Technologies Available for Collaboration
+ Neurological disease modeling
Fred Gage Fred "Rusty" Gage is a world leader in neurogenesis and president of the International Society for Stem Cell Research. He has developed novel cellular models of neurological diseases (schizophrenia, MS, autism, Alzheimer’s, Parkinson’s) using human induced pluripotent stem cells (iPSCs) derived from donor patients and differentiated to specific neuronal cell types. These models are useful for studying disease mechanisms, identifying targets, screening compounds and stratifying patients. They are more predictive of disease phenotypes than current models. Gage has also developed an in vitro myelination model using iPSCs to be used for screening of pharmacological compounds and to better understand diseases such as schizophrenia and Parkinson’s.
+ Animal models of neuronal loss in diseases such as Parkinson's
Martyn Goulding The fundamental mechanisms that contribute to the cognitive and motor deficits that accompany neurodegenerative diseases are poorly understood, due in large part to the progressive nature of these diseases. Goulding's lab studies the immediate and downstream effects of neuronal cell loss, such as ongoing changes to spared neurons or to other cell types that make up the circuit, and determines how they adapt to the loss of a particular neuronal cell type. By selectively ablating specific neuronal cell types, in a time- and spatially-dependent manner, one can perform “surgical” lesions and examine the resultant changes with much greater precision. This allows for a more precise evaluation of the attendant cellular, synaptic and physiological changes that occur in response to the initial lesion. He has used this approach to develop a model of Parkinson's disease.
+ A safe approach to regenerative medicine
Juan Carlos Izpisua Belmonte Juan Carlos Izpisua Belmonte has developed a proprietary cellular approach that promises to become a safe, rapid cure for a variety of diseases. He has developed a technology to convert human fibroblasts to progenitor cells, without inducing pluripotency. The entire procedure from fibroblast to endothelial/smooth muscle cells can be completed in 2 weeks. The intermediate progenitor cells are proliferative, thus therapies would not be limited by cell number. Additionally, these cells do not exhibit the pluripotency characteristics of iPSCs/ECs and therefore do not have the safety concerns of pluripotent cells. The progenitor cells can then be differentiated to a variety of cell lineages, depending on the indication to be treated.
As an example, his lab has generated endothelial and smooth muscle cells to treat retinopathy. These cells, when implanted in vivo formed new functional vessels, allowing for blood circulation, demonstrating the connection of the newly formed vessels to the pre-existing vasculature. This approach is currently in preclinical toxicology studies. They postulate that this therapeutic approach could be validated in humans in cases of retinal vein occlusion where treatment requires revascularization, and this can easily be monitored in a timely fashion.
In addition to therapeutic uses, this technology can be used to screen for compounds that promote differentiation, potentially providing new therapeutic compounds and/or alternative therapeutic classes to the drugs currently used to manage disease.
The technologies developed here are applicable to a broad set of applications and indications beyond retinopathy. We believe that peripheral arterial disease (PAD), critical limb ischemia and wound repair, amongst others, are large markets that would benefit from this vascular regeneration approach. Beyond that, this approach to safely and quickly produce large quantities of a variety of cell types for allogenic or autologous treatments can be applied to cells beyond the vascular system. This approach could solve many of the issues currently facing the field of regenerative medicine.
+ Therapeutic compounds for neurodegenerative and metabolic disease
Pamela Maher Pamela Maher has developed a series of compounds with beneficial effects in treating Alzheimer’s and other neurodegenerative diseases, and diabetic complications. These compounds demonstrate anti-inflammatory activity, anti-glycation activity, and an ability to maintain the cell's major endogenous antioxidant, glutathione, under conditions of stress (activating Nrf2 and ATF4). They have also been shown to be neuroprotective and enhance memory, with excellent pharmacological properties and no obvious toxicity in acute or long-term studies..
