Active Projects

2021 Development Grants

Small molecule modulators of bile acid metabolism to treat NAFLD

Small molecule modulators of bile acid metabolism to treat NAFLD/NASH

Snehal Chaudhari, Yoojin Lee (MGH), Raymond T. Chung (MGH), and A. Sloan Devlin
 
Liver diseases are growing worldwide health concerns and place significant burdens on healthcare systems. The prevalence of non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and liver cirrhosis is rising. There is a large, unmet need for effective treatments for these conditions. There are currently no approved medications for NAFLD/NASH, and while off-label usage of type 2 diabetes medications has become common, evidence for benefits has been limited. Drugs in the pipeline target later stages of fibrosis and display modest effects. Our data indicate that conjugated bile acids, a large class of host-produced endogenous metabolites, protect against pathogenic intestinal permeability, an early feature of NAFLD/NASH that contributes to the development of liver inflammation and injury. Our goal is to use small molecule inhibitors of gut bacterial enzymes that chemically modify bile acids to modulate the in vivo pool of these metabolites. We will test whether these inhibitors shift the bile acid pool toward beneficial conjugated bile acids and away from damaging unconjugated bile acids and thereby present a novel treatment strategy for NAFLD/NASH.

A natural beta interferon-inducing therapeutic glycolipid

A natural beta interferon-inducing therapeutic glycolipid from the microbiome that prevents and treats severe viral infection
 
Tiandi Yang, Sungwhan Oh (BWH), Seung Bum Park (Seoul National University), and Dennis Kasper
 
One important clinical aspect of the current COVID-19 pandemic, as well as in influenza infection, is the wide variety of clinical presentations. Infections with either virus can lead to a clinical course that is anywhere on a spectrum from asymptomatic nasopharyngeal carriage to rapidly progressive fatal systemic disease. It has been shown that an important regulator of viral disease severity is host interferon beta (IFNβ)which is a crucial mediator of antiviral immunity and homeostatic immunoregulation. Our work has found that host natural IFNβ is regulated by the microbiome and specifically by glycolipids present on the surface of microbes from the phylum Bacteroides. We discovered that the critical Bacteroides molecule responsible for IFNβ induction is the outer membrane-associated lipooligosaccharide(LOS). LOS molecules regulate the IFNβ response both locally and systemically through induction in colonic dendritic cells and we have identified the molecular mechanism by which this occurs. The LOS of Bacteroides exists naturally in multiple structural variations. Our goal in this proposal is to identify a specific structural analog of the numerous glycolipid structures belonging to the lipooligosaccharides(LOS) of the Bacteroides phylum. Once we purify a specific IFNβ inducing structure, we will test it for prophylaxis and therapy in models of influenza and COVID-19 infection. Since these structures can be synthesized, our approach presents an exciting opportunity to develop a low-cost approach to minimizing severity of viral diseases as well as other diseases for which type 1 interferons can be used therapeutically.

Gene therapy for the treatment of Wolfram Syndrome II

Gene therapy for the treatment of Wolfram Syndrome II
 
Michael Florea, David Anderson, Luk Vandenberghe (MEEI), and Amy Wagers
 
Wolfram Syndrome II is a progeria (early aging disease) characterized by accelerated senescence and death by mid-adulthood. There is no existing treatment. The disease affects multiple organ systems, and is caused by loss of function of the Cisd2 gene, which normally is expressed in many different cell types. As a result, it is thought that effective treatment of Wolfram Syndrome II will require multi-organ rescue of Cisd2 expression. Unfortunately, standard gene transfer technologies have not achieved sufficiently broad and uniform gene delivery to meet this therapeutic goal. We therefore created a new system (DAEUS) that overcomes the limitations of standard vector systems, and applied it successfully to ameliorate disease pathology in Cisd2 knockout mice. With Q-FASTR, we aim to perform dose-ranging studies and optimize component ratios of the DAEUS-Cisd2 system, ultimately deriving a dose-guiding model for achieving optimal therapeutic effects. This effort will de-risk our approach and lay a foundation for further development of multi-organ gene therapies.

2021 Pilot Grants

Novel biologics for cancer therapy

Novel biologics for cancer therapy
 
Chun-Ting Wu, Raphael Ferreira, and George Church
 
Despite recent successful CAR-T outcomes in liquid tumors, its effect on solid tumors has not been achieved. This is mostly because the immunosuppressive tumor microenvironment inhibits the functions of T cells. Here, we have designed a novel biologic, which interacts with tumors in a different manner, that overcomes the CAR-T therapies’ limitations. This novel cancer-elimination mechanism is independent of inherent immune functions, such that it would not be inhibited by the tumor microenvironment. Our technology opens up brand new approaches for engineered cells to eliminate cancer.

