Peptide Inhibitors Targeting Sodium Channels to Treat Amyotrophic Lateral Sclerosis
Abstract
Novel peptidic ion channel inhibitors derived from spider venoms are an emerging class of drugs to treat complex neurological disorders. Their unique ion channel subtype selectivity and high potency make superior drugs compared to commonly used small molecule drugs, including Riluzole. Riluzole is currently used in the treatment of Amyotrophic Lateral Sclerosis (ALS) and is the only drug capable of extending the lives of people affected by this devastating disease. Because our novel NaV inhibitors can selectively target sodium channels (NaV) subtypes in motor neurons, they are able to reverse motor neuron hyperexcitability linked to the early onset and progression of ALS and common pathological mechanism in all types of ALS while maintaining the normal function of vital organs such as the heart and the skeletal muscles. This way, these spider venom-derived NaV inhibitors are safer drugs that can be administrated at doses to rich their maximum benefit to ALS patients. Riluzole, conversely, is also an ion channel inhibitor targeting a broader range of ion channels, and, therefore, its therapeutic efficacy is impeded by poor therapeutic index and high risks of serious side effects. Besides ALS, these novel NaV inhibitors can treat a range complex neurological disorders where hyperexcitability of neurons is associated to initiation and progression of disease. Beneficial therapeutic effects with low to nil side effects are an important aspect of our drug development strategy. Therefore, we have opted to initially administrate our ALS selective peptide NaV inhibitors via injection in the spinal canal hoping to accelerate its transition into clinical trials. Further research is being undertaken to develop small molecule derivatives displaying the same therapeutic benefits which will be available for oral administration in the future. Our research is developing drugs that will benefit both types of ALS patients, familial and sporadic, as the disease mechanisms targeted by our drugs are common in both types of ALS. More specifically, the peptide inhibitors we are designing can reverse the hyperexcitability of motoneurons, which is characteristic of the early onset of ALS and occurs before the neurodegeneration is established, which persists during the progression of this disease. Such motor neuron hyperexcitability is also observed in preclinical models of ALS, which facilitates the preclinical relevance and development of useful leads for clinical trials. Furthermore, we are focusing on biomarkers demonstrating the reduction of hyperexcitability in neurons, which is well established by members of our proposed research team. If funded, this research proposal will expedite the transition of our novel ALS selective peptide NaV inhibitors from preclinical to clinical trials, as we have already identified a peptide lead with proved therapeutic efficacy in a preclinical model of motor neurodegeneration in zebrafish, and in rodent motor neurons ex vivo preparations in which our drug lead was able to reverse hyperexcitability to normal neuronal function. We project that at the end of this proposed research project in 2025, we will have lead candidates available to initiate clinical trials. Additionally, this proposal will fill a major gap in applying naturally occurring NaV inhibitors and optimized derivatives in research for novel drugs to treat ALS. If funded, this proposal will provide a pathway for the development of other related drugs using a similar strategy by targeting ion channels in motor neurons to reverse ALS. Research in novel ion channels inhibitors derived from spider venoms is rapidly expanding and benefiting from modern scientific methods to investigate and develop such peptide inhibitors into useful drugs. Our research team is composed of experts in the scientific methods required for this research, and we have direct access to the instrumentation required to execute this state-of-the-art resear
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310146
Entities
People
- Fernanda Cardoso
Organizations
- United States Army
- University of Queensland