+ Fisetin/DHA combination for treating cognative decline
Pamela Maher Pamela Maher studies the use of fisetin/DHA combinations in treating cognitive decline and other problems associated with Alzheimer's disease. After years of work in this area, Maher and her colleagues have a better understanding of how these compounds reverse the cognitive problems associated with aging and disease. We are seeking partners to ensure that this work gets applied to product development.
+ Novel molecular targets for treating schizophrenia.
Kuo-Fen Lee Dysfunctions in the glutamate, GABA and serotonin systems have also been implicated in schizophrenia. Most mechanistic studies have so far been focused on DA modulation of the neural circuitry in the prefrontal cortex (PFC) or the striatum, and related them to behavioral phenotypes of schizophrenia. However, little is known about the upstream regulatory circuits of these pathways. To best understand how cholinergic neurons exert their functions in distinct pathways and how to overcome the difficulty of mAChR subtype selectivity and peripheral side effects, Lee's group has profiled and characterized genes that are uniquely or selectively expressed in cholinergic neuron subtypes and which uniquely regulate electrophysiology of mAChR subtypes. His lab is currently investigating the organization and function of a vastly underexplored but potentially highly important neural pathway from the cholinergic MT to DA neurons, and seeking potential causes, as well as molecular and cellular targets for treating schizophrenia.
+ Repair of synaptic connections following injuries such as stroke
Nicola Allen Allen's lab investigates the molecular pathways that lead to connections between neurons, known as synapses, in the developing brain. Her group focuses on signaling interactions between neurons and astrocytes, a class of star-shaped glial cell. The hypothesis is that astrocytes play a crucial role in dictating synapse formation and function via the release of specific proteins that determine the type of synapse that will form, and the strength of that synapse. They are exploring whether these developmental findings can be used to address diseases such as stroke, by promoting the repair of synaptic connections following injury.
+ Optogenetics in the treatment of Parkinson's disease
Xin Jin Numerous motor and mental disorders, from Parkinson's disease to obsessive-compulsive disorder, have been linked to the dysfunction of basal ganglia circuits. Jin’s lab employs a vast array of tools, including quantitative behavior, genetics and optogenetics, in vivo physiological and optical techniques to dissect the neural circuits and molecular mechanisms underlying action learning and selection in freely behaving mice.
+ Imaging of specific neuronal cell types in awake, behaving animals
Axel Nimmerjhan Glial cells, the second major cell type in the brain, account for about ninety percent of human brain cells and more than fifty percent of the brain's volume. Over the past few years, it has become clear that glial cells make crucial contributions to the formation, operation and adaptation of neural circuitry. Work in Nimmerjahn’s lab is centered on innovating light microscopic tools that enable the study of these electrically largely non-excitable cells and their interaction with other cells in the intact mammalian brain. They have created tools for cell-type-specific staining and genetic manipulation, for imaging cellular dynamics in awake, behaving mammals and for automated analysis of large-scale imaging data. This work has broad implications for our view of glial cells, the way information is processed in the brain, the interpretation of functional brain imaging signals and the treatment of neurodegenerative brain disease.
+ In vitro model of myelination and MS
Fred Gage Fred “Rusty” Gage is a world leader in neurogenesis and president of the International Society for Stem Cell Research. He has developed novel cellular models of neurological diseases (MS, autism, Alzheimer’s, Parkinson’s) using human induced pluripotent stem cells (iPSCs) derived from donor patients and differentiated to specific neuronal cell types. He has shown these to be useful for studying disease mechanisms, identifying targets and screening test compounds, and to be more predictive of disease phenotypes than current models. Dr. Gage has also developed an in vitro myelination model using iPSCs to be used for screening of pharmacological compounds and to better understand diseases such as MS.
Summary of myelination model:
Myelin is an electrically insulating material that forms a membrane layer, the myelin sheath, around the axon of a neuron. It is produced by oligodendrocytes in the central nervous system and Schwann cells in the peripheral nervous system. Myelination increases speed of impulse propagation by saltatory conduction through uninsulated portions of axon called Nodes of Ranvier. Loss of myelin membrane, as occurs in many neurological disorders such as multiple sclerosis, leads to disruption of electrical communication between neurons and permanent neuronal functional deficits including loss of motor control and cognition impairment. Multiple sclerosis alone affects over 400,000 people in the United States and more than 2.1 million people worldwide.
