This Funding Opportunity Announcement (FOA) solicits cooperative agreement applications for projects to develop strategies to target the human pancreatic environment in-vivo to deliver regulatory cells, molecules or gene constructs that can protect or replenish functional beta cell mass, or to engineer cellular or synthetic sentinel biomarkers that can safely monitor the islet tissue environment in individuals at risk of developing Type-1 Diabetes (T1D).
T1D is characterized by the development of an autoimmune response that leads to the specific destruction of the pancreatic beta-cells. While some progress has been made in recent years to partially protect residual beta cell mass in recently-diagnosed individuals and to measure disease progression in patients with T1D with sub-optimal sensitivity, strategies for initiating, maintaining and monitoring a full arrest of disease progression are still needed. In addition, in spite of the encouraging identification of molecules that may have an impact on beta cell replication, robust and safe therapeutic strategies to replenish beta cell mass in patients with T1D have yet to be developed.
The promising outcome of cadaveric islet transplantation has demonstrated that beta cell replacement can be therapeutic for the treatment of T1D. It has prompted the search for alternative and abundant sources of beta cells for replacement therapy, and much progress has been made in differentiating insulin-producing cells from stem/progenitor cells for possible clinical use. At the same time, our rapidly evolving knowledge in areas such as islet-cell plasticity, epigenetic control of cell identity, cellular reprogramming, genome editing and gene therapy, synthetic biology and engineering of therapeutic compounds with cell-specific properties could be leveraged to develop therapeutic alternatives to islet transplantation, such as the safe and controlled replenishment of functional beta cell mass using the remaining islet non-beta cells as a cell source, or the protection of residual beta cell mass following systemic delivery of islet-specific immunomodulatory agents or protective cell-engineering gene constructs.
This initiative proposes to fill technological and scientific gaps that currently prevent the development of innovative therapeutic strategies for preserving or replenishing functional beta cell mass in T1D, including in the following areas:
- Great progress has been made in recent years in identifying small molecules that may regulate beta cell replication and beta cell mass, although validation of their efficacy often relies on surrogate markers of cell division, casting doubt about the true biological activities of these promising compounds. Better in-vitro platforms to screen for or validate the biological activity of small molecules, drugs, or biologics that have the potential to regulate the regeneration, differentiation or immune protection of human beta cells are needed, particularly for the high-throughput phenotypical screening of dissociated human islets.
- While there has been a strong emphasis on trying to modulate beta cell numbers by directly targeting the residual beta cell mass, fewer efforts have been invested in targeting, recruiting or modifying other cells within or around the islet (such as alpha, duct, acinar, vascular and peri-vascular cells) in order to increase beta cell mass or to improve the islet disease environment through engineering of paracrine activities or control of cell fate or function.
- While many genes or regulatory RNA species in the human islet have been identified as possible therapeutic targets, and while gene-editing technologies and a new generation of gene-therapy vectors are evolving rapidly, we still lack the practical means of delivering regulatory constructs to specific cell types within the islet compartment, or of targeting disease-relevant RNAs using small molecules.
- Circulating human cells have the potential to be used for therapeutic or disease-monitoring purposes. For example, immune cells could be engineered in-vitro to acquire specific cell-homing properties and deliver natural or synthetic therapeutic compounds to the islet compartment after re-introduction into the patient.
- Innovative engineering strategies could also be used to develop safe, sensitive and specific synthetic or cell-based biomarkers that can report on the state of the islet environment in individuals at risk of developing T1D, for example through the release of inert molecules that can easily be identified and quantified in body fluids.
- The transdifferentiation of a variety of pancreatic non-beta cells into regulated insulin producing cells remains an attractive regenerative medicine strategy, particularly if the resulting pseudo-beta cells can evade the existing autoimmune environment in patients with T1D. The development of such a strategy will require a combination of technological improvements, from the design of effective cell fate-controlling molecules or constructs, to the production of highly-specific delivery vehicles (viral vectors or targeting complexes), and the building of relevant preclinical models for in-vivo validation.
Research Opportunities and Scope
This Funding Opportunity Announcement encourages the development of innovative tools and strategies for the therapeutic targeting of relevant cell types residing within or around the human islet with the long-term goal of protecting or replenishing functional beta cell mass in patients with T1D, or for the non-invasive monitoring of the islet environment in individuals at risk of developing T1D or diagnosed with the disease. Contributions to this initiative could include, but are not limited to, the discovery, development or optimization of:
- Next-generation medium- to high-throughput screening platforms using single (or a small number of) primary human islets for the discovery, validation or optimization of novel regulators of islet cell plasticity or beta cell mass, stress, survival, immunogenicity and/or function; emphasis should be on platforms or devices that could be easily manufactured, could be readily distributed to and adopted by the biomedical research and drug-discovery communities, and can provide dynamic readouts of islet function through the use of technologies such as high-content imaging or stable isotope labeling with amino acids in cell cultures (SILAC); next-generation xenotransplantation platforms for the functional validation of targeted therapeutic strategies using human islets in-vivo, that may include the reconstitution of components of the human autoimmune environment to assess the efficacy of immunomodulatory interventions.
