chemotherapeutic agents for tumor-specific intracellular release, 2) cross the blood brain barrier, and 3) designed to work as potential SPECT/PET tracers for tumor detection.
This technology is an antibody-based gene editing method which only requires co-administration of the 3E10 antibody with a donor DNA carrying the edited sequence. 3E10 is a cell-penetrating antibody that binds DNA and transports the donor DNA into cells, where it binds to RAD51 to alter the function of the RAD51 DNA repair pathway to promote gene editing. The antibody/donor DNA combination can be given by IV injection and could be applied to genetic disorders such as sickle cell disease.
Age-related macular degeneration (AMD) is a leading cause of blindness, affecting more than 8 million individuals in the United States alone. Although nutritional supplements are recommended for patients with intermediate risk or advanced AMD, there is still no effective therapy for the 90% of AMD patients with the “dry” or atrophic form. The team at Opti-Peutics used a high-throughput screen to identify novel compounds that protect RPE cells from oxidative damage.
Therapeutic interventions for Angioimminoblastic T cell lymphoma have limited efficacy. TKine Therapies has identified a promising target CXCR5 which is involved in metastasis and found on the cell surface in T cell lymphomas. They have developed a small molecule inhibitor of CXCR5 which is potent at nanomolar concentrations in vitro and which has demonstrated activity in a mouse model of CXCR5-expressing T cell lymphoma.
Mucosinix has a new class of antibiotics which have not been shown to trigger resistance in MRSA culture. This new antibiotic class shows promise as a treatment for multidrug resistant microbes.
Despite it being a rare disease, pulmonary arterial hypertension (PAH) is a costly and deadly condition of the pulmonary artery. Verso therapeutics is pursuing an HDAC inhibitor as a treatment for PAH which restores normal pulmonary vasculature unlike existing treatments which fail to address the abnormal architecture.
MAEGI is a new class of immunotherapy which activates a customizable group of genes for personalized cancer treatment. It can be used as an off the shelf cancer treatment or a highly customized treatment specific to certain cancer types or patients.
EPO-VG are implantable grafts composed of cells which release a steady dose of erythropoietin (EPO) to patients with end stage renal disease. These grafts reduce the cardiovascular risks associated with single dose EPO injections, improving cost and patient outcomes.
Inferior vena cava (IVC) filters are implantable devices that prevent clots from embolizing from the legs to the lungs. Even though the FDA recommends retrieval of the filter when the risk of VTE or bleeding has resolved, IVC filter removal is technically challenging and sometimes impossible because of tilt and scarring. The team has developed and patented a device that can safely retrieve filters in any configuration.
Peripheral arterial disease (PAD) is often treated with the placement of unidirectional sheaths into the arteries of patients. These surgeries often require multiple insertion sites, increasing the risk associated with the surgery. This technology is a bidirectional sheath which reduces the number of insertion sites by half, reducing the complications and cost of PAD treatment.
While obesity is a growing worldwide epidemic, there are few effective treatments. This technology aims to inhibit a degradation pathway, therefore increasing heat and calorie burn in patients with obesity.
Therapeutic options for glioma cancers are limited, and the survival rate for glioma patients is poor. Athena is progressing NAMDT inhibitor therapy by applying it to cancers with specific mutations, thus increasing the efficiency and decreasing toxicity of treatment.
We have applied a unique, robust, and comprehensive image-based assay developed in our laboratory to discover small molecule inhibitors of nucleolar function. Results from pilot screens on FDA-approved drugs reveal 83 unique hits that include known and putative antineoplastic agents.
We have developed a computational platform for de novo designing of dual inhibitors that can simultaneously engage their targets and (most importantly) augment protein-protein interactions. Employing this strategy and iterative modifications, we have designed and synthesized a mutant selective inhibitor for ALK2, depicting a proof-of-concept for this platform towards the treatment of FOP and DIPG.
A vast majority of drugs and biologics fail to enter the brain for treatment of brain cancers and neurological diseases. Our discovery yielded key insights into how the immune system naturally overcomes the blood brain barrier to fight infections. We leverage this insight to enable safe and transient drug access to the CNS using a simple intranasal peptide delivery approach.