,br> The myelination process has mostly been studied with isolated primary cells, in postmortem tissues, or with animal models. All approaches are restricted by variability among individuals, by the intrinsic differences between animal and human models and by the limited number of cells and animals, making large-scale experiments difficult. Embryonic stem cells (ESCs) allow for a relatively uniform population of a large number of cells and induced pluripotent stem cells (iPSCs) offer an opportunity to compare healthy and patient cells directly. We have established an in vitro (in a dish) myelination model using ESC- and iPSC-derived oligodendrocytes and neurons. Our assay will contribute to basic understanding of myelin formation leading to refined treatment strategies. Due to the reproducibility and reliability, our proposed assay will be available for pharmacological compounds screening and adaptation by other research groups to test their hypotheses. Currently, we achieved successful myelin formation using mouse ESCs and we are already gaining knowledge on the mechanics of myelin wrapping.
+ Compound for the treatment of ischemic stroke
David Schubert Currently, tissue plasminogen activator (tPA) is the only drug approved for the treatment of ischemic stroke. Given the limitations with the use of this drug, there is a need for new drugs that promote neuronal survival following stroke. Dr. Schubert has developed a novel patent-protected compound, termed CNB-001, that has neurotrophic activity, enhances memory, and blocks cell death in multiple toxicity assays related to ischemic stroke. It has demonstrated efficacy in multiple animal models of stroke, and also has anti-inflammatory activity in microglia and macrophages. The compound improves the behavioral outcome of rabbit ischemic stroke even when administered 1 hour after the insult, a therapeutic window in this model comparable to tPA. The target for this molecule is 5-lipoxygenase, which it binds with an EC50 of 70nanomolar. CNB-001 also demonstrates efficacy in models of traumatic brain injury, lung inflammation and Alzheimer’s disease. This compound is currently under development for the treatment of ischemic stroke. Dr. Schubert is currently completing a series of animal efficacy models. While he has conducted some toxicity and PK studies, he is seeking funding to carry out a fully PK/Tox/ ADME study in order to attract investment interest.
+ HDAC inhibition to reduce hepatic glucose output and treat type II diabetes
Marc Montminy Montminy and his colleague Reuben Shaw have recently demonstrated the role that Class II HDACs play in regulation of liver gluconeogenesis. Using cellular models of gluconeogenesis, and animal models of insulin resistance, they have demonstrated that HDAC inhibition reduces hepatic glucose output and gluconeogenic gene expression. Based on these results they propose that deacetylase inhibition represents a potentially important, but to date unexplored, approach to drug development, and could complement the current set of type II diabetes drugs.
+ Cancer metabolism
Reuben Shaw Shaw has made a number of significant contributions to the field of cancer metabolism, and organized the AACR Cancer & Metabolism meeting in 2009 and the Keystone Cancer & Metabolism meeting in 2012. He has demonstrated the efficacy of using metabolism drugs in the treatment of cancers lacking the tumor suppressor gene LKB1.
+ A cell-based screen to identify therapeutic compounds for pancreatic cancer
Ronald Evans Desmoplastic stroma is a defining feature of pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, and contributes to tumor progression and resistance to therapy. Pancreatic stellate cells (PSCs) are the main cell type causing the desmoplastic reaction. Quiescent PSCs in a normal pancreas act as lipid-storing cells with a limited secretome, whereas activated PSCs in the tumor microenvironment produce a vast array of secreted proteins implicated in cancer progression. Dr. Evans has hypothesized that restoration of the quiescent PSC phenotype will disrupt PSC–tumor cell communication and impair tumor growth. His lab has developed a screen to identify small molecules that revert PSCs to their quiescent phenotype using the accumulation of lipid droplets as a hallmark of the quiescent state.
