Two New ALS Biomarkers in the Pipeline

April 07, 2017

Two different potential biomarkers for amyotrophic lateral sclerosis (ALS) have been identified, which it's hoped will help stratify patients and guide clinical trials of new therapies.

One biomarker — known as p75 — can be measured in the urine and so is an easy, convenient test. It is applicable to all types of ALS. The other — known as poly(GP) protein — is measured in the cerebrospinal fluid (CSF), so is not as convenient. It is applicable only to one genetic subtype of the disease that accounts for about 10% of all ALS cases.

The p75 biomarker is described by a team led by Stephanie R. Shepheard, PhD, Flinders Medical Center, Adelaide, Australia, in a paper in the March 21 issue of Neurology.

The poly(GP) protein is reported in a paper in the March 29 issue of Science Translational Medicine, with lead author Tania F. Gendron, PhD, Mayo Clinic, Jacksonville, Florida.

In the Neurology paper, Dr Shepheard et al write that: "Frustration over the continued failure of…ALS clinical trials and the absence of therapeutic options for this fatal disease has fueled interest in the prospect that biomarkers may hold great promise for advancing therapy development efforts.

"Prognostic biomarkers, which aid in predicting the future course of disease, might be used to identify more homogeneous subsets of patients at the time of trial enrollment. Pharmacodynamic biomarkers, which have the potential to show that a biological response has occurred in a patient who has received an experimental therapeutic, may help in assessing the efficacy of drugs," they write. "Disease progression biomarkers (i.e., those that show a change over time as disease advances) may also serve as markers of pharmacodynamic effect."

They note that the cytoskeletal proteins neurofilament light and phosphorylated neurofilament heavy are showing promise as prognostic markers and potential pharmacodynamics biomarkers, but they do not reflect disease progression.

p75: Biomarker of Motor Neuron Degeneration

In searching for a suitable candidate as a marker of disease progression, they have focused on the common neurotrophin receptor (p75) as a biomarker of motor neuron degeneration.

They point out that the extracellular domain of p75 (p75 ECD) is present at elevated levels in the urine of patients with ALS compared with healthy individuals and that urinary p75 increases in a mouse model of the disease.

In the current study, they measured urinary p75 ECD  levels in 45 healthy controls and 54 patients with ALS, 31 of whom were sampled longitudinally.

Results showed that levels of p75 ECD increased gradually in patients with ALS as their disease progressed over a 2-year study period and that those who began the study with lower levels of urinary p75 ECD survived longer than patients who had higher levels of the protein initially, suggesting that it could be a prognostic marker of the disease.

The researchers explain that p75 is important early in life but does not appear in adults unless motor neurons are injured.

Commenting for Medscape Medical News, Amelie Gubitz, PhD, program director, neurodegeneration, National Institute of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, Maryland — which funded the study — explained that p75 ECD appears to be a more subtle tool to measure disease progression than standard clinical scales available at present.

"Right now we only have functional tests — measurements of muscle strength — to assess progression of ALS.  But these can be highly variable and can be affected greatly by how motivated the patient is feeling at the time. They can also be quite involved and sometimes not that sensitive. There is a lot of interest in trying to find additional, more sensitive measures." 

But she cautioned that the current study of p75 should still be regarded as exploratory. "The patient numbers are quite small, but the data look very promising — we need further trials with more patients to confirm these results."

She added that a urine test is very accessible. "It has a low burden on the patient and is very convenient and easy to perform. It also seems to provide an objective measure of disease progression."

Dr Gubitz noted that the p75 protein may not be specific for ALS. "It may also be increased in other neurological diseases or brain or spinal cord injuries. It is a marker of nerve cell damage or degradation, so it is not really suitable as a diagnostic tool for ALS, but it should be useful for measuring progression over time once the disease has been diagnosed. "

She added: "This will be very useful in clinical trials to assess the effect of a drug therapy. It should also be suitable for stratifying patients — ALS can be very variable, with some patients progressing very slowly and others much faster."

Poly(GP) Protein: Marker of Genetic ALS

The second paper describes a possible biomarker based on the protein made by the aberrant gene in the most common genetic cause of ALS.

Dr Gendron explained that the mutation in the C9ORF72 gene causes hundreds or thousands of repeat sequences to be expressed in the RNA and resulting dipeptide repeat proteins, one of which is the poly(GP) protein.