Studies on Immunogenic Lipids from the Gut Microbiome

Studies on Immunogenic Lipids from the Gut Microbiome
 
Munhyung Bae, David Szamosvari, Sunghee Bang, and Jon Clardy
 
The gut microbiome’s composition influences human health both positively and negatively, and most of these influences involve regulating inflammatory immune responses. (1) For example, multiple studies, including in vivo human studies, have shown that Muciniphila akkermansia has positive effects on metabolism and response to cancer immunotherapy, but the underlying molecular mechanism for these responses remains unknown. Finding the answer to this and many similar questions is complicated because it requires deconvoluting the interaction of two complex systems: the gut microbiome and our immune systems. In collaboration with Ramnik Xavier’s laboratory (MGH, Broad, and Department of Genetics) we believe that we have found the answer: a small phospholipid making up part of the M. akkermansia’s cell membrane. Synthetic lipid recapitulates the effects of isolated lipid and of the intact bacteria. We plan to explore the structure-activity space to develop therapeutic agents that could be used as vaccine adjuvants, metabolic disease modifiers, and cancer chemotherapy enhancers.

CNS drug delivery by identifying small molecule inhibitors

CNS drug delivery by identifying small molecule inhibitors of a newly identified key regulator of the blood brain barrier
 
Joseph Amick and Chenghua Gu
 
A major obstacle in treating neurological diseases and brain tumors is to deliver drugs or antibodies across the ‘blood brain barrier’ (BBB). My lab’s discoveries have changed our understanding of how the BBB restricts blood-brain communication1-4. The BBB is formed by a single layer of endothelial cells that lines the blood vessel walls and act as a gatekeeper for the brain. Historically, the restricted permeability of brain vasculature has been attributed to tight junctions5. However, substances can also cross endothelial cells by transcytosis, and we discovered that transcytosis is actively inhibitedin brain endothelial cells. We identified a novel multi-transmembrane protein Mfsd2a as a key regulator for BBB function, and demonstrated that interfering with Mfsd2a and its downstream pathway upregulates transcytosis and causes the BBB to become permeable1-3. We propose to develop small molecule inhibitors as therapeutic agents that specifically target Mfsd2a function as a strategy to facilitate drug delivery across the BBB

A novel monoclonal antibody that targets SARS-COV-2 3a

Development of a novel monoclonal antibody that targets SARS-COV-2 3a
 
William Robins and John Mekalanos
 
The damage to the lung and other organs during SARS-CoV-2 infection is driven by inflammation induced by the virus. Independent of vaccine-based strategies, distinct efforts to curtail severe acute and chronic lung disease by targeting inflammation following infection have not yet been proven completely safe and efficacious. The complex interactions between SARS-CoV-2 virus and the immune system during virus replication appear to be distinct from that of other respiratory viruses and are not yet entirely understood. There are SARS-CoV/SARS-CoV-2 gene products demonstrated to induce and modulate inflammation. This includes viroporin 3a, the virus-encoded K+ efflux membrane protein on the cell surface that activates the NLRP3 inflammasome. The exposed N-terminal 42 amino acid 3a ectodomain extends out from the channel pore and appears to be under strong immune selection based on our pan-genome covariance analysis of lineage B b-coronaviruses. We propose screening and identifying human mAbs with high affinity to exposed extracellular regions of 3a including ectodomain. Using cloned and purified mAbs as candidates, we will use established screens to find those that inhibit 3a activities including viroporin ion channel activity, and may then reduce both inflammation and pathogenesis.

