Author: Devon Sheppard Edited by: Inês Barreiros, Emil Fristed
Alzheimer’s Disease (AD) is the most common form of dementia and has terrible consequences for both those affected and their loved ones. But drug development for AD has struggled, and current options remain largely ineffective. Even with an expanding understanding of the root causes of the disease, targeted treatments have not fulfilled their potential therapeutic promise, leading to a desperate need for new treatment modalities. Two shifts in AD drug development have begun happening recently. Firstly, a shift towards therapeutics based in biomolecular development. Secondly, a shift towards the role of inflammation in AD. These two developments are opening up a range of new targets and modalities that could hopefully have a tremendous impact on finding effective treatments for this disease.
Alzheimer’s Disease severely impairs memory, mental health and acuity, and - eventually - bodily function. Based on estimates from Alzheimer’s Disease International, the number of people afflicted with dementia is projected to double to 74.7 million by 2030 , the majority of which are classified as AD. In addition to the personal and familial impact, the social and economic costs are tremendous. AD is in the five leading causes of death in high income nations. Costs of this disease are estimated at £26.3 billion annually in the United Kingdom (UK) alone., There remains a lack of effective AD therapeutics, both clinically available and in development.
Most of our current understanding, and consequently focus of drug development, of AD pathology is based on two specific proteins present in the brain: amyloid-beta (Aβ) and tau. These proteins begin to clump together first into small, soluble multi-protein jumbles, and later into much larger clusters called plaques. The stage at which aggregation of these proteins starts damaging neurons was originally thought to be connected with the observable formation of plaques in the brain. But in 2002, scientists discovered that early neuronal damage and subsequent cognitive decline generally happened before the formation of those larger plaques This suggested that it is the presence of the smaller, soluble protein aggregates of Aβ that are toxic.,  Because of this, the best therapies would need to target these early stages of aggregation and help the brain get rid of soluble Aβ aggregates, without adverse effects impacting neurons or cognitive function.
Despite intensive research and the dire need for effective treatment, there remains a dearth of effective therapeutics on the market and it continues to be a critically important area of research and drug discovery. The vast majority of therapies (99.6%) put into clinical trials between 2002 and 2012 were unsuccessful . The focus over the past decade for therapeutics that have progressed to phase III trial has been almost exclusively on small molecules moderators and have continued with little to no success. This consistently poor outcome in successful drug discovery has led a number of companies, such as the pharmaceutical giant Pfizer, to redirection their research and development away from AD towards disorders where clinical treatments have proven more successful.
The currently clinically available AD drugs are small molecule drugs, Memantine and Tacrine. These drugs work on the chemical neurotransmitter communication system in the brain, specifically the NMDA (a neurotransmitter receptor) or cholinesterase (an enzyme that breaks down neurotransmitter). These are critical for neural communication pathways that become compromised when neurological tissue is damaged or destroyed – a hallmark of AD. When tissue and neurons within the brain die, the production of key elements of communication pathways, including neurotransmitters, are lost. Using drugs to replace the absent elements can alleviate some of the symptoms of their loss, but the destruction of tissue continues. Memantine and Tacrine have been the only clinically available treatment for AD for a number of years. These therapies can, to some degree, alleviate symptoms by compensating for the underlying neuronal loss, but have no direct impact on the disease progression.
A notable class of drugs currently in phase III clinical trials (required to obtain FDA approval) which target the Aβ protein directly, to help the brain remove it, are antibodies - large molecules used by the immune system to recognise infectious agents. Using antibody targeting to boost the brain’s ability to clean itself of the protein toxicity is an approach based on our current understanding of the disease. One of the therapies in phase III clinical trials is Aducanumab, an antibody targeting Aβ, being developed by Biogen Inc with initial discovery by Neurimmune. However, these antibody approaches have not been as promising as initially hoped and what had seemed to be a rational approach to therapeutic intervention, has not delivered the expected results.
There are several fundamental changes occurring within the hunt for AD therapies that are poised to alter the therapeutic landscape significantly and provide new and potentially powerful targets for drug discovery. The first is the major shift in drug discovery and development to biologics, or biotherapies, big molecule drugs based on molecules naturally occurring in normal biology. Secondly, there has been a shift in focus from the role of the Aβ protein to a focus on inflammation in the brain, and its role in tissue destruction.