New biomarker for novel CD8 T cell subset that drives systemic sclerosis immunopathology, including monoclonal antibodies anti-human C10orf128 and new targets for small molecule inhibitor therapy. Monoclonal antibodies recognized 5-10% of circulating T cells. Humanized version of them are likely therapeutic agent for systemic sclerosis after humanization. Also so likely have a monoclonal antibody specific for mouse homolog of C10orf128 to enable an animal preclinical model for T cell depletion studies. There is no effective treatment for systemic sclerosis; 50,000 individuals have Ssc; fatal disease. Potential applications include pulmonary fibrosis, asthma with scarring among others.
Kawasaki Disease is an illness that causes inflammation (swelling and redness) in blood vessels throughout the body that comprises three phases, the first of which is usually a lasting fever. The condition most often affects kids younger than 5-8 years years old. Catching Kawasaki disease early is key - children can be treated relatively easily if the disease is detected early, however becomes much more dangerous the longer it goes in diagnosed. The first sign of the disease, fever, is unspecific to Kawasaki disease, and by the time later symptoms manifest, much more aggressive intervention needs to be taken. Thus, a diagnostic that can identify Kawasaki Disease is critical to successfully treating the 5,000-20,000 cases that arise each year in the US, and more globally.
Idiopathic pulmonary fibrosis (IPF) is a deadly chronic lung disease with median survival of 3 years and with a worse prognosis than lung cancer. 6 million people worldwide are affected - 200,000 in North America are affected with 45,000 dying each year. The progressive decline of lung function characterizing it is interspersed with unpredictable disease flares called acute exacerbations of IPF (AE-IPF) that accelerate lung function loss and increase morbidity and mortality. The annual incidence of AE is up to 20% with a mortality ranging from 35-90%, demonstrating the severity of IPF disease progression and the importance for active disease monitoring (ER visits and hospital stays can amount to >$11,500 per case). Current therapeutics are unable to predict how an individual patient will progress and whether they will respond to available interventions. The market size for biomarker chip detection of PIF is ~$3B, underscoring the need for a more robust treatment for PIF.
Our technology combines novelty in bioabsorbable stent technology and regenerative medicine. Our team has unrivaled experience in both technologies and have taken the project funded by the European commission to an advanced stage in development. Our initial therapeutic target will be peripheral vascular disease where there is no comparative technology in use or development. Beyond this, there is potential widespread application of the device and concept to the heart, brain, liver and cancer treatments where the combined technology can provide a unique state of the art therapeutic system.
Currently available drug-eluting stents release drugs such as sirolimus or everolimus, which stop smooth muscle growth to prevent in-stent restenosis. However, they also block endothelial cell growth and create risk of thrombosis and mandate long-term antiplatelet medication. Nevertheless, yearly, 10% of these stents fail due to late thrombosis or stenosis. We discovered a drug combination (Fas ligand and nitric oxide) which inhibits smooth muscle growth more potently than sirolimus or everolimus but does not affect endothelial growth. This project will lead to the development of a next generation DES with a unique biologically selective effect on smooth muscle and endothelium.
The three members of the endocrine FGF family, FGF19, FGF21 and FGF23 are important circulating hormones that regulate a variety of critical metabolic processes. Endocrine FGFs mediate their cellular processes by binding to and activating FGF-receptors (FGFR) in complex with Klotho proteins. Based on the crystal structure of ligand occupied Beta-Klotho new potent engineered endocrine molecules were developed for treatment of metabolic disease that will benefit from therapeutic stimulation of FGF21 cellular pathway such as pancreatitis, Nash and obesity. Moreover, also potent inhibitors including small molecules will be developed for treatment of bone disorders (XLH) and liver cancer, respectively.
Our goal is to develop a new cancer drug that is an antibody drug conjugate (ADC). It targets the pi subunit of the Gamma Aminobutyric Acid Receptor (GABRP) that is aberrantly expressed in a broad range of solid tumors. The target was discovered by the Pusztai lab and a provisional patent application has been submitted. We will use the Blavatnik Fund to perform affinity maturation, generate humanized anti-GABRP antibody conjugated to emtansine and assess the anti-tumor activity in vitro and in vivo.
Multidrug-resistant Gram-negative bacilli (MDRGNB) have emerged as a challenging cause of hospital-acquired infections and present a critical need for innovative antibacterial development. Two new oxopyrazole agents targeting penicillin binding proteins (PBPs) based on a non-beta-lactam core have superior MIC50 values to current billion-dollar last resort antibiotics like Ceftazidime/Avibactam or Meropenem. One shows broad Gr- efficacy while the second oxopyrazole is selective for Acenitobacter baumannii. On target, good in vivo PK, no mammalian toxicity, no off-target liability. Seeking funding for definitive in vivo efficacy studies.