Small molecule drugs for advanced cancer with ecDNA amplicons

Small molecule drugs for advanced cancer with ecDNA amplicons
 
Tae Yoo, Patrick Flynn, and Timothy Mitchison
 
Impact: There is a huge need for drugs to treat advanced and metastatic solid cancers. Cells in such cancers usually have aberrant genomes with highly amplified oncogenes. Drugs have been developed to target certain amplified oncogenes as proteins, but this has been difficult in many cases. Our idea is to target the amplified DNA itself by exploiting fundamental differences in its chromosomal organization compared to normal DNA. Recent analysis showed that 20-60% of common solid tumors contain amplified DNA in the form of small, circular chromosomes called extrachromosomal DNA (ecDNA). These autonomous genetic elements, previously called “double minutes”, are typically 0.2-2MB in length, present at 2-100copies per cancer cell and absent from normal cells. They lack centromeres and segregate inefficiently at mitosis, resulting in copy number fluctuations that allow rapid evolution of cancer genotype. ecDNA is a highly abnormal state of chromosome organization that is specific to cancer cells. We propose it constitutes a druggable vulnerability and have identified a candidate target based on its DepMap dependency scores and cell biology.
Research Objectives: Develop an enzyme assay suited for inhibitor screening on the candidate target and test inhibitor scaffolds from in silico prediction or/and HTS screens. In parallel, develop cell-based assays for genetic depletion of the candidate target and test if it is selectively required for mitosis in cancer cells with high ecDNA copy number.

A platform for transcriptome time-series

A platform for transcriptome time-series in single cells with applications to hematopoietic stem cells
 
Charlotte Strandkvist, Allon Klein, and Johan Paulsson
 
We will integrate live time-lapse imaging with genome-wide sequencing of RNA and chromatin, where one sister cell is harvested at every division in low-stress environments with exceptional uniformity in time and space. This provides vertical transcriptome time-series along lineages of single cells, while also providing information about growth, morphology and spatiotemporal reporter dynamics. We established feasibility of all key steps. As a proof-of-principle application we will use the platform to establish long-term maintenance, expansion and monitoring of primary tissue cells -- a ‘holy grail’ in regenerative biology and cell-based therapies. Specifically, we will expand hematopoeitic stem cells in culture for transplantation, while continuously tracking cell states along the lineages. If successful, this pilot will set the stage for optimizing additional stem cell and immunotherapy protocols, and produce (1) a commercializable research platform, (2) derivative methods to expand cells for therapy, and (3) cellular products that result from them.

Enzyme prospecting for better diagnostics

Enzyme prospecting for better diagnostics
 
Seungwoo Chang, Joseph Loparo, and Michael Springer
 
The SARS-CoV-2 pandemic has highlighted the limitations in diagnostic testing approaches. Cheap, robust, and field-deployable tests that did not require instrumentation would change the nature of how we could respond and contain disease spread. A major limitation in the generation of point-of-need (PON) assays is enzyme performance. Many enzymes have been optimized to work well with high end machines, but similar effort has not been put into enzyme engineering for enzyme that will make field-deployable assay work well. Specifically, we need enzymes that perform rapidly and robustly, in vitro, at ambient temperature as opposed to elevated temperatures. Here we will use a combination of enzyme prospecting and enzyme engineering together with high throughput screening approaches to identify enzymes that have promissing characteristic for PON test development.

2020 Development Grants

Evaluating novel transcription modulators for therapeutic impact

Evaluating splicing modulators for therapeutic impact in cohesin-mutant AML and MDS cells

Benjamin Martin, Zuzana Tothova (DFCI), and Karen Adelman

Cohesin is a multi-subunit protein complex that forms a ring-like structure around DNA. Cohesin is essential for sister chromatid cohesion, chromosome organization into looped domains, DNA damage repair and transcription regulation. Germline loss-of-function mutations in cohesin subunits cause a family of developmental disorders termed cohesinopathies. In addition, cohesin is one of the most frequently mutated protein complexes in cancer, including myeloid malignancies, with recurrent somatic loss-of-function mutations in core components of the cohesin ring and its modulators. Importantly, cancer-associated mutations in cohesin rarely affect chromosome integrity, but instead selectively impair gene-regulatory functions. However, how cohesin affects gene activity remains enigmatic, offering no clues towards intervention. Consequently, there are no targeted therapeutic approaches available to treat disease involving cohesin mutations. Recently, we discovered that cohesin mutations common in myeloid malignancies such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) disrupt RNA splicing. We propose to define the aberrant RNA species generated in cohesin-mutant AML cells, using state-of-the-art molecular and computational approaches to capture nascent transcripts and characterize RNA processing. Through detailed investigation of gene activity and splicing profiles in cohesin-mutant AML cells, we hope to discover genes with alternative splicing events that may present opportunities for therapeutic targeting. Our goal is to leverage this knowledge to develop targeted approaches that will selectively kill cohesin-mediated disease. The findings from these studies have the potential to lead directly to one or more clinical trials within the next several years.

