Prana Details Data Showing that PBT2 Reduces Cognitive Impairment Caused by Tau Protein Accumulation
Summary of new data presented at the 11th International Conference on Alzheimer’s and Parkinson’s Disease
Melbourne – 8th March, 2013 Prana Biotechnology (NASDAQ:PRAN; ASX:PBT). Following on from the announcement released on 4th March, 2013 and at the request of the Australian Securities Exchange, the company is pleased to provide further detail in respect to the presentation of the new data demonstrating the ability of PBT2 to reduce the damage to brain cells, caused by the accumulation of the tau protein and preventing subsequent cognitive impairment.
The data was generated in an animal model that over produces the tau protein giving rise to ‘tangle like’ inclusions similar to those which cause neuronal death in Alzheimer’s disease (AD). Importantly, whilst the anti-aggregation effects of PBT2 on Abeta have been well documented1, these results were generated in a model which is independent of the presence of Abeta, indicating that PBT2 has the ability to prevent neuronal damage via multiple metal mediated pathways, including Abeta and tau aggregation.
The data is being presented by Prana scientist Associate Professor Paul Adlard on 9th March 2013 in his presentation entitled, “Metal Chaperones are novel therapeutic agents for tauopathy”.
"These findings provide further evidence that by targeting specific metal imbalances in the brain, PBT2 possesses the ability to ameliorate Alzheimer's pathology in relevant mouse models for both senile plaques and neurofibrillary tangles. This data, in combination with the previously reported Phase IIa clinical trial results2 for PBT2 in Alzheimer's disease further support PBT2 as a potentially promising therapy for this devastating disease", commented Rudy Tanzi, the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard Medical School and Prana’s Chief Scientific Advisor.
Associate Professor Robert Cherny, Prana’s Head of Research commented,”Prana scientists have shown that the Metal Protein Attenuating Compound, PBT2 improves cognitive impairment, Abeta burden and tau hyperphosphorylation in the APP/PS1 transgenic mouse model of AD which overexpresses Abeta1. Recent literature supports the notion that metals modulate the properties of tau and may affect the formation of neurofibrillary tangles (NFTs)3,4,5 which are a feature of several neurodegenerative diseases. In human beings, certain mutations in the gene encoding the tau protein lead to hereditary fronto-temporal dementia (FTD) and Parkinsonism collectively known as tauopathies. Indeed AD itself has been defined as an "Aβ-mediated tauopathy”.
PBT2 is currently in a 12 month Phase II Alzheimer’s disease clinical trial, the IMAGINE trial, which is now fully enrolled and will be completed at the end of the year.
Experimental Methodology 6
The rTg(tauP301L)4510 mouse line is a transgenic mouse model of human tauopathy. From an early age rTg(taup301L)4510 mice display neurofibrillary tangles (NFT) like pathology in the neocortex which progresses into the hippocampus and limbic structures with increasing age. This is manifested biochemically by an age-dependent transition of accumulating tau species from soluble 55 kDa to insoluble hyperphosphorylated 64 kDa. The mice develop significant cognitive impairments from 4 months of age. In our study, rTg(tauP301L)4510 mice (n=10-15/group) were aged to approximately 12 months at which time they were administered either vehicle or PBT2
(30mg/kg) by daily oral gavage for six weeks. Prior to culling and tissue collection the cognitive performance of the animals was examined using a standard test of cognition, the Y-maze. A stereological analysis of NFT burden and neuron number was conducted by histology and other biochemical endpoints assessed by Western blot.
Administration of PBT2 resulted in significant improvement in performance in the Y maze, a significant reduction in the number of NFTs and a significant increase in cortical and hippocampal neurons in the rTg(tauP301L)4510 mouse model. A significant increase in the levels of the PP2A protein (implicated in tau phosphorylation events) in PBT2 treated animals suggest that the drug may directly act upon biochemical pathways which lead to NFT formation as well as any potential interaction with tau itself 4.
1 Adlard P, et al (2008) Rapid restoration of cognition in Alzheimer's transgenic mice with 8- hydroxy quinoline analogs is associated with decreased interstitial Abeta. Neuron 59:43-5510.
2 Lannfelt et al. Safety, efficacy, and biomarker findings of PBT2 in targeting Aβ as a modifying therapy for Alzheimer’s disease: a Phase IIa, double-blind, randomised, placebo-controlled trial. Lancet Neurology (2008) vol. 7, pp. 779-86. Lannfelt et al. Errata: Lancet Neurology (2009) vol. 8, pp. 981.
3 Insook K, et al (2011) Zinc stimulates tau S214 phosphorylation by the activation of Raf/mitogen-activated protein kinase-kinase/extracellular signal-regulated kinase pathway. Neuroreport: 22:839–844.
4 Craddock TJA et al, The Zinc Dyshomeostasis Hypothesis of Alzheimer's Disease. PLoSOne e33552. doi:10.1371/journal.pone.0033552.
5 Xiong et al (2013) Zinc induces protein phosphatase 2A inactivation and tau hyperphosphorylation through Src dependent PP2A (tyrosine 307) phosphorylation. Neurobiol Aging. 34:745-56.
6 Ramsden M et al (2005) Age-Dependent Neurofibrillary Tangle Formation, Neuron Loss, and Memory Impairment in a Mouse Model of Human Tauopathy (P301L). J Neurosci, 25: 10637- 10647.