Novel peptide therapeutics for Alzheimer’s disease — ASN Events
  1. Schedule
  2. Poster Session 2 - Wine Tasting
  3. Novel peptide therapeutics for Alzheimer’s disease

Novel peptide therapeutics for Alzheimer’s disease (#377)

Dorothy Wai 1 , Joseph Nicolazzo 1 , Ray Norton 1
  1. Monash Institute of Pharmaceutical Sciences, Monash University, Melbourne, VIC, Australia

Alzheimer’s disease (AD) is an incurable neurodegenerative disease that is the leading cause of dementia worldwide [1]. A key characteristic of AD is the deposition of plaques formed by the amyloid-β (Aβ) peptide. However, despite extensive development efforts, anti-Aβ therapies have shown very modest clinical impact on cognitive decline [2]. Therefore, there remains an urgent and unmet need for novel therapeutics that target different pathological mechanisms in AD. The voltage-gated potassium channel KV1.3 is upregulated in pro-inflammatory microglia that mediate neuroinflammation in AD. KV1.3 blockade has been shown to be therapeutically beneficial in animal models of AD by shifting microglia away from a pro-inflammatory phenotype, reducing neuroinflammation, and improving cognitive function [3].

HsTX1[R14A] is a potent peptide blocker of KV1.3 (IC50 45 pM) that is highly selective (>2000-fold) for KV1.3 over closely-related KV1 channels [4]. We have shown that HsTX1[R14A] reduces microglial activation in vitro and in an animal model of neuroinflammation [5,6]. Compared to other peptide inhibitors of KV1.3, HsTX1[R14A] is more potent and selective for KV1.3, simpler and cheaper to make, and more stable chemically and proteolytically. It thus represents a highly promising molecule for AD therapeutic development.

Our recently published data show that unmodified HsTX1[R14A] at 1 mg/kg is able to improve cognitive function in a mouse model of sporadic AD (the most common form of AD) [7]. Given its size and polarity, HsTX1[R14A] likely accesses the brain as a consequence of blood-brain barrier (BBB) disruption in this model. I will describe our current efforts towards improving the brain uptake of HsTX1[R14A], which will decrease the dose of peptide required and enable treatment before the disease progresses to a stage where the BBB is compromised. This work will position HsTX1[R14A] as a novel brain-penetrant drug lead for further clinical development.

  1. Li, X., Feng, X., Sun, X., Hou, N., Han, F., and Liu, Y. (2022) Front Aging Neurosci 14
  2. Plascencia-Villa, G., and Perry, G. (2020) Int Rev Neurobiol 154, 3-50
  3. Ramesha, S., Rayaprolu, S., Bowen, C. A., Giver, C. R., Bitarafan, S., Nguyen, H. M., Gao, T., Chen, M. J., Nwabueze, N., Dammer, E. B., Engstrom, A. K., Xiao, H., Pennati, A., Seyfried, N. T., Katz, D. J., Galipeiau, J., Wullf, H., Waller, E. K., Wood, L. B., Levey, A. I., and Rangaraju, S. (2021) Proc Natl Acad Sci USA 118, e201354118
  4. Rashid, M. H., Huq, R., Tanner, M. R., Chhabra, S., Khoo, K. K., Estrada, R., Dhawan, V., Chauhan, S., Pennington, M. W., Beeton, C., Kuyacak, S., and Norton, R. S. (2014) Sci Rep 4, 4509-4518
  5. Nicolazzo, J. A., Pan, Y., Di Stefano, I., Choy, K. H. C., Babu Reddiar, S., Low, Y. L., Wai, D. C. C., Norton, R. S., and Jin, L. (2022) J Pharm Sci 111, 638-647
  6. Babu Reddiar, S., Jin, L., Wai, D. C. C., Csoti, A., Panyi, G., Nortons, R. S., and Nicolazzo, J. A. (2021) Toxicon 195, 29-36
  7. Pan, Y., Kagawa, Y., Sun, J., Lucas, D. S. D., Takechi, R., Mamo, J. C. L., Wai, D. C. C., Norton, R. S., Jin, L., and Nicolazzo, J. A. (2023) Neurotherapeutics (doi: 10.1007/s13311-023-01387-z)
#AusPeptide2023