HIV-1 Vaccine using SPLANDID Antigen Presentation Technology

Application of the SPLANDID Antigen Presentation Technology to HIV-1 Vaccine Development

Alessandro Piai, Yongfei Cai, Bing Chen, and James J. Chou.

The HIV-1 envelope glycoprotein (Env) is a transmembrane protein sitting in the viral membrane and it is also a major target for B-cell based vaccine development. Previous large clinical trials of vaccine candidates involving recombinant Env preparations mostly focused on various soluble forms of its ectodomain. These efforts have been disappointing, however, probably because we do not fully understand how effective antibodies are generated in some infected patients and what is the best form of the Env that can induce such an antibody response by vaccination. To facilitate Env immunogen design, we have recently developed an antigen presentation technology known as SPLANDID that allows presentation of transmembrane immunogens in a membrane environment on nanoparticles suitable for in vivo immunogenicity studies. This HMS patented technology now affords the opportunity to test novel HIV-1 Env immunogens that include the membrane-related components in a membrane environment and better mimic the native Env on the virion surface. We plan to use the new technology to display membrane-bound Env immunogens and evaluate their potential as vaccine candidates by defining their antigenicity in vitro and testing their immunogenicity in animals.

 

A novel biologic and therapeutic target for diabetes

A novel biologic and therapeutic target for the treatment of diabetes

José Rivera-Feliciano, Timothy R. Kunz, Elias S. Peterson and Douglas A. Melton

It is estimated that more than 422 million people in the world have diabetes; by 2021 the cost burden of diabetes in the United States is on track to be $512 billion. Diabetes, characterized by elevated blood glucose (sugar) levels, results from either beta-cell malfunction (Type 2) or beta-cell demise after an autoimmune attack (Type 1). The hormone insulin, produced by pancreatic beta-cells, reduces circulating levels of glucose after a meal primarily by shuttling glucose to muscle and fat. Current strategies to treat diabetics include insulin injection, augmenting endogenous insulin secretion, increasing glucose absorption, or increasing glucose excretion. Hypoglycemic (low blood glucose) episodes after insulin injection are life threatening and this risk usually results in patients underdosing. Here we describe the discovery of a novel peptide hormone, we call ERSEQ08, present in human beta-cells, that can reduce blood glucose levels in mice. Importantly, this effect is independent of insulin action. Surprisingly, ERSEQ08 lowers blood glucose, in a glucose dependent manner, without causing hypoglycemia—thus overcoming one of the major setbacks with current diabetic treatments. While it is well known that pancreatic beta cells make Insulin, this new finding may represent a second system by which beta cells regulate glucose metabolism.

The potential to bypass insulin resistance presents a novel therapeutic paradigm to treat diabetes. As a biologic, this hormone may complement or replace some of the therapies used as the current standard of care in diabetes treatment. As an inroad into a novel signaling system controlling glucose homeostasis, this discovery has the potential to lead to a new kind of drug for diabetics.

Our main objectives using the Q-FASTR funds are: to test the activity of recombinant human ERSEQ08 protein to lower blood glucose levels in mice; to develop a cell-based assay to identify ERSEQ08’s mechanism of action; and, to find the minimal active fragment required for ERSEQ08’s function.

Development of an inexpensive at-home influenza kit

Development of an inexpensive at-home influenza kit and detection technology

Sarah Boswell, Jason Qian, Zhixiang Lu, Mary Pettit, and Michael Springer

Influenza is a major drain on the US economy. Antiviral drugs are most effective against influenza when taken early, often before patients seek medical help. Tests exist for influenza but are only effective when influenza titer is high and/or require sophisticated medical equipment. Here we will build off of methods we are combining and developing for the specific detection of barcoded microorganisms (a DARPA funded project) to develop and optimize a quantitative, cheap, rapid, sensitive, selective, and field-deployable method for detecting influenza. We aim to develop this influenza detection system into an affordable ‘at-home’ system allowing individuals to detect influenza early, thereby increasing the efficacy of antiviral drugs and eliminating unnecessary trips to the ER.