Alzheimer's Disease (AD) is a progressive, degenerative disease that is the most common cause of dementia. Brain cell connections and the cells themselves to degenerate and die, eventually destroying memory and other important mental functions. No cure exists, but medications and management strategies may temporarily improve symptoms. An estimated 5.7 million Americans are living with AD in 2018, projected to be 13.8 million by 2050.
Adjuvant therapeutics are therapies given after the initial or primary treatment of a disease or condition, for example, therapeutics given after a surgery to maximize its effectiveness. Pharma companies make diagnostics for the metastatic setting, to enrich the population that will benefit from the drug. However, the big prize for Pharma is the adjuvant setting, which sees at least double and up to 10 times more patients than the metastatic setting. Despite this, pharma companies rarely make diagnostics for the adjuvant setting. For example, in the immunotherapy space, 1 in 5 lose thyroid function and 1 in 100 die from the drug used to treat the condition during the course of treatment.
Over 95% of rare disease have no treatment or cure: there are over 7,000 known rare diseases collectively affectiting 30 million Americans. Many of these disease are genetic disorders, in which there can be considerable genetic variation between patients. Current drug development pipeline does not cater to rare mutations, as drug development often takes more than 10 years and over $2B to get a drug to market, making the small patient populations inhibiting. Even if a therapy is developed, genetic variation of the disease means not all patients in the already-small patient population may be able to be treated, limiting their impact and incentive to develop these therapies.
PARP inhibitors are promising targeted therapy for cancers with defective homologous recombination (HR) repair. However, as PARP inhibitor become widely used, there will be an increase in patients with PARP inhibitor resistance. To overcome this problem, we have developed DB4, a small molecule drug that inhibits HR repair. Combining DB4 and the PARP inhibitor olaparib inhibits the progression of resistant ovarian cancer and increases the survival time of tumor-bearing mice. Thus, we request the Blavatnik fund to continue developing DB4 for improving its potency and PK properties in vivo and conducting efficacy studies with patient-derived cancer xenograft models in mice.
Solid tumors often contain areas of hypoxia or oxygen deficiency. Hypoxia makes tumor cells more aggressive, metastatic and resistant to therapy. Hypoxia is an independent marker of poor patient survival. There are no drugs or effective therapy against hypoxic tumor cells. Hypoxia is the achilles heel' of solid tumors that is common to all solid tumors independent of genetic background. All aggressive late stage tumors are predicted to contain variable fractions of hypoxic tumor cells. Thus, a successful hypoxia-targeting drug has the potential to be used in the treatment of most, if not all, solid tumors. The team has identified a class of antiprotozoandrugs with the ability to kill hypoxic tumor cells - nifurtimox (NFMX) and benznidazole (BZND). NFMX & BZND specifically inhibits clonogenic growth of hypoxic tumor cells with strong selective killing of severely hypoxic tumor cells by inducing lethal damage to the cells' DNA. The team seeks to confirm these findings in vivo and for combination radiotherapy.
1 in 400 Americans carry a breast cancer gene (BRCA) mutation - such a mutation increases the likelihood of developing breast cancer from 12 to ~70% by age 80, and raises the lifetime risk of ovarian cancer from 1.3% to 44% (BRCA1) or 17% (BRCA2). Additionally, men with BRCA1 or BRCA2 mutations are also at increased risk for breast and prostrate cancers, and both men and women with either mutation are at an increased risk of pancreatic cancer. BRCA proteins are essential for DNA repair, making BRCA-deficient cells (i.e. those with a BRCA mutation) susceptible to synthetic lethality and providing an opportunity to kill cancers with the mutation. PARP-inhibitors invoke synthetic lethality to kill BRCA-mutated cells via PARP-trapped lesions, however cells can become resistant to this mode of therapy, creating an unmet clinical need for these cancers. Indeed, nearly 300,000 new cases of breast or ovarian cancer will be diagnosed in 2019, making the need for an improved synthetic lethality agent urgent.
Human Immunodeficiency Virus (HIV) is a deleterious virus that attacks white blood cells (Specifically CD4 T cells) that fight infection, compromising the immune system and it's ability to fight infection. Untreated, HIV reduces the number of CD4 cells (T cells) in the body - the damage to the immune system makes it increasing difficult for the body to fight off infections and other diseases. Eventually, those infected with HIV develop Acquired Immunodeficiency Syndrome (AIDS), where infections or cancers take advantage of a very weak immune system, including infections that could otherwise be adequately defended against. There is no effective cure for HIV; it can only be managed by antiretroviral therapy (ART). Thus, there is a large unmet clinical need for a cure for HIV.
