Enhancing ACMSD Activity as a Novel Gene Therapy for ALS
Abstract
Our understanding of the molecular mechanisms of what causes neuronal cells to die in ALS is incomplete. It is likely that we are looking at multiple disease processes that eventually lead to one common downstream effect that results in ALS. To that end, our research focuses on the lowest hanging fruit in therapeutic development, the study of common pathways. The kynurenine (KYN) pathway is a normal, albeit complex, cellular pathway, vital for the metabolism of tryptophan, which is an essential amino acid. The pathway includes a branch responsible for both the production of the neuroprotective compound picolinic acid (PIC) as well as the neurotoxin quinolinic acid (QUIN). In healthy conditions, this pathway exists in a balanced equilibrium, however, during disease the balance of the pathway can shift, resulting in a proportional increase of QUIN relative to PIC. This type of change has been detected in Lou Gehrig s disease (ALS) as well as in numerous neurodegenerative diseases such as Parkinson s (PD), Alzheimer s (AD), Huntington s (HD). Based on such data we evaluated key intervention points in the disease and noted that one step, modulated by the protein ACMSD, gears the pathway either towards increased production of PIC (high ACMSD) or QUIN (low ACMSD) with the resultant effect on the cellular milieu. Thus, we propose that if we were able to control ACMSD levels that we should be able to control this crucial step of the KYN pathway and thus provide a cellular environment that protects neurons from dying. In parallel/pilot studies we have tested the efficacy of this new therapeutic idea in animal models of PD, AD, and HD. In every model, we observed the expected therapeutic effect, observing reduced inflammation and neuronal protection. Consequently, we here propose to do the analogous study in a mouse model of ALS. We plan to use gene therapy, using viral vectors especially engineered in our lab to target specific cells of the brain and spinal cord. We will pair the vectors with the new method of subpial delivery to the spinal cord, to assess the therapeutic potential of gene-therapy-mediated increased of ACSMD in a mouse model of ALS. Following vector delivery, we will assess if motor function and survival of the mice are improved. In addition, we will conduct a number of postmortem studies to assess the health of neurons and the overall extracellular environment as it relates to inflammation and activity of the KYN pathway. The scientific team is centered around the Barrow Neurological Institute, a world-leading center for ALS clinical trials, accordingly the team stands poised to rapidly pursue a clinical trial path for all forms of ALS following the successful execution of these studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310985
Entities
People
- Fredric Manfredsson
Organizations
- United States Army