A new therapeutic approach is now in development for patients with ALS who have this gene mutation using antisense oligonucleotides targeting this repeat RNA. In preclinical models, it has reduced the amount of abnormal repeat proteins manufactured.

In the current study, the scientists show that the poly(GP) protein can be detected in CSF in  patients with ALS who have the C9ORF72 genetic mutation. They also treated a mouse model that expresses C9ORF72-repeat expansions with an antisense oligonucleotide drug designed to inactivate the expansions and found that the levels of the poly(GP) protein were reduced in mouse brain and CSF following treatment.

"We believe that this protein is a marker of the causative pathological mechanisms that give rise to ALS — the amount of repeat RNA," Dr Gendron said.

She also suggested that the protein could be a good marker of whether the oligonucleotide therapies are having an effect. "When these drugs get to clinical trials, we need to know whether they are hitting their target. A reduction in the poly(GP) protein will show that it is working correctly. We have shown this already in mice. We believe this poly(GP) protein will be able to help guide the development of future ALS therapeutics.

Dr Gendron noted that it could also be possible to use such a biomarker to assess therapies in asymptomatic patients, which is currently not possible as the clinical scales used at present measure progression of symptoms.

"It is thought that in the past ALS drugs have been given too late in the course of the disease to have much effect. We can now identify patients who carry the ALS genetic mutation with a gene test before they develop symptoms. And this poly(GP) protein cold be a practical way of assessing whether drugs are working in this group," she suggested.

The researchers estimate that this genetic mutation accounts for about 5% to 10% of all ALS cases. The same mutation can also cause frontotemporal dementia, so this protein could also be useful as a biomarker to track that condition.

Commenting on the poly(GP) study for Medscape Medical News, Dr Gubitz said, "The poly(GP) protein has tremendous potential as a pharmacodynamic biomarker for emerging drugs that target the C9orf72 repeat expansion mutation. The poly(GP) immunoassay will potentially provide a powerful tool to measure target engagement and molecular activity of repeat expansion-specific drugs in upcoming clinical trials for this form of ALS."

The study by Dr Shepheard and colleagues was supported by the NIH Rare Diseases Clinical Research Network (RDCRN) Clinical Research in ALS and Related Disorders for Therapeutic Development (CreATe) Consortium, Motor Neurone Disease Research Institute of Australia, Flinders University Centre for Neuroscience and FMC Foundation, ALS Association, Muscular Dystrophy Association, ALS Recovery Fund, and Australian Rotary Health (Neville and Jeanne York PhD Family Scholarship for Motor Neuron Disease). The CReATe Consortium is a part of the NIH RDCRN, an initiative of the Office of Rare Diseases Research, National Center for Advancing Translational Sciences (NCATS). CReATe is funded through collaboration between NCATS and the National Institute of Neurological Disorders and Stroke (NINDS). Dr Shepheard received a PhD scholarship from Australian Rotary Health.

The study by Dr Gendron and colleagues was supported by the NIH/National Institute on Aging, the NIH/NINDS, the intramural research program of the NIH/NINDS, the US Department of Defense (Amyotrophic Lateral Sclerosis Research Program), Mayo Clinic Foundation, Mayo Clinic Center for Individualized Medicine, Amyotrophic Lateral Sclerosis Association, the Robert Packard Center for ALS Research at Johns Hopkins, Target ALS, Association for Frontotemporal Degeneration, Biogen, the ALS Therapy Alliance, ALS Finding a Cure Foundation, the Brain Science Institute, the Muscular Dystrophy Association, the Italian Ministry of Health and STRENGTH project funded by EU Joint Programme–Neurodegenerative Disease Research, and CReATe, and Advancing Research and Treatment for Frontotemporal Lobar Degeneration consortia, which are part of the RDCRN.  

Anti-GP antibodies generated by Dr Gendron and coauthor Leonard Petrucelli, MD, that were used in this study have been licensed to commercial entities. Dr Gendron and Dr Petrucelli have a US patent #9,448,232 titled "Methods and Materials for Detecting C9ORF72 Hexanucleotide Repeat Expansion Positive Frontotemporal Lobar Degeneration or C9ORF72 Hexanucleotide Repeat Expansion Positive Amyotrophic Lateral Sclerosis."  

Neurology. Published March 21, 2017.  Full text 

Sci Transl Med. Published March 29, 2017.  Full text  

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