LBT-3627: Modulating Tregs via VPAC2 Activation Resulting in a Novel Immunomodulatory Disease-Modifying Approach to ALS Treatment
Abstract
Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease affecting select motor neurons in the brain stem, spinal cord, and cerebral cortex. Ongoing muscle denervation leads to generalized weakness, progressive paralysis, respiratory muscle failure, and death within 3-5 years. Currently, there are only minimal treatment options available, none of which extend life. Recent human clinical research has found significant differences in T cell function between fast- and slow-progressing ALS cases in addition to both groups having significantly lower T regulatory cell (Treg) function, highlighting the role of the immune system (T cells in particular) in ALS disease progression. Lower Treg function suggests an unbalanced immune system indicating that pro-inflammatory (T responder or Tresp) cells are able to divide unchecked. Pro-inflammatory Tresp cells and anti-inflammatory Treg cells are essentially equal and opposite forces in a normal, healthy immune system. However, in ALS and other neurodegenerative disorders like multiple sclerosis (MS) and Parkinson s disease there is growing evidence that immune balance is shifted into a pro-inflammatory, Tresp-dominant, state. Vasoactive intestinal peptide (VIP) is a naturally occurring peptide hormone that is responsible for, among several things, restoring balance to the immune system. However, differences in VIP have been observed with ALS symptom onset in both humans and in transgenic animal models of ALS (SOD1). ALS patients have reduced levels of VIP in cerebrospinal fluid compared to healthy controls, suggesting that changes to the VIP signaling system may play a role in ALS disease progression. VIP analogs have been used in ALS animal models and have resulted in delayed disease onset and extension of life, emphasizing the therapeutic potential of the VIP signaling pathway. However, each of these earlier candidates, including naturally occurring VIP, have liabilities that prevented serious therapeutic development. Accordingly, Longevity Biotech has developed a stable and selective VIP analog, LBT-3627, yielding the first true therapeutic candidate. This ALS Therapeutic Idea Award proposal intends to evaluate LBT-3627 in both preclinical disease models as well as in an ex-vivo human study. LBT-3627 is a novel immunomodulator that has been shown to rebalance dysregulated immune systems and is currently in development for Parkinson s disease and Multiple Sclerosis. We hypothesize that LBT-3627 will restore Treg function lost in SOD1 mice, resulting in a slowing of disease progression, as well as in ALS patient T cells, collectively demonstrating its disease modification potential. Two gender-balanced animal studies and one ex-vivo human study are proposed in an effort to evaluate our hypothesis. The animal studies will utilize the well-characterized model of SOD1^G93A mice. The SOD1^G93A mouse model is based on a mutation in the SOD1 gene, which is known to contribute to both inherited and sporadic ALS cases. Importantly, the immune deficits seen in ALS patients are mirrored in this model. The first study is designed to determine a dose response profile for LBT-3627. The second study is designed to evaluate the impact of LBT-3627 on the rate of disease progression and immune function. In the proposed ex-vivo human study, pre-existing blood samples from ALS patients and controls will be obtained from biobanks and treated with LBT-3627. Pro-inflammatory Tresp cells and anti-inflammatory Treg cells will be isolated and Treg cell function will be measured by how efficiently Tresp divisions are suppressed. This study will give us the opportunity to see if the Treg cells from ALS patients can be restored to healthy functional levels. Ultimately, this work could yield a novel treatment option for ALS patients. The proposed studies should confirm the clinical viability of LBT-3627 by starting treatment at symptom onset in the s
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010227
Entities
People
- Sarah Olmstead
Organizations
- Longevity Biotech (United States)
- United States Army