Protein therapeutics for treatment of chronic/inflammatory pain

Protein therapeutics for treatment of chronic and inflammatory pain

Bruce Bean, Clifford Woolf, Jeff Way, and Peter Sorger

 

Chronic and inflammatory pain affect millions and new treatments are urgently

needed. Despite significant investment in opioid safety and formulation, there is little exploration of drugs with fundamentally novel mechanisms of action. Our goal is to develop such medicines based on novel protein therapeutics that block pain sensation by silencing multiple NaV sodium channels in nociceptors. The failure of NaV1.7 inhibitors as analgesics1 suggests that blocking more than one channel will be necessary. We will therefore take an approach involving a multivalent scaffold and small proteins that inhibit several NaV channels with tunable selectivity and potency. Activity will be measured by differential screening against human iPSC-derived sensory, cortical, and motor neurons. Over a two year period we expect to achieve hit/lead generation for 10-30 distinct molecules and optimization of the most active for testing in animals.

2020 Pilot Grants

Target Identification of Neuroprotective Kinase Inhibitors for AD

Target Identification of Neuroprotective Kinase Inhibitors for Alzheimer’s and Related Dementias

Mark Albers, Peter Sorger, Gary Bradshaw

Alzheimer’s dementia (AD) affects nearly 6 million US patients and costs > $250B/year. No therapies slow its devastating course. We have discovered a root cause of neuronal cell death in disease-relevant regions of autopsied AD brains: inflammation caused by cytoplasmic double stranded RNA (cdsRNA). cdsRNA triggers neurodegeneration in mouse models that can be recapitulated in cultured human neural cells. This proposal focuses on small molecule kinases inhibitors that we have shown to block cdsRNA-mediated neuronal death. The active molecules (some of which are approved therapeutics) are annotated as JAK kinase inhibitors but this class of compounds is known to have a complex poly-pharmacology. Moreover, not all JAK inhibitors on signal transduction in neurons rescue cell death. We have therefore conducted a genome-wide CRISPR/Cas9 screen and found than none of the three members of the JAK family rescue cdsRNA-mediated neuronal death when knocked down. Thus, JAK kinase inhibition does not appear to be sufficient (and perhaps not even necessary) to rescue neuronal death. We propose to identify “off-target” proteins – most likely kinases - that are preferentially bound by neuroprotective JAK inhibitors relative to inactive molecules. We will confirm the relevance of these targets by generating knockout human neural cells using CRISPR/Cas9 and then proceed to small molecule screening. This will allow us to leverage extensive experience in kinase inhibitors, particularly those exhibiting therapeutically relevant poly-pharmacology, to target AD and other neurodegenerative diseases.

Novel therapeutic targets for treating pain/chronic itch

Identifying novel therapeutic targets for treating pain and chronic itch

 

David Ginty, Nikhil Sharma, Jing Peng

 

The perception of painful stimuli begins with detection of noxious stimuli by somatosensory neurons called nociceptors. Itch-inducing compounds, on the other hand, are detected by neurons called pruriceptors. We have recently identified the genes expressed in all somatosensory neuron subtypes, including nociceptors and pruriceptors, throughout development and into adulthood. This analysis revealed six transcriptionally distinct subtypes of nociceptors and two subtypes of pruriceptors, each with strikingly distinct gene expression profiles. Importantly, our findings reveal new candidate therapeutic targets to block nociceptors and pruriceptors. We found that select members of the GPCR superfamily, which account for nearly 1/3 of known drug targets, are expressed in nociceptors and pruriceptors, but not other sensory neuron subtypes. We will to leverage our knowledge of somatosensory neurons and the newly identified GPCRs they express to develop new drugs for treating pain and chronic itch while avoiding undesirable side effects. We will focus on drugs that activate Gi/o-coupled GPCRs expressed in nociceptors and pruriceptors because activation of these GPCR subtypes silence neuronal activity.

Structure-guided discovery of novel antibiotics

Structure-guided discovery of novel antibiotics inhibiting bacterial cell wall formation

Francois Thelot and Maofu Liao

The emergence of drug-resistant Gram-negative bacteria causes a significant global health problem, because the available antibiotics are limited and the discovery of new compounds cannot keep pace with the emergence of drug-resistant strains. The difficulty to combat these pathogens is largely due to their unique dual-membrane cell wall which efficiently blocks the entry of antibiotics. Lipopolysaccharide (LPS) in the outer membrane of Gram-negative bacteria plays key roles in cell wall formation and antibiotic resistance. Thus, LPS biosynthesis is a particularly attractive target for developing new classes of antibiotics. LPS is synthesized in the inner membrane and subsequently transported to the outer membrane, a process critically dependent on two ATP-binding cassette transporters (MsbA and LptB2FGC). My laboratory has made important contributions in characterizing the structure and function of these LPS transporters. Here we propose to leverage our experience and mechanistic insights of MsbA to develop novel antibiotics. This will be achieved by establishing a targeted screening pipeline that comprises chemical screen, cryo-electron microscopy (cryo-EM), computational docking, and activity assays. Once established, this pipeline can be applied to target many other bacterial membrane transporters.