THE RISE OF THE BIOLOGICS
Biologics, or biotherapeutics, combine the complexity and precision of biological entities with the direct targeting of the pharmaceutical industry. Molecules, often proteins, already serving a specific biological role, can be harnessed and altered functionally for a specific therapeutic purpose. They have transformed the pharmaceutical industry and drug discovery in other therapeutic areas in a number of ways already. They are the fastest growing sector of drug development across the board, with monoclonal antibodies being the largest percentage. The transition to targeted monoclonal antibodies – antibodies produced from a singular source – had tremendous success in a range of rare and difficult to treat illnesses. The ability for antibodies to bind their target with such a high degree of specificity and affinity make them an ideal scaffold for targeted activity.
Humira, a monoclonal antibody produced by AbbVie Pharmaceutical Research & Development, is used to treat rheumatoid arthritis, among a range of other disorders. It is currently the most widely sold drug globally. It is followed by the drug Eylea, a fusion protein combining a region of a growth factor receptor with a human antibody and used in the treatment of diabetic macular oedema (a type of vision loss seen in diabetics). It is not only the commercial success that has changed drug development, but the ability to select therapeutic targets with the precision provided by recombinant protein and antibodies.
A NEW FOCUS ON INFLAMMATION
With the introduction of large-scale genetic analysis in Alzheimer’s (www.alzgene.org), an increased understanding of disease processes has confirmed the role of Aβ while also implicating other systems whose roles are less clear. Included within the genes of significance are those which implicate inflammation in disease progression.
The role of inflammation in disease progression centers on a type of cell within the brain, the microglia, and its active role in inflammation. Microglial cells can be thought of as immune cells of the brain, and play a role in recognition and destruction of infectious material within the central nervous system. TREM2, a protein expressed on the microglial cell surface, recognises proteins known to interact with Aβ. It provides a direct link between the proteins responsible for plaque formation and microglial regulation. Mutations in TREM2, affecting for example its appropriate processing and functioning, are associated with Alzheimer’s progression.
Work from Dr Beth Stevens’ group at Harvard Medical School has shown how loss of synapses, the connections between neurons, through microglial activity are required for diseases development in a mouse model of Alzheimer’s disease.  Another microglial cell surface protein, CR1, has been shown to contribute to Alzheimer’s Disease risk. The CR1 protein recognises a part of the immune system that attaches to and labels tissue for destruction by microglia.
As pieces of the cellular machinery required for effective microglial activation and response to inflammation are being identified and understood functionally as part of a bigger protein complex, the ‘inflammasome’, new targets are emerging. One of the newest targets, Nlpr3, a crucial component of the inflammasome, plays a critical role in the formation of the complex that activates proinflammatory genes and switches cells towards a state of activation. Michael Heneka from the German Center for Neurodegenerative Diseases and Eicke Lat at University of Bonn, observed that lack of Nlpr3 suppressed disease progression in a mouse model of Alzheimer’s Disease. Heneka has founded IFM Therapeutics to pursue the inflammasome and Nlpr3 as targets for drug development. The Dementia Consortium has also joined researchers at The University of Manchester with MRC Technology Centre for Therapeutics Discovery to target Nlpr3 in the inflammasome for inhibition.
THE FUTURE OF AD DRUGS
While therapies targeting Aβ directly have yet to show significant therapeutic value, targeting inflammatory processes that play a significant role in early tissue destruction may be a key to successful drug development. In the search for new therapeutics and translational research the new momentum in drug discovery has included a shift towards biotherapeutics. The identification of these completely novel putative targets and systems would not be possible without the broad scope of academic investigation, such as the shift in focus towards neuroinflammation. Biologics, even more so than small molecule approaches, often have a foundation in collaborative efforts between academia and industry. For example, Humira was developed by Cambridge Antibody Technologies, with efforts from the Medical Research Council, Australian company Peptech, and Cambridge professor Sir Greg Winter. Couple that with the clinical focus in the pharmaceutical industry and initiatives like The Dementia Consortium and we might be on our way to create a more promising pipeline to bring effective therapeutics to those who need them, as efficiently as possible. In total, the Dementia Consortium, UK Dementia Research Institute, and Drug Discovery Alliance have combined the efforts of seven academic institutions, eight pharmaceutical industries, and two different research charities towards the identification and translational efforts towards new therapies for AD.,, It is believed that the combination of a focus on the role of inflammation in early processes and the pursuit of novel biologics will hold the key to answering yes to the possibility of new drugs for Alzheimer’s Disease.
 ( https://www.alz.co.uk/research/world-report-2016)
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