A novel approach to the therapy of Alzheimer's disease based on peptide nanoliposome inhibitors of Aβ and tau aggregation

Allsop, David and Taylor, Mark Neville and Fullwood, Nigel James and Michael, Maria and Aggidis, Anthony and Vincent, Shoona and Dale, Mark (2017) A novel approach to the therapy of Alzheimer's disease based on peptide nanoliposome inhibitors of Aβ and tau aggregation. Journal of Prevention of Alzheimer's Disease, 4 (4). pp. 385-386. ISSN 2426-0266

Abstract

Introduction: Considerable advances have been made over the last 30 years in understanding the neuropathology, biochemistry and genetics of Alzheimer’s disease (AD). Disappointingly, there are only five approved drugs that treat the symptoms of AD. Many of the new drugs in development aim to modify the disease process itself, by impacting one or more of the many wide-ranging brain changes that AD causes. Many disease modifying drugs have failed in clinical trials. These drugs have been targeted mainly at Aβ and consist of inhibitors of β-secretase or γ-secretase, which block Aβ production, or immunotherapy based on antibodies to Aβ, which results in clearance of plaque amyloid from the brain. These drugs have run into various problems including mechanism-based side effects (e.g. secretase inhibitors) and vasogenic oedema and micro-haemorrhages in the brain (the immunotherapy approach). Moreover, these drugs were probably given too late during the course of AD, when damage to the brain is likely to be irreversible. There have been relatively few selective and potent inhibitors of Aβ and/or tau aggregation in clinical trials. Methods: Our proposed therapeutic candidates consist of modified peptides that inhibit the aggregation of either Aβ or tau attached covalently to the surface of nanoliposomes which are composed of cholesterol and sphingomyelin. They also contain a PEGylated lipid which has a maleimide group for covalent linkage to a thiol group (cysteine residue) on the peptide. The external surface of these liposomes is therefore decorated with multiple copies of the peptide. The peptide developed against Aβ aggregation is retro-inverted (D-amino acids, with sequence reversal) and so is stable against proteolysis [1]. This retro-inverted peptide is linked to a ‘TAT’ sequence for targeting to the brain and for intracellular drug delivery [2]. Similar types of peptide-liposome system are under development for the inhibition of tau and combination inhibition of Aβ/tau aggregation. Results: Our inhibitory peptides bind with high affinity to Aβ and prevent its assembly into oligomers and fibrils, as demonstrated by several different in vitro and in vivo experimental systems [1-4]. Very low concentrations of the inhibitory peptide are required to reduce the aggregation of Aβ when the peptide inhibitor is attached to liposomes [3]. The peptide-liposomes rescue cultured neuronal cells from the toxic effects of pre-aggregated Aβ, cross a BBB cell model, enter the brains of normal C57/BL6 mice, and protect against memory loss in the APPSWE transgenic mouse model [3]. The peptide-liposomes also reduce amyloid plaque load by ~30% when injected peripherally (once per day, over 21 days) into transgenic APPSWE/PS1ΔE9 mice, or into APPSWE mice. Electron microscope studies show that the liposome-peptide captures Aβ and binds to the free ends of Aβ fibrils, apparently terminating fibril growth [4]. The peptides have no effect on cytochrome P450 drug metabolizing enzymes, and the peptide-liposomes are non-toxic to cultured cells. In the case of the tau-directed peptides, they inhibit the formation of tau fibrils in an in vitro aggregation assay and have the potential to be developed along similar lines to the Aβ inhibitors. Conclusions: Secretase inhibitors for Aβ, and immunotherapy for Aβ and tau, are already in the advanced stages of development/clinical trials. Our approach is different to this and specifically targets the very early stages of aggregation of these molecules. Multiple inhibitory peptides attached to the liposome surface create a potent, multivalent inhibitor that can cross the BBB and prevent oligomer and fibril formation. In the case of Aβ, we have shown that our peptide-liposomes are potent inhibitors of oligomer formation, and this is seldom clear for other drugs. Moreover, our peptide-liposomes hide from the immune system, and so should not invoke an undesirable pro-inflammatory response. Liposomes can be derivatized with multiple different peptides so that they are directed against more than one therapeutic target. Importantly, there is increasing recognition that combination therapies may be warranted to address the complex biology of AD and our development allows for Aβ or tau peptide inhibitors alone or in combination to be attached to the surface of the same population of liposomes, resulting in a therapeutic with dual action against plaques and tangles. If the development of our inhibitory peptides, either attached independently to different liposomes or in combination, are successful, we must rethink and revise the FDA and EMA guidance on developing drugs for early stage AD. [1] Taylor M., et al. (2010) Biochemistry 49, 3261–3272; [2] Parthsarathy V., et al. (2013) PLoS ONE 2013;8(1): e54769; [3]. Gregori M., et al. (2017) Nanomed: Nanotech. Biol. Med. 13, 723-732; [4]. Sherer M., et al. (2015) Journal of Physics: Conference Series 644, 012040, 10.1088/1742-6596/644/1/012040.