Objective
Our current objective is to utilize existing stored blood from CLVer trial participants to define how verapamil works to partially preserve β cell function in humans with T1D. We are requesting funding to conduct analyses of novel biomarkers of pancreas, islet, and β cell health, as well as testing to identify potential mechanistic effects of verapamil on metabolic health.
Background Rationale
Type 1 diabetes (T1D) develops through a cascade of steps leading to autoimmune β cell destruction. Targeted immunomodulation has shown some efficacy to attenuate T1D progression, but effects are often heterogeneous and demonstrate limited long-term effectiveness. Insufficient consideration of the role of nonimmune contributors in T1D development, such as the β cell itself, may play a role in this lack of long-term effect. Emerging data suggest that metabolic stress pathways intrinsic to the β cell, initially activated to increase survival and insulin production, can ultimately impact progression to cell death or, indirectly by sending signals to immune cells, promote immune infiltration and β cell destruction. Thus, there is an urgent need to identify novel therapies targeting non-immune mechanisms of disease, such as β cell health. Ultimately, approaches combining such treatments with targeted immunomodulation could provide precision approaches to T1D disease-modifying therapies.
One therapeutic agent that has recently garnered significant interest in this area is verapamil, a calcium channel blocker initially developed and established as an antihypertensive. Verapamil was identified as an agent potentially impacting β cell health in a preclinical drug screen designed to identify agents capable of reducing activity of thioredoxin-interacting protein (TXNIP), a protein which has been implicated in β cell death. Additional testing showed that verapamil treatment led to reduced β cell death, increased β cell mass, and reduced hyperglycemia in preclinical models of type 1 and type 2 diabetes. A subsequent small trial in 26 adults with recent onset T1D showed that 12 months of oral verapamil treatment was associated with preservation of β cell insulin secretion compared to placebo. Follow-up mechanistic testing in a subset of trial participants suggested that the drug may have more far reaching impacts than initially anticipated, including effects on the immune system. Although promising, given the small sample size these findings required verification with larger cohorts to ensure applicability to the broader T1D population.
This issue was addressed by the recently published CLVer (CLosed loop Verapamil) randomized controlled trial, funded by the JDRF, which treated 88 children age 8-18 years with newly diagnosed T1D with 52 weeks of daily oral verapamil or placebo. Consistent with the above adult data, compared to placebo, verapamil preserved endogenous insulin secretion by about 30%. Furthermore, the medication was well tolerated with limited side effects. These exciting findings have galvanized interest in this drug as an affordable, safe, and easily administered therapeutic agent that could be used in combination with immunotherapies for T1D prevention or intervention.
While the CLVer study verified a beneficial impact of verapamil on preservation of insulin secretion in children with new onset T1D, robust mechanistic data explaining how it works are lacking. Blood samples were collected throughout the CLVer study, with a plan to secure separate funding to do mechanistic analyses if the study showed a positive benefit of the drug. The current proposal requests funding to use these existing samples to perform laboratory assessments including of measures of immunology; inflammation; exocrine function; and β cell stress, secretion pathways and cell death.
Description of Project
Type 1 diabetes (T1D) develops through a cascade of steps leading to autoimmune β cell destruction. Targeted immunomodulation has shown some efficacy to attenuate T1D progression, but effects are often heterogeneous and demonstrate limited long-term effectiveness. Insufficient consideration of the role of nonimmune contributors in T1D development, such as the β cell itself, may play a role in this lack of long-term effect. Emerging data suggest that metabolic stress pathways intrinsic to the β cell, initially activated to increase survival and insulin production, can ultimately impact progression to cell death or, indirectly by sending signals to immune cells, promote immune infiltration and β cell destruction. Thus, there is an urgent need to identify novel therapies targeting non-immune mechanisms of disease, such as β cell health. Ultimately, approaches combining such treatments with targeted immunomodulation could provide precision approaches to T1D disease-modifying therapies.
One therapeutic agent that has recently garnered significant interest in this area is verapamil, a calcium channel blocker initially developed and established as an antihypertensive. Verapamil was identified as an agent potentially impacting β cell health in a preclinical drug screen designed to identify agents capable of reducing activity of thioredoxin-interacting protein (TXNIP), a protein which has been implicated in β cell death. Additional testing showed that verapamil treatment led to reduced β cell death, increased β cell mass, and reduced hyperglycemia in preclinical models of type 1 and type 2 diabetes. A subsequent small trial in 26 adults with recent onset T1D showed that 12 months of oral verapamil treatment was associated with preservation of β cell insulin secretion compared to placebo. Follow-up mechanistic testing in a subset of trial participants suggested that the drug may have more far reaching impacts than initially anticipated, including effects on the immune system. Although promising, given the small sample size these findings required verification with larger cohorts to ensure applicability to the broader T1D population.
This issue was addressed by the recently published CLVer (CLosed loop Verapamil) randomized controlled trial, funded by the JDRF, which treated 88 children age 8-18 years with newly diagnosed T1D with 52 weeks of daily oral verapamil or placebo. Consistent with the above adult data, compared to placebo, verapamil preserved endogenous insulin secretion by about 30%. Furthermore, the medication was well tolerated with limited side effects. These exciting findings have galvanized interest in this drug as an affordable, safe, and easily administered therapeutic agent that could be used in combination with immunotherapies for T1D prevention or intervention.
While the CLVer study verified a beneficial impact of verapamil on preservation of insulin secretion in children with new onset T1D, robust mechanistic data explaining how it works are lacking. Blood samples were collected throughout the CLVer study, with a plan to secure separate funding to do mechanistic analyses if the study showed a positive benefit of the drug. The current proposal requests funding to use these existing samples to perform laboratory assessments including of measures of immunology; inflammation; exocrine function; and β cell stress, secretion pathways and cell death.
Anticipated Outcome
We are performing a comprehensive mechanistic analysis of stored samples from the CLVer study. We anticipate gaining a far greater understanding of how this drug works to preserve beta cell function.
Relevance to T1D
The success of the verapamil trial, CLVer, has galvanized interest in this drug as an affordable, safe, and easily administered therapeutic agent for new onset type 1 diabetes. Insulin secretion was 30% greater at one year in subjects that received verapamil compared to placebo. This is less than some other therapies which have targeted the immune system (e.g. teplizumab, ATG, abatacept). However no single agent has yet provided a durable, long-lasting impact on β cell loss. Increasingly, attention is shifting to combination therapy. Verapamil is an attractive agent for synergistic grouping with other identified drugs because it acts via a different (albeit incompletely understood) mechanism. Understanding all the ways that verapamil is beneficial to the beta cell will help determine its place in combination protocols.