Pathway-driven identification of therapeutic targets for combatting Alzheimer's disease.

Lead Research Organisation: King's College London
Department Name: Inst of Psychiatry School Offices

Abstract

The suffering and financial burden associated with Alzheimer's disease are so great due to the protracted nature of the disease. Beginning with problems remembering things, it progresses through an inability to recognise ones family and friends and to carry out daily tasks, leading to sufferers becoming completely dependent on others, bedridden, and eventually dying often up to 10 years after diagnosis due to pneumonia or other common infections. We have no effective treatment for this insidious disease! Mutations in the APP gene cause the familial or inherited form of Alzheimer's disease. The mutations cause the brain to make more of a substance called beta-amyloid, which aggregates into deposits to form senile plaques. There is growing evidence that these plaques are probably a marker of the disease rather than the cause, even a way for the brain to protect itself from the "soluble", toxic form of beta-amyloid.
Our nerve cells make connections with each other called synapses, through which they communicate and store information. These connections are the basis of how we learn and remember. Among the many toxic effects of beta-amyloid, one of the earliest and most important is its ability to break down the connections between nerve cells: Beta amyloid is said to be synaptotoxic. Very recently we have discovered the "signaling pathway" activated by beta-amyloid in nerve cells, and in the brains of sufferers, that causes several of the characteristic features of the disease, including the loss of synapses. This pathway is called the wnt-planar cell polarity (wnt-PCP) pathway. Quite remarkably, another lab have just discovered that the protein made by the APP gene, from which beta-amyloid is also made (by being cut up into small pieces), is a part of the receptor found on the surface of nerve cells that drives the wnt-PCP pathway. This means that the beta-amyloid "toxicity" pathway we have discovered is controlled by the actions of APP, a gene responsible for the inherited form of Alzheimer's disease. This represents a major breakthrough in our understanding of the disease. We now want to explore this pathway in great detail for two reasons. One, it will tell us a much more about the mechanism driving the disease in the brains of people with the disease. Secondly, by understanding the mechanism and knowing what each component does in it we will be able to work out how to block the processes and slow down, or even halt, the disease. It is only by understanding the mechanism we will be able to identify new therapeutic targets and be able to begin the process of finding drugs that work effectively on them. We propose a project of work to achieve this over the next 3.5 years. We have three lines of "attack". One, we will use a novel peptide array technology to rapidly and cost effectively "map" how specific components in this pathway interact, or bind, with one another, including APP and beta-amyloid. This technique enables us to make small peptides (bits of proteins) that can block these interactions. Two, we will use these peptides and other techniques to work out what each component does in the signaling pathway, in nerve cells, including working out exactly how beta-amyloid exerts its effects on nerve cell connections. Three, having achieved this we will be in the position to determine exactly where the disease mechanism should be attacked in order to prevent the crucial synaptotoxic effects of beta-amyloid. The peptides we will have generated to help identify the best targets will then be used to generate "binding assays" which can be then be optimised for future drug screening purposes aimed at finding drugs that act in the desired way upon the target. All such drug screening activities will be undertaken follow on from this, and will be dependent upon our obtaining further funding to do so.

Technical Summary

Our aim is to gain a better understanding of the signaling mechanisms driving beta-amyloid neurotoxicity, to identify effective and tractable novel therapeutic targets in the pathway and to develop assays suitable for future high throughput screening ready to identify small molecules acting on them. We are in a unique position to do this following our discoveries concerning the pathway activated by beta-amyloid, which mediates its neurotoxic properties including; tau phosphorylation, neuronal death, synaptotoxicity and, in vivo, cognitive impairment. This pathway, the wnt-Planar Cell Polarity (wnt-PCP) pathway, is also detectable in the Alzheimer's disease (AD) brain. Of major significance for our understanding of AD pathology, the beta-amyloid precursor protein (APP), from which beta-amyloid is derived, has been identified as a necessary component of the wnt-PCP pathway where it is needed to drive it through recruitment of Abl: Thus, the beta-amyloid induction of wnt-PCP signaling is APP-dependent! Our understanding of the pathway will now enable us to decipher it further and more fully define the roles of APP and beta-amyloid within it. We will employ a range of techniques in cell lines and neurons, and validate findings in tissues from animal models and man. In the process we will identify novel, apt therapeutic targets through which to target the disease. Our adoption of peptide array technology to rapidly and accurately map specific protein-protein interactions, will not only help pathway elucidation but will also generate binding peptides, with which, and their binding partner proteins, we will generate assay suitable for future high throughput screening. Thus at the end of this project we will be in good position to commence small molecule identification with a battery of neuron based assays in place ready to evaluate active compounds. Such undertakings will, of course, be dependent on our obtaining further funding.

Planned Impact

In the long term this project is predicated on potential benefit to the general public and the health services through identification of novel therapeutic targets and hence effective therapeutics.
In the medium term the wider beneficiaries include the academic community, both those in our immediate groups and our collaborators but also further afield who will benefit from the data and reagents/tools we will generate.
We have also established collaboration with Astra Zeneca relevant to, but not part of, the current proposal. We have a memorandum of understanding and confidentiality agreement with AZ whereby we propose to co-develop therapeutics based on our early understanding of the pathway we have identified.
One manifestation of this close and growing collaboration is an MRC CASE studentship jointly supervised by Lovestone for KCL and Mene Pangalos for Astra Zeneca where we are transferring all our in vitro experiments that led to the identification of the pathway we are investigating to human neurons derived from induced pluripotent stem cells.
The further work to derive therapeutic targets from the current proposal will strengthen our links with Astra Zeneca and in turn the resources that AZ have already committed and will further consider, will enable rapid application of translational elements of this proposal.

