Beyond CuATSM: Novel Copper Complexes for Improved ALS Therapy
Abstract
A small copper-containing molecule known as copper-ATSM or CuATSM is one of the most promising potential amyotrophic lateral sclerosis (ALS) treatments to emerge in recent years. Scientists have shown that CuATSM protects vulnerable neurons like those that are affected by ALS from being damaged by a variety of toxic processes that are thought to play a role in ALS. There are at least eight reports that CuATSM can improve outcomes in mouse models of ALS. Based on these studies, CuATSM is now being tested in human clinical trials and early results are encouraging. So far, most studies of CuATSM have focused on mutant SOD1 models but there is growing evidence that this complex has activity in other forms of ALS, including sporadic ALS. However, CuATSM has some drawbacks. The main problem is that it has a small therapeutic window -- this means there is only a small difference between the dose that is high enough to be effective in ALS and the dose that is low enough to not have toxic side effects. Consequently, some patients on the trial may not be getting a sufficiently high dose of CuATSM for it to be effective, but it is not possible to raise the dose further without causing side effects. Another problem is that researchers do not understand exactly how CuATSM works in ALS and that makes it difficult to know which individual patients or which types of ALS will respond to treatment. It also makes it hard to design a better CuATSM and so there has not been much research in this area to date. The idea for this project stems from our work in the cancer field where we have been evaluating copper complexes as potential anticancer agents. Using new approaches that our group designed, we have synthesized and characterized a large number of copper complexes similar to CuATSM. We have found some complexes that have a much higher activity against cancer cells than non-cancer cells (i.e., a large therapeutic window). It is believed that this activity stems from the ability of copper complexes to enter cells and release copper inside them. Copper complexes are designed so that they release copper in stressed cells (like cancer cells or ALS affected cells) but not in normal healthy cells. Thus, they selectively target copper delivery to either cancer cells or ALS-affected cells, but the outcomes are opposite. Cancer cells have plenty of copper to start with and die due to excess copper, whereas ALS neurons appear to be copper-deficient and have many proteins inside them that need copper to function properly, so they are rescued and protected by the delivery of copper. Our vision for this project is to develop new copper complexes that greatly improve upon CuATSM and are optimized for the following features: (1) highly selective delivery of copper to ALS-affected cells, which should provide improved activity with minimal side effects; (2) ability to reach the brain and spinal cord where they need to be; (3) oral bioavailability so they can be taken as a daily pill; (4) new complexes that can be patented, so that pharmaceutical companies will want to license them or partner with us to pursue clinical trials; and (5) a well-defined mechanism of action to help move them quickly through regulatory approvals. We propose to also develop a version of this complex made with a radioactive form of copper (64Cu). This can be used as an imaging agent and biomarker that might predict which persons with ALS are most likely to respond to this therapy. Those patients with uptake of the radiolabeled copper complex in certain regions of their brain (which can be detected by standard PET scanning) would be good candidates for treatment with the (non-radioactive) daily pill version of the copper complex. Those patients who did not show brain uptake in the biomarker scan would avoid undergoing a therapy unlikely to benefit them and could seek alternative treatment options. Our project is at an early stage of development, but we wa
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310773
Entities
People
- Levi Beverly
Organizations
- United States Army
- University of Louisville