We have developed a novel linker technology that can enable potent targeting of nanomedicines for therapeutic and diagnostic applications. We further have a unique clinical pipeline for development of this technology using ex vivo perfusion of non-transplanted human organs. Our primary lab, the Tietjen lab, has developed a robust pipeline for preclinical research on human kidney and liver with the capacity to expand to heart and lung in the future. This provides a direct path to clinical impact in organ transplantation and will enable broad translation for a variety of indications.
GlimmerX has developed a fast, robust point-of-care diagnostic development platform based on glycoconjugate immunochemistry for common infectious diseases, such as leptospirosis, sepsis, UTI and meningitis that is better than current technologies. To establish proof of principle for our platform, we focus on glycans in leptospirosis, which has a large unmet US and global diagnostics need for veterinary and human disease. In a pilot project, Blavatnik funds would be used for PCT fees, and CRO costs for GLP antigen production, monoclonal antibody production and animal experiments to validate our approach, and they would leverage CT Innovations matching funds and SBIR funding.
Leptospirosis is the Ebola virus of the bacterial world, difficult to diagnose, and for which there is a 20% mortality rate. Leptospirosis is a global health threat, particularly for travelers and for soldiers. The vaccine for human leptospirosis is unsafe and of unknown efficacy, creating a vast domestic and global demand for an effective vaccine that is currently unmet. Current vaccines are bacterin type vaccines and of limited efficacy, duration, and safety, however LeptoX is offering a first-in-class vaccination (first for animals, to be developed for humans) that outcompetes its competitors in all of these categories.
Novel Therapeutics that Stop Glioblastoma and Other Aggressive Cancers. Sidera's team brings together world-class experts and recognized pioneers in clinical oncology and synthetic biology to discover new targets and small molecules for aggressive cancers. Sidera has identified potent compounds that reduce tumor volume and extend lifespan in rodent models of aggressive human brain cancer. Their innovative platform technologies have spawned partnerships with big pharma to broaden their portfolio and bring them closer to improving patient outcomes.
Peritoneal carcinomatosis is a late stage manifestation of colon and ovarian cancer with a poor prognosis. Intraperitoneal (IP) chemotherapy is effective, but current methods lead to toxicity, which is not easily tolerated by patients. We propose a new approach, in which the chemotherapy drug is encapsulated in bioadhesive nanoparticles (BNPs) that can be delivered locally by established IP infusion methods. These BNPs are retained for many days in the IP space, and slowly release chemotherapy drugs, maximizing effectiveness, while minimizing toxicity.
Idiopathic Pulmonary Fibrosis (IPF) is a highly lethal, orphan lung disease with limited treatment options. Vittix Therapeutics, led by Dr. Naftali Kaminski, Chief of the Pulmonary Section at Yale University, has identified thyroid hormone small molecule mimetics as a novel therapeutic approach, targeting mitochondrial function in lung epithelial cells and to date, has produced compelling in vivo proofs of concept. Received a Blavatnik Award in May 2019.
Activating the innate immune system within tumors is a promising new direction in immunotherapy because it can be used against a broad spectrum of tumor subtypes and it ensures that cells throughout the tumor microenvironment become sensitized, resulting in attack and destruction by T cells. RIG-I is a particularly sensitive trigger of innate immune response in tumors, so agonists of this receptor are promising immunotherapy agents. Through a unique class of RIG-I agonists called Stem-Loop RNAs (SLRs), the scientific team is evaluating the efficacy of SLRs as immunotherapy and antiviral agents.
Blockchain ecosystems are not as secure as originally thought. The CertiK platform is a formal verification framework for building fully trustworthy smart contacts and blockchain ecosystems. Different from the traditional testing approaches to detect bugs, the CertiK platform mathematically proves that blockchain ecosystems are bug-free. CertiK has developed modular verification techniques to decompose such an otherwise prohibitive proof task into smaller ones that can be automatically solved in a decentralized style.
Rarebase Therapeutics is focused on overcoming cancer chemo-resistance. The scientific merits of Rarebase are based on a series of groundbreaking discoveries made by Andrew Xiao’s lab at Yale School Medicine. They have revealed that the increased presence of a novel, critical base in DNA (N6-methyl adenine) is the major culprit for cancers to acquire resistance. The main goal of Rarebase Therapeutics is to identify chemical inhibitors to block the synthesis of this base, thereby overcoming resistance of cancers to standard therapies.