- Novel receptors or transmembrane proteins (including postranslationally modified isoforms) that are highly-specific of adult human beta cells or other islet cell types, and that can be used as molecular anchors in the context of a targeted therapeutic strategy in-vivo;
- Reagents or molecular complexes that can serve as cargo delivery vehicles to facilitate the safe, efficient and specific delivery of small molecules or regulatory gene constructs to human beta cells or other cell types within relevant pancreatic compartments.
- Therapeutic molecules engineered for exclusive activity in human islet cell subtypes, including multivalent synthetic ligands or regulatory compounds that require a cell-specific environment for activation; innovative combination of bioactive molecules to achieve the double objective of restoring beta cell mass and silencing autoimmunity;
- Small molecules or combination of therapeutic agents that can reverse immune and endocrine failures observed in early disease, such as beta cell-specific regulators of ER stress, processing/repair pathways, senescence and/or immunogenicity; support could be for compound discovery, lead optimization, or the development and validation of drug-like versions of promising molecules before clinical use;
- Gene constructs encoding a protein or regulatory RNA that can impact beta cell survival, mass or immunogenicity following in-vivo delivery through viral or non-viral vectors; strategies for islet cell-specific genome editing; validation strategies using advanced preclinical platforms (such as non-human primates) to convincingly demonstrate in-vivo efficacy and preclinical toxicology prior to first in man;
- Engineering of immune-privileged beta cells through expression of non-endogenous immunomodulatory molecules, such as proteins used by viruses, parasites or cancer cells to evade immune surveillance;
- Strategies to specifically target cells or tissue compartments within the islet environment other than the pancreatic beta cells for the purpose of modifying that environment to help protect or replenish functional beta cell mass;
- Strategies to reinforce protective pathways or anatomic structures in and around the human islet that naturally contribute to responses against environmental stresses or immune attacks. Examples include strengthening the peri-islet basal membrane, reducing the immunogenicity of human islet beta cells, interfering with the specific homing of activated T cells to the human pancreatic islet, blocking immune cell infiltration through the islet vascular or lymphatic capillaries or improving the health or function of tissue components such as islet blood vessels or neuronal networks that may be disrupted in the early stages of T1D in humans;
- Engineering of patient-derived circulating cells, such as T regulatory cells, with specific cell-homing properties and the ability to deliver therapeutic or immunomodulatory agents to the human islet compartment, to include nonendogenous regulatory proteins or molecules;
- Cell-based or synthetic sentinel biomarkers that could be delivered to the human islet compartment and release non-degradable processed products in blood or urine in response to pancreatic islet stress, inflammation, injury or autoimmune events for the non-invasive monitoring of early disease processes.
Projects that are mostly focused on developing delivery vehicles or cell-targeting strategies need to demonstrate efficacy of delivery to the human islet environment in-vivo using biological or imaging-based readouts.
Projects that are exclusively focused on developing new imaging-based strategies for in-vivo monitoring of beta cell mass or function are not responsive to this FOA. However, the use of imaging-based reporter systems to validate in-vivo efficacy of new islet-targeting strategies is considered responsive.
The long-term outcome of the projects proposed in response to the current initiative should be the development of safe and highly-specific products or reagents that could be administered orally or systemically to patients with T1D, at risk of developing T1D or with severe insulin deficiency unrelated to T1D, and could have a reasonable chance of being used in the clinic in the foreseeable future. To demonstrate the translational potential of their approach, applicants will need to validate within the funding period of the grant the efficacy of the proposed therapeutic or diagnostic strategy in vivo using human cells or tissues (engraftment models), or large animal models that would be adequate for assessing efficacy and toxicity prior to first in man. Biological efficacy should be demonstrated following systemic, oral or surgical administration of the therapeutic or diagnostic agent in the relevant preclinical system.
Successful applicants will join the Consortium on Targeting And Regeneration (CTAR) that was created in 2014 to support the development of innovative strategies to increase functional human beta cell mass in vivo through the controlled manipulation of beta cell replication or islet plasticity, or the reprogramming of adult non-beta cells into beta-like cells, or the protection of residual beta cell mass from autoimmune destruction in T1D (http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-13-015.html ). CTAR is one of the five consortia that constitute the Human Islet Research Network (HIRN), created in 2014 to support innovative and collaborative translational research to understand how human beta cells are lost in T1D, and to find innovative strategies to protect and replace functional beta cell mass in humans.
Successful applicants will be expected to work collaboratively with all of their CTAR and HIRN colleagues and to contribute to an environment of sharing and trust across the network. All methods, reagents, resources, biomaterials, protocols, data and models developed by CTAR investigators are expected to be made available to the research community, as appropriate and consistent with achieving the goals of the program. All participants will be expected to adhere to the sharing policies developed by the HIRN as a term of the award. CTAR Program Director(s)/Principal Investigator(s) (PD(s)/PI(s)) must participate in the annual HIRN Investigator Scientific Retreat, as well as in CTAR Steering Committee teleconferences to be held at least bi-annually. All participants will be obligated to abide by the policies adopted the majority vote of the CTAR Steering Committee and the HIRN Trans-Network Committee (see “Cooperative Agreement Terms and Conditions of Award, Section VI.2.).
Deadline: January 26, 2019 (letters of intent); February 26, 2019 (full proposals)
Filed Under: Funding Opportunities