Targeting Proinflammatory Mediators to Restore Treg Homeostatic Expansion and Function in ALS, In Vitro Studies as Surrogates for In Vivo Applications
Abstract
Background: ALS is a disease in which specific types of neurons that signal to muscles, called motoneurons, rapidly degenerate, often causing death due to respiratory failure within 3-5 years of diagnosis. Two forms of ALS exist: The familial ALS, or fALS, form arises from inheriting one copy of one of 12 known mutated genes that can override the activity of the healthy gene copy to cause disease, and sporadic, or sALS, which represents greater than 90% of ALS cases where the disease arises with no known reason. Both types of ALS have a similar disease course and ensuing poor prognosis. There currently are no effective treatments for ALS other than a drug called RNS60, which only increases lifespan by 3 months. Research suggests that specific activated immune cells that reside inside and outside of the central nervous system appear to play a role in initiating and augmenting disease severity. A different type of immune cell called regulatory T cells, or Tregs, for short, are fundamental for maintaining health as they function to suppress the aberrant activation of immune cells, keeping the immune system from attacking one s own body, which is the fundamental problem in autoimmunity. These Tregs can be isolated from the blood and tested for how well they suppress the activation of other immune cells. The Tregs in ALS patients have been found to exist at lower numbers and be less suppressive than those isolated from healthy donors. Furthermore, a recent clinical trial was performed where three sALS patients received injections of their own Tregs that had been isolated and grown to larger numbers in an incubator. In this way, the patient Treg frequency was greatly increased, and strikingly, they exhibited a significant slowing of ALS disease progression. This result suggests the exciting possibility that optimizing Treg function in ALS could provide an efficacious treatment to markedly slow disease progression. Unfortunately, however, the beneficial effect of the injected Tregs was only short-term as disease progression resumed within 2-4 months. We propose that this short window of efficacy may indicate that the injected Tregs were inactivated over time by unknown factors associated with the disease. We have begun testing this possibility and have found that the other cells in the blood (called antigen presenting cells or APCs) and the fluid phase of the blood (plasma) that contains proteins and metabolites, can both functionally inactivate the Treg, while the similarly isolated APCs or plasma from healthy donor samples did not inactivate the Treg. The scientific goals the project is designed to achieve are (1) to identify how Tregs are inactivated by the other cells in the ALS patient circulation and by the patient plasma; and (2) to determine if specific anti-inflammatory drugs that are commonly prescribed in various autoimmune diseases or if compounds in a library of over 1,000 FDA-approved inhibitory drugs, are able to block the Treg inactivation induced by patient APCs and plasma. Such neutralizing drug compounds could then represent potential drugs for future clinical trials aimed at enhancing Treg function with the goal of slowing the progression of ALS. The ultimate applicability of the proposed research is to identify compounds that may represent future therapeutics via their ability to enhance Treg function in ALS and block the in vivo mechanisms that result in Treg inactivation in ALS. As the short-term results of the published phase 1 clinical trial suggest, where the administration of an increased number of Tregs gave intervals of reduced disease progression, being able to maximize Treg stability in vivo could be expected to have longer-lasting effects on slowing ALS progression. It is likely that such a therapeutic that targets and enhances in vivo Treg function should be equally effective in treating both types of ALS (fALS and sALS), as fALS and sALS have similar disease course and patho
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110137
Entities
People
- Clare Baecher-allan
Organizations
- United States Army