Oral Presentation 8th Venoms to Drugs 2023

Venom-derived peptide therapeutics for Alzheimer’s disease (#45)

Dorothy C C Wai 1 , Joesph A Nicolazzo 1 , Raymond S Norton 1
  1. Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, 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 only 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 the neuroinflammation observed 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 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.

We have shown 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).6 Given its size and polarity, HsTX1[R14A] likely accesses the brain as a consequence of disruption of the blood-brain barrier (BBB) in this model. Here we 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 disrupted. This work will position HsTX1[R14A] as a novel brain-penetrant drug lead for clinical development.

  1. Li, X., Feng, X., Sun, X., Hou, N., Han, F. & Liu, Y. Front Aging Neurosci 14, 937486 (2022).
  2. Abbott, A. Nature 616, 26-28 (2023).
  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. et al. Proc Natl Acad Sci U S A 118, e2013545118 (2021).
  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. et al. Sci Rep 4, 4509 (2014).
  5. Nicolazzo, J. A., Pan, Y., Di Stefano, I., Choy, K. H. C., Reddiar, S. B., Low, Y. L., Wai, D. C. C., Norton, R. S. & Jin, L. J Pharm Sci 111, 638-647 (2022).
  6. 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. & Nicolazzo, J. A. Neurotherapeutics (2023).