Objective
A loss of β-cell mass and biologically active insulin is a key feature of type 1 diabetes. Thus, increasing β-cell mass, for example with small molecules, has become an area of major research interest in the diabetes community. Our groups have recently reported the discovery of small molecules capable of inducing human β-cell proliferation, suggesting that β-cell regeneration may become a feasible therapeutic strategy in diabetes. Despite these promising advances, the potential for inducing wide-ranging proliferation across multiple cell types makes such an approach risky. A more attractive strategy involves delivering a small molecule precisely and specifically to β-cells; even better would be a prodrug strategy, where the small molecule is pharmacologically activated only upon delivery to a β-cell. Here, we aim to develop zinc-based prodrugs (ZnPD) for targeted β-cell delivery of small molecules that promote β-cell proliferation. This small molecule-based system will enable us to perform early-stage preclinical validation that selective β-cell delivery will be safer and more effective than nonselective systemic administration.
Background Rationale
The dysfunction and/or death of β-cells are hallmarks of Type 1 Diabetes (T1D). As such, much effort and many resources have been expended to identify inducers of human β-cell proliferation and, excitingly, several targets/pathways have been identified. However, the perceived systemic on-target liabilities of the identified targets/pathways have jeopardized their therapeutic potential. The narrow therapeutic window of these targets is the major bottleneck. For example, the reported β-cell mitogens activate oncogenic pathways (c-Myc or TGFβ).2-5 The targets for protection of β-cells from pro-inflammatory cytokines have met a similar fate. We can continue the search for new targets, but identifying β-cell selective mitogens is extremely challenging, especially because they may not even exist. Alternatively, we can widen the therapeutic window of existing targets using approaches employed in cancer treatment. For example, a prodrug approach can be used, where an administered compound is converted to an active drug only at the site of action.8 Prodrug approaches have enabled therapeutic development of highly toxic agents, including nitrogen mustards. Selective delivery of the drug to the site of action can also widen the therapeutic window, a strategy that has been successfully accomplished using Antibody-Drug Conjugates (ADCs). Like prodrugs, ADCs have enabled therapeutic development of extremely toxic chemotherapeutic agents, including maytansine that indiscriminately disrupts microtubule assembly. Compared to nitrogen mustards and maytansine, the β-cell targets have better therapeutic indices in pre-clinical studies. Targeted release of therapeutic agents offers a dual advantage, which is important for chronic treatments of T1D. It increases the maximum tolerated dose by decreasing liabilities and lowers the minimum efficacious dose by accumulating drug at the site of action. Development of methods for accurate and precise measurement of β-cell mass will enable monitoring of disease progression and be invaluable in clinical trials.10 Current imaging modalities rely on semi-specific β-cell markers and pick up significant non-specific signals due to the presence of these markers in other cells. Targeted release of imaging agents to β-cells will improve the signal to background ratio, and specificity. Thus, the development of reagents for targeted release of cargo in β-cells will have a wide-ranging impact on T1D diagnosis and monitoring, and therapeutic development.
Description of Project
Patients suffering from type 1 diabetes must undergo burdensome, often lifelong, exogenous insulin dependence. Up to now, the only available replacement therapy is to transplant islets from cadaveric donors. However, such procedures present hurdles such as the scarcity of available donors and the rejection of transplanted cells by the patient’s own immune system. Also, over time, the transplanted islets tend to die. To circumvent these effects, we and other have identified several therapeutic targets to induce beta cell proliferation and protection. However, the realization of the therapeutic potential of these targets requires targeted release as the therapeutic window of these targets is narrow. We propose to apply chemical biology approaches to develop methods for targeted release of bioactives in beta cells in vivo.
Anticipated Outcome
Increasing β-cell mass, for example with small molecules, has become an area of major research interest in the diabetes community. We aim to develop ZnPD for targeted β-cell delivery of small molecules that promote β-cell proliferation. This prodrug system will enable us to perform early-stage preclinical validation that selective β-cell delivery will be safer and more effective than nonselective systemic administration.
Relevance to T1D
Increasing β-cell mass, for example with small molecules, has become an area of major research interest in the diabetes community. We aim to develop ZnPD for targeted β-cell delivery of small molecules that promote β-cell proliferation. This prodrug system will enable us to perform early-stage preclinical validation that selective β-cell delivery will be safer and more effective than nonselective systemic administration.