A biomarker is any biological indicator that doctors or researchers can objectively measure and evaluate to determine an individual’s health.
Examples of common biomarkers include body temperature and heart rate, a mutated gene or brain and spinal cord images obtained through imaging techniques such as MRI.
Because of the difficulties in pinpointing the causes of ALS, and because diagnoses typically are made after symptom onset (when damage already has occurred), there is an urgent need for biomarkers in ALS. Several types are needed: diagnostic biomarkers that can indicate the presence of the disease early on; prognostic indicators that are able to indicate its progression; predictive biomarkers that can tell physicians or researchers whether, or how well, an individual is likely to respond to a proposed therapy; and pharmacodynamic biomarkers that indicate how a drug behaves in the body.
Biomarkers in drug development
In drug development, biomarkers can help determine patient selection criteria for clinical trial eligibility; ensure that randomized study groups within a trial are similar in makeup; provide quick indicators about the experimental treatment’s activity and effects; and help researchers determine the most appropriate dose.
Biomarkers’ greatest impact, however, lies in:
- helping drug development teams confirm that an experimental therapeutic reaches selected targets within the body and produces the desired response; and
- providing a robust and reliable indication that an experimental drug is likely to work, thus making it more attractive to pharmaceutical companies to move the therapeutic to market.
Ideally, biomarkers must demonstrate solid accuracy and consistency in measurement, both within a single individual and across a group of individuals.
They should demonstrate a clear link either to ALS, a potential ALS therapeutic or both. A relatively easy method should exist for clinicians or researchers to take samples needed for measurement. Other considerations include expense, data turnaround time and standardization across a disease.
Although the biomarkers currently in use for ALS do not yet meet all these criteria, they nonetheless provide useful information to researchers and physicians.
Mutations in genes associated with familial forms of ALS include the SOD1, TDP43, FUS, FIG4 and VAPB genes, among others. Generally (but not always) if a person has a particular mutation in one of these genes, he or she has a high likelihood of developing ALS.
MDA grantee Kamal Sharma, associate professor in the department of neurobiology at the University of Chicago, and colleagues currently are studying a potential biomarker — a cell called a V2a neuron — to determine its correlation with onset and severity of ALS.
With MDA support, Michael Benatar, associate professor of neurology and epidemiology at Emory University in Atlanta, has been researching the early stage (prior to symptom onset) of familial, or inherited, ALS, working with individuals with an SOD1 mutation. Benatar’s team has collected physical, functional and neurological data over time in an effort to discern biomarkers of the disease process. Additional studies with individuals with mutations in other ALS-associated genes such as TDP43 and FUS are under way.
The MDA-supported ALS Therapy Development Institute (ALS TDI) in Cambridge, Mass., is seeking biomarkers to use specifically in conjunction with its lead experimental drug candidate, ALSTDI-00846, which is designed to act on a specific immune system pathway.
ALS TDI has collected approximately 600 blood samples from ALS patients since 2007 and has found that approximately half have biomarkers indicating upregulation (increased activity) of the immune system pathway targeted by ALSTDI-00846.
In the future, biomarkers are poised to play a critical role in personalized medicine, in which treatments are created based on an individual’s specific physiological and genetic makeup.
Now and in the near future, biomarkers will help speed the pace of basic and translational research, and facilitate the ultimate goal: the development of safe and effective therapies for ALS.