Juan Carlos Izpisua Belmonte Izpisua Belmonte’s lab has also recently produced cancer stem cells from human induced pluripotent stem cells (hiPSCs), which led to glioblastoma (GBM) formation upon orthotopic injection into the brain of nude mice--the first time that an animal model of GBM is able to recapitulate infiltration of human cancer cells. He proposes to use these cancer stem cells (CSC) as a model to assess and screen novel anti-cancer drugs, and as CSC-specific immunogens to induce protective memory, as well as effector, T-cell responses against tumor growth.
+ SKIP and cancer therapy
Katherine Jones Jones has identified Ski-interacting protein (SKIP) as an important regulator of a number of central cancer pathways. SKIP is an essential protein that controls cell survival and stress resistance. It is a required coactivator of TGF-beta, Notch and nuclear receptor genes. It is strongly inhibited by flavone-type CDK inhibitors such as flavopiridol. Jones is characterizing all the members of the SKIP complex and identifying the most promising interactions and enzyme activities to screen for inhibitory small molecules as lead candidates for cancer therapeutics.
+ Combination cancer therapy
Jan Karlseder Jan Karlseder, through his studies on telomere deprotection, has identified the universal mechanism that initiates the DNA damage response and leads to cell death upon exposure to mitotic inhibitors, such as those used in cancer treatment. Based on these studies, he is proposing treatments with mitotic inhibitors in combination with either DNA damage-sensitizing agents such as PARP and CHK inhibitors, or telomerase inhibitors.
+ ULK1 Inhibitors, in combination with mTOR inhibitors as a cytotoxic cancer therapy
Reuben Shaw The serine-threonine kinase mammalian target of rapamycin (mTOR) plays a major role in the regulation of cell growth, and metabolism. Given that the mTOR pathway is hyperactivated in a number of cancers, it has been proposed that mTOR inhibitors will have broad therapeutic application across many tumor types, and Rapamycin and its analogs (rapalogs) as well as ATP-competitive inhibitors of mTOR are being actively pursued as therapeutic candidates. In 2012, the National Cancer Institute listed more than 200 clinical trials testing the anticancer activity of these inhibitors, both as monotherapy and as a part of combination therapies for many cancer types. However, mTOR inhibitors as single agents have modest activity, and combination therapies are being developed with the idea of overcoming resistance to the mTOR inhibition, and increasing efficacy.
While the role of mTOR in cell growth is well known, its role in autophagy has only recently been identified. Autophagy is the cellular process by which cells break down intracellular proteins and organelles under conditions of stress, freeing up metabolic intermediates and promoting cell survival. Dr. Shaw’s work recently demonstrated that a complex controlling the initiation of autophagy, composed of a kinase called ULK1, is inactivated by mTOR (Egan et al., Science 2011). Thus, inhibiting mTOR will lead to activation of autophagy which is a major pathway promoting cell survival. The propensity of mTOR inhibitors to promote tumor cell survival via ULK1-dependent autophagy may help explain why rapalogs are primarily cytostatic, and only effective as disease stabilizers rather than for regression. Dr. Shaw has postulated that combining inhibition of ULK1 with rapamycin treatment might convert the standard cytostatic effect of mTOR inhibitors into a cytotoxic effect, once the survival benefit of ULK1-initated autophagy is removed. His laboratory has developed a variety of inducible, genetically-engineered mouse models that give biological readouts of treatment regimes in settings that are predictive of human cancer subtypes. He has also developed a vast array of in vitro assays to test biological hypotheses across all members of the relevant pathways, and to screen for ULK1 inhibitors. He is currently developing small molecule inhibitors with a collaborator.
+ Cancer models that replicate the characteristics of human disease
Inder Verma Current efforts to discover cancer therapeutics are mainly based on cell-based screens and animal models that do not reflect the human disease. Verma has successfully developed lentiviral vector-mediated mouse models for glioblastoma, lung adenocarcinoma and small cell lung cancer (SCLC). These models faithfully reproduce the characteristics of human disease in terms of histopathology, cell origin, genetic mutations and tumor microenvironment.
