21 September 2018
Dementia is the most common manifestation of neurodegeneration and will newly affect an estimated 225,000 people in the UK this year – roughly equivalent to one new diagnosis every three minutes. Dementia is not a disease itself, but refers to the cognitive decline and behavioural changes that can occur in neurodegenerative conditions such as Alzheimer's, Parkinson's and Huntington’s.
With the UK annual economic cost of dementia estimated to be £23 billion and growing (almost equalling the combined costs of cancer, heart disease and stroke), the need for disease-modifying treatments has never been more pressing. However, effective therapies for neurodegeneration remain something of an enigma.
Exploring the use of genomic technologies to understand these diseases and develop new therapeutic approaches is an area of increasing interest.
As the word suggests, neurodegeneration involves the gradual destruction of neurons within the central nervous system. Neurodegenerative diseases encompass hundreds of progressive, disabling and largely incurable conditions including some rare diseases and metabolic disorders, most of which occur in the later stages of life. In the vast majority of cases, currently available drugs can modestly slow disease progression and offer symptomatic relief, but cannot halt or reverse neurodegeneration.
Many rare neurodegenerative diseases are caused by known genetic mutations, and these tend to have an earlier age of onset and a strong family history component. The underlying causes of more common neurodegenerative diseases, such as Alzheimer's, are far more complex and less well understood. In most of the diseases that cause dementia, we know that accumulation of abnormal proteins within and/or around neurons and localised inflammation lead to neuronal damage, but we do not know what triggers this process. Although genetic factors contribute significantly to disease risk, most of these are common or unknown susceptibility genes which have only a small impact on risk individually, but which may interact with each other and with environmental factors to cumulatively increase predisposition to disease. Most lifestyle and environmental factors associated with dementia, such as smoking and physical inactivity, are non-specific and common to other conditions such as cancer and cardiovascular disease.
The most significant barrier to using genomics in the context of neurodegenerative disease is this lack of specific genetic biomarkers for the more common conditions. However, as researchers identify new susceptibility genes, the potential for a number of clinical applications is raised, including:
Risk prediction and personalised prevention – a better understanding of the contribution of genetic and lifestyle factors to disease susceptibility may make it possible to develop accurate risk prediction tools.If those individuals most susceptible to neurodegenerative disease can be identified, they could be offered personalised support for health behaviour change and gain early access to interventions that prevent or delay progression of neurodegeneration.
Diagnostic and prognostic investigations – Genetic testing for neurodegenerative diseases is currently only carried out in early-onset cases or where there is a strong family history of a particular condition. With more specific genetic biomarkers, clinicians would be better equipped to refine diagnoses (such as to identify the underlying diseases in dementia), and provide better prognostic information to patients, more accurately predicting the onset and/or progression of the disease and how it may respond to available treatments. Incorporating the factors that can affect age of disease onset into clinical investigations (such as the DNA repair genes implicated in Huntington’s disease) may improve the relative benefits of genetic testing for incurable diseases, for instance by informing a patient’s reproductive choices.
Development of targeted therapies – Genes and their encoded proteins are attractive targets for novel molecular and pharmacological therapies, which could be designed to specifically disrupt the dysfunctional cellular processes involved in neurodegeneration. Where disease-causing genetic mutations are known, molecular therapies that harness the potential of gene editing techniques might be used to edit/delete disease-causing genes or insert functional genes into cells.
Our understanding of the genetic basis of many neurodegenerative diseases remains incomplete, and it is too early to consider routinely using genomics for prediction, diagnosis or guiding clinical decision-making. Until research generates more specific genetic biomarkers for common and complex conditions, the greatest health impacts will be achieved through the development of effective treatments for the rare inherited diseases caused by genetic mutations that are already known.
Biotechnology and pharmaceutical companies are already making progress in designing effective molecular therapies for rare neurodegenerative diseases, which are already in clinical use in the EU and US for a type of spinal muscular atrophy and in ongoing trials for metachromatic leukodystrophy. Similar therapies for genes associated with Parkinson's disease, Alzheimer's disease, motor neurone disease and frontotemporal dementia are in early stages of development or early phase clinical trials. One recent highly-publicised breakthrough is a molecular therapy for Huntington’s disease that suppresses production of the huntingtin protein, and has caused no drug-related adverse effects in ongoing clinical trials.
With over 100 ongoing clinical trials for Alzheimer's disease alone and clear support from the UK government for understanding and developing effective treatments for dementia, complex neurodegenerative diseases remain a very active area of research.
Continued success of molecular therapies for neurodegenerative diseases will depend on better identifying suitable therapeutic targets, ensuring patient safety with regard to drug delivery and adverse effects, and collecting evidence of long-term effectiveness.
Despite considerable research activity, efforts to develop effective treatments for the most common neurodegenerative conditions such as Alzheimer's disease have, to date, been largely unsuccessful. Recent clinical trials of a promising drug designed to prevent amyloid protein deposition in the brain were halted prematurely, owing to lack of demonstrable patient benefit. However, with over 100 ongoing clinical trials for Alzheimer's disease alone and clear support from the UK government for understanding and developing effective treatments for dementia, complex neurodegenerative diseases remain a very active area of research. Understanding the underlying mechanisms of disease is the first step towards developing effective treatments, and one in which genomics has the potential to make a significant contribution.