Publications

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Sellers KJ (2018) Amyloid ß synaptotoxicity is Wnt-PCP dependent and blocked by fasudil. in Alzheimer's & dementia : the journal of the Alzheimer's Association

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Troakes C (2017) Clusterin expression is upregulated following acute head injury and localizes to astrocytes in old head injury. in Neuropathology : official journal of the Japanese Society of Neuropathology

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Khan A (2023) Masking the transmembrane region of the amyloid ß precursor protein as a safe means to lower amyloid ß production in Alzheimer's & Dementia: Translational Research & Clinical Interventions

 
Description ARUK Pilot scheme
Amount £49,969 (GBP)
Funding ID ARUK-PPG2015B-8 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2015 
End 10/2016
 
Description PhD studentships
Amount £109,550 (GBP)
Funding ID ARUK-PhD2016-4 
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2016 
End 09/2019
 
Description KCL SEEK Joint venture 
Organisation PepTcell Ltd
Country United Kingdom 
Sector Private 
PI Contribution SEEK are a company who specialize in repositioning drugs and making novel formulation there of. KCL and SEEK have signed a joint venture agreement around a number of drugs, one of which is fasudil. The inclusion of fasudil was entirely enabled by the MRC project award to myself.
Collaborator Contribution The partners are to develop a novel oral formulation of fasudil. This should enable IP to be obtained around it for the treatment of Alzheimer's disease. The IP will be joint help by KCL and SEEK.
Impact The agreement was signed off only this week, on 10/2/200. The development of the oral formulation has now to commence.
Start Year 2020
 
Title Clinical trial commencing 
Description We are very excited and pleased to announce that our proposed Phase IIa clinical trial of Fasudil has now received full approval and recruitment of subjects into the trial will begin next month, April 2024. The funding we obtained to conduct this trial was primarily awarded based on the preclinical data we obtained with UKRI-MRC support, i.e., this award. The trial ID is EU CT no.:2023-506514-44-00. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2024
Development Status Under active development/distribution
Clinical Trial? Yes
UKCRN/ISCTN Identifier EU CT no.: 2023-506514-44-00 N.B., this ID number gas been assigned to the trail by EU authorities and will become active in April.
Impact Fasudil is marketed as an injectable for the treatment of brain hemorrhage. For this phase IIa trial we have generated an oral form of the drug. Thus should the drug prove effective for early stage Alzheimer's disease we shall me in an advantageous position ready to go into large scale production of the drug as an oral, for further trials and in the longer term as a prescription treatment. 
 
Title Funding for a Phase 11a Clinical Trial of fasudil 
Description On the basis of data obtained by the MRC award we have now obtained two lots of funding to conduct a phase 11a clinical trial of fasudil in an AD population. The first award of £1.5M was made in December (2019) to PI Prof Dag Aarsland. A second award of £2.3M was made in 2020 from the ADDF to PI Professor Ballard. Now Aarsland, Ballard and myself are seeking approval from the MHRA to administer fasudil orally for 12 months. Once approval is obtained recruitment for the trial will commence. The trail is to be conducted at three centers, King's College Hospital, Exeter, and Norway. We have now had encouraging meetings with the MHRA and are now having the drug synthesized, formulated as an oral and matching placebo manufactured by Patheon. Once these are ready we shall seek formal approval for the trail and recruitment will commence. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2021
Development Status Under active development/distribution
Impact Related to this I, via King's, have drawn up an agreement with SEEK pharma for them to develop a novel, propriety, oral formulation of the drug fasudil. Fasudil is off patent. It is hoped this novel formulation will enable KCL and SEEK to obtain IP for its further development and use as a treatment for Alzheimer's disease. 
 
Description AAIC conference oral presentation 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact An oral presentation on the work funded by this award was given by Dr Marcahant to the AAIC, July 2016, held in Toronto. The talk received considerable attention and lead to further collaborative work, now on going.
Year(s) Of Engagement Activity 2016
 
Description AlzForum coverage 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact Our work on Fasudil was covered on the Alzforum web site and there was commented on by a number of others working on AD.
Year(s) Of Engagement Activity 2018
URL https://www.alzforum.org/news/research-news/does-app-promote-synapse-loss-av-production-through-wnt-...
 
Description Newspapers 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Our publication in Translational Psychiatry was pick up on in several Newspapers both in print and on line, Including a quarter page in the Times, and coverage in The Daily Mail, and the Independent.
Year(s) Of Engagement Activity 2018
URL https://www.thetimes.co.uk/article/hope-for-alzheimer-s-drugs-after-discovery-of-brain-s-vicious-cyc...
 
Description Patient and Public Input group meeting. 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact I presented our work concerning Fasudil and the potential it holds as a treatment for Alzheimer's disease to Biomedical Research Centre dementia theme Patient and Public Input group meeting. They were exceptionally interested to hear about our recent findings and our on going efforts to seek funding to enable us to conduct a Phase IIa clinical trial of fasudil for AD.
Year(s) Of Engagement Activity 2018
 
Description Radio 4 Live appearnace 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Upon the publication of our report in Translational Psychiatry I was invited to the BBC for a live interview on The Today Programme, on BBC Radio 4, where I was asked about and discussed the potential of repositioning Fasudil as a treatment for Alzheimer's disease based on our findings in mice and rats.
Year(s) Of Engagement Activity 2018
URL https://www.bbc.co.uk/radio/play/b0bk1c4b