+ New targets for triple negative breast cancer
Geoff Wahl Geoff Wahl's work on the link between development and cancer has demonstrated that the invasive and proliferative processes of mammogenesis resemble phases of cancer progression. Expression profiles of isolated fetal mammary stem cells (fMaSC) and associated stroma exhibit striking similarities to profiles of triple negative and Her2+ breast cancer. Gene expression, transplantation and in vitro analyses revealed mechanisms, including ErbB and FGF pathways that regulate fMaSC growth. These and other candidates potentially provide new targets for diagnosis, prognosis and therapy of cancer.
+ Cancer metabolism
Reuben Shaw Reuben Shaw is pioneering work in cancer metabolism (he co-organized the AACR Cancer & Metabolism meeting in 2009 and the Keystone Cancer & Metabolism meeting in 2012). He is particularly interested in the role of LKB1 and downstream players, as demonstrated by the efficacy of phenformin as a therapeutic in inducible K-ras mouse models of lung cancer.
+ Mouse models of non-small cell lung carcinoma
Reuben Shaw Shaw’s models are based off an inducible K-ras oncogene expressed in mouse epithelium once the mice inhale an adenovirus expressing cre-recombinase. His lab crossed the K-ras model to a ubiquitous promoter driving conditional luciferase expression only in cells that Cre has entered. In this fashion, they derive a signal from the tumor cells proportional to tumor mass which arises spontaneously in vivo in the accurate setting of the lung and from the accurate genetic lesions found in human non-small cell lung cancer (NSCLC). They combined the conditional K-ras luciferase mice with mice conditionally inactivated for the p53 tumor suppressor, AMPK, or the LKB1/STK11 tumor suppressor. Importantly, K-ras, p53, and LKB1 are the three most commonly mutated genes in human NSCLC, and the K-ras p53 (KP) mice and K-ras LKB1 mice (KL) develop consistent aggressive carcinomas within 8 weeks of inhaling cre-recombinase which allows the scientists to rigorously test therapeutics in real time in these models.
+ TAM receptor modulators as anti-virals and anti-inflammatories
Greg Lemke Greg Lemke is a leading authority in the area of TAM receptor kinases and their role in immune regulation and viral responses. He is developing molecules that modulate these receptors and act as anti-inflammatories, vaccine adjuvants and anti-virals.
+ Therapy for hemophilia
Juan Carlos Izpisua Belmonte Izpisua Belmonte is one of the world's leading experts in the use of stem cells, and particularly iPSCs in the treatment of disease. He has developed a proprietary cellular approach that promises to become a safe, rapid cure for a variety of diseases. He has developed a technology to convert human fibroblasts to progenitor cells, without inducing pluripotency. The entire procedure from fibroblast to endothelial cells can be completed in 2 weeks. The intermediate progenitor cells are proliferative, thus therapies would not be limited by cell number. Additionally, these cells do not exhibit the pluripotency characteristics of iPSCs/ECs and therefore do not have the safety concerns of pluripotent cells. The progenitor cells can then be differentiated to a variety of cell lineages, depending on the indication to be treated. A focus of his work is the gene-correction of fibroblast cells with factor VIII, and their subsequent conversion to endothelial cells as a cellular therapy for hemophilia.
+ Therapy for hemophilia
Inder Verma Verma is one of the pioneers of lentiviral-based gene therapy. His current focus is on the production of autologous hepatocytes from patient-derived induced pluripotent stem cells (iPSCs). His lab generates iPSCs from patient tissues using an excisable 6-factor lentiviral-reprogramming vector. They then correct these excised iPSCs for the expression of factor IX (FIX) using a lentiviral transgene. The resultant clones with functional FIX can then be screened for integration of the viral backbone in safe harbor regions and for its robust expression, subsequent to which they will be differentiated in vitro to the hepatic lineage, with a view to producing a cell-based therapy for hemophilia.