2019 Development Grants

Monoclonal antibody therapeutics for Argentine hemorrhagic fever

Monoclonal antibody-based therapeutics for Argentine hemorrhagic fever

Lars Clark, Brian Gowen (USU), and Jonathan Abraham

Viral hemorrhagic fevers (VHFs) pose continuing threats to public health. Most have limited treatment options or vaccines, which underscores a point of vulnerability in public health. Passive immunization is an attractive treatment strategy; for example, transfusion of the monoclonal antibody (mAb) cocktail ZMappTM was a lead approach during the 2014-2016 Ebola virus outbreak. Results of testing in humans with ZMappTM did not reach statistical significance, suggesting that further studies would be required to fine-tune the approach. A mAb derived from the blood of an Ebola survivor, mAb114, was also recently deployed for testing in humans in the ongoing Ebola virus outbreak in the Democratic Republic of Congo.

While these investigational therapies are promising, there remains a large, unmet need for therapies against all agents that cause VHFs. We chose to focus on Argentine hemorrhagic fever (AHF) caused by the arenavirus Junin because antibody transfusions have a well-established track record of successfully treating this infection. We will isolate mAbs from the blood of AHF survivors, characterize the molecular basis for their antiviral activity, and test these for therapeutic effect in small animal models. We will also determine if the antibodies we isolate cross-react with Machupo, Guanarito, Sabia, and Chapare viruses, which are related arenaviruses that cause VHFs in South America and lack effective therapies. Once completed, the work would position candidate mAbs for pre-clinical testing in non-human primates, thus facilitating their translation into human use.

Targeting apoptotic pathways for ALS, AD and PD

Targeting apoptotic pathways for ALS, Alzheimer’s Disease and Parkinson’s Disease

Sooyeon Jo, Laurel Heckman (BCH), Clifford Woolf (BCH), and Bruce Bean

The proposed work follows our recent discovery that targeting a class of voltage-dependent potassium channels inhibits death of motor neurons derived from induced pluripotent stem cells (iPSCs) from patients with ALS. These experiments were motivated by single cell RNA-expression data showing altered expression of a channel regulatory subunit in ALS motor neurons compared to their isogenic controls. This discovery serendipitously converged with an ongoing project developing small molecule modulators of these channels as investigational tools. We have now found that one of these compounds mitigates cell death of ALS patient iPSC-derived motor neurons. We therefore propose to test its ability to delay disease progression in a mouse model of ALS, to develop more potent inhibitors with drug-like properties, and to test the efficacy of these modulators in animal models of Parkinson’s disease and Alzheimer’s disease as a new treatment paradigm for preventing neurodegeneration by inhibiting apoptosis.

Developing novel therapeutic approaches for CNS drug delivery

Developing novel therapeutic approaches for CNS drug delivery by targeting a newly identified key regulator of the blood brain barrier

Urs Langen and Chenghua Gu

A major obstacle in treating neurological diseases and brain tumors is to deliver drugs or antibodies across the ‘blood brain barrier’ (BBB). My lab’s recent discoveries have changed our understanding of how the BBB restricts blood-brain communication. The BBB is formed by a single layer of endothelial cells that lines the blood vessel walls and act as a gatekeeper for the brain. Historically, the restricted permeability of brain vasculature has been attributed to tight junctions. However, substances can also cross endothelial cells by transcytosis, and we discovered that transcytosis is actively inhibited in brain endothelial cells. We identified a

novel multi-transmembrane protein Mfsd2a as a key regulator for BBB function, and demonstrated that interfering with Mfsd2a and its downstream pathway upregulates transcytosis and causes the BBB to become permeable. We propose to develop therapeutic agents that specifically target Mfsd2a function as a strategy to facilitate drug delivery across the BBB.

2018 Development Grants

Development of a new precision therapeutic for an important cancer target

Development of a new precision therapeutic for an important cancer target
Vidyasiri Vemulapalli, Jonathan LaRochelle, and Stephen Blacklow

The focus of this proposal is to develop a new class of potent and selective small molecule inhibitors of a genetically validated cancer target for further therapeutic development by enhancing the potency of our initial hit. Our inhibitors will occupy a unique niche in the landscape of small molecule precision therapeutics in cancer.