Loss of brain synapses is highly correlated with symptom progression in Alzheimer’s dementia, but there is currently no treatment to slow or halt synapse loss. Allyx’s prion protein antagonists rescue synapses and memory function by interrupting the deleterious signaling triggered by amyloid without removing plaque itself and are effective at reversing deficits after they develop.
Neuro-ICUs are faced with frequent shortcomings in maintaining brain care. Access requires one large or multiple smaller access points and devices require multiple external interface devices & monitors that frequently face challenges in the synchronization, analysis, and interpretation of data. The NeuroProbe System is a portable multimodal implant (EEG, temperature, oxygen, pressure, blood flow) that offers equal or better sensitivity via a single point of access along with synchronized sensor data via a single output connection. NeuroProbe has completed FDA pre-submission and developed prototype NeuroProbe and NeuroMonitor devices, with a system prototype demonstration ongoing in Summer 2019.
Moving Therapeutic Proteins Into the Cytosol and Nucleus. Exolva is using CPMPs (cell-permeant miniature proteins) to deliver therapeutic enzymes and gene-editing tools to correct inborn genetic disease. CPMPs are small, folded proteins that contain a specific array of five Arg residues on an ⍺-helix backbone. CPMPs can reach cytosol and nucleus with efficiencies as high as 75%. CPMPs possess many advantages relative to previous, purported ‘cell-penetrating peptides’, including low toxicity, high and tunable stability, enzyme cargo retains enzymatic activity, among other features.
Macrophage Migration Inhibitory Factor (MIF) plays a key role in inflammatory disease and cancer, being an important regulator of the innate immune response. MIF is an inflammatory cytokine; when bacterial antigens are present, it binds to CD74 on other immune cells to trigger an acute immune response. MIF regulates cell proliferation by binding to receptor CD74 in MAPK (ERK) and AKT signal pathways. It also inhibits apoptosis of cancer and inflamed cells by blocking p53, making it an attractive drug target for cancer therapies.
Modulation of MAP Kinase Phosphatases in Targeting Liver Disease. A novel platform for allosteric targeting of MAP kinase phosphatases to achieve nodal regulation of signaling pathways that can be leveraged for therapeutic purposes.
A Novel Platform to Develop piRNA-Based Therapeutics for Cancer Treatment. PIWI-interacting RNAs (piRNAs) is a novel pathway for nucleic acid based targeted therapy. piRNAs consist of small non-coding RNAs that interact with PIWI proteins. The PIWI/piRNA pathway protects the genome from destabilizing transposon activity by using piRNA to guide PIWI proteins to transposable genome sites, leading to gene specific methylation in somatic cells. piRNAs offer potential advantages because the longer piRNA seed sequences results in higher target specificity, higher tissue specificity, higher efficacy, and lower toxicity over siRNA and miRNA techniques. Short-term focus is currently on treating liver cancer because of the relative ease of drug delivery and lack of effective treatments.
The Blue Vertical-Cavity Surface-Emitting Laser (BlueVCSEL) is a breakthrough for projection, display technology, & lighting. Overcoming previous obstacles to commercialization, the team has utilized patented techniques to create the world's first stacking-fault-free semi-polar GaN-on-sapphire materials to make Blue VCSELs a commercial reality.
Cysteine protease enzymes are widely used in a range of chemical manufacturing applications. A naturally found amino acid selenocysteine increases activity of cysteine protease enzymes when subsituted for cysteine. Sec-U-Lar is utilizing this property to substitute selenocysteine in cysteine protease enzymes, increasing their activity more than 100-fold.
Evolution-Proof Therapy Against Multi-Drug Resistant Bacterial Pathogens with Efflux Pump-Targeting Phage. Multi-drug resistant (MDR) Pseudomonas aeruginosa is a common pathogen in the lungs of those with cystic fibrosis. These infections are notoriously difficult to manage and new approaches to control them are desperately needed. Based on our prior therapeutic success treating lung infections with virulence and resistance targeting bacteriophage, we plan to expand our patient population and perform a small clinical trial at Yale-New Haven Hospital examining the safety and preliminary effectiveness of phage therapy to treat lung infections in those with cystic fibrosis. Received Blavatnik Awards in May 2018 and May 2019.