+ Increasing production of recombinant proteins
Geoff Wahl Wahl’s lab has identified a protein tag that results in an estimated 10- to 50-fold increase in the yield of unstable proteins from mammalian cell lines. They have demonstrated this with a number of very different proteins produced from CHO and human cancer cell lines. Given the recent nature of this discovery, it has not yet been published. However, Dr. Wahl and his colleagues would be very interested in discussing the possibility of applying the system to proteins that you may have difficulty producing, or for which you would simply like to increase yields.
+ High throughtput screen for modulators of protein-protein interactions (PPI)
Geoff Wahl Many myths exist around the difficulties of developing PPI antagonists. As a result, this approach is severely under-exploited, despite the fact that the extensive human interactome presents opportunities that dwarf current drug targets. Professor Wahl and his team have developed a platform cell-based assay in high-throughput format to screen for inhibitors and agonists of protein-protein interactions. This novel-screening platform combines an inducible protein expression system with the bi-molecular luciferase complementation (BiLC) assay, allowing for the interrogation of transient and dynamic PPIs, identification of novel intracellular protein interaction partners, and screening and characterization of PPI antagonists and agonists. The assay was initially developed to screen for inhibitors of p53-MDM2/MDMX in cancer, but is broadly applicable to many protein-protein interactions, including K-Ras Inhibitors.
+ Enzyme engineering for the production of chemical intermediates
Joseph Noel Noel is a world leader in enzyme engineering. One focus he has with his colleagues at the Center for Biorenewable Chemicals (www.cbirc.iastate.edu) is developing enzymes that permit microbial production of chemical intermediates at commercial levels. His work has already led to the formation of Allylix (www.allylix.com) a company that makes terpene products for a variety of markets. He is interested in exploiting his work on pyrone synthesis as a source of sustainable, cheap chemical intermediates for the food, chemical, cosmetics and other industries.
+ Regenerative medicine and chondrogenesis
Juan Carlos Izpisua Belmonte Juan Carlos Izpisua Belmonte is one of the world's leading experts in the use of stem cells, and particularly iPSCs in the modeling and treatment of disease. His lab has developed in vitro protocols to differentiate human iPSCs into chondrocytes, and has reporter cell lines for chondrogenesis. These have been adapted for high-throughput screening of compounds that promote chondrocyte maturation and regeneration for use in combination therapies of osteoarthritis (OA).
+ Motor neuron dysfunction in ALS and spinal muscular atrophy (SMA)
Sam Pfaff A major challenge in studying SMA has been the lack of appropriate model systems. Dr. Pfaff has developed a novel embryonic-stem cell-based model of SMA that phenocopies the pathology of human SMA, and can be used to study the basis of the disease and screen for compounds that might increase survival of motor neurons. Through these studies he has identified a new transcription factor and associated pathway that could yield new avenues for therapeutic intervention in SMA.
+ Cardiac regeneration in vivo through miRNA downregulation
Juan Carlos Izpisua Belmonte Heart failure remains one of the leading causes of mortality in the developed world. Whereas the mammalian heart is endowed with certain regenerative potential, endogenous cardiomyocyte proliferation is insufficient for functional heart repair upon injury. Interestingly, non-mammalian vertebrates, such as the zebrafish, can regenerate the damaged heart by inducing cardiomyocyte dedifferentiation and proliferation. By screening regenerating zebrafish hearts, Izpisua Belmonte’s lab identified the downregulation of a set of miRNAs as a key process driving cardiomyocyte dedifferentiation. Experimental downregulation of these miRNAs in primary adult murine and human cardiomyocytes led to an increase in the number of proliferating cardiomyocytes. AAV-mediated in vivo downregulation after acute myocardial injury in mice induced mature cardiomyocyte proliferation, diminished infarct size and improved heart function. These studies represent the first time that such a cardiac regenerative response has been demonstrated in an in vivo model through miRNA downregulation, and are a proof-of-concept on the suitability of activating pro-regenerative responses for healing the diseased mammalian heart.