An exciting prognostic and potentially pharmacodynamic serum biomarker may be commercially available for horses very soon. We are borrowing some technological advances from ALS (amyotrophic lateral sclerosis) research. Recently, we discussed biomarkers that are used in human neurological disease monitoring when we met with researchers at the University of Miami ALS Center (UM ALS). They have validated neurofilament light as a prognostic and potential pharmacodynamic biomarker for ALS. Neurofilament light (NFl) was not only useful for identifying disease but changed quickly in response to treatment! We are investigating the utility of this marker in horses with polyneuritis equi, PNE.
Biomarkers are molecules that can be measured in serum and it is feasible that neurodegenerative diseases such as polyneuritis equi (PNE), equine motor neuron disease (EMND) and equine protozoal myeloencephalitis (EPM) could be identified using a simple serum test. Particularly important is NFl may respond quickly to appropriate therapy. In mice and men, NFl levels decrease in days. No one has yet published data from horses with PNE.
The UM ALS Center addressed several issues. Which assay should be selected? Do NFl and pNfH (phosphorylated neurofilament heavy) yield the same information or should both be measured? And how do levels relate to disease progression? The UM ALS group found that others made statements about prognostic and potential pharmacodynamic utility of neurofilaments. The studies were single center, measured either NFl or pNfH, but not both, used only a single assay to quantify NF levels, evaluated blood or CSF (but not both) and examined either survival or decline in function, but not both. In a UM ALS paper, the authors used a multi-center study with head-to-head comparison to three different assays in serum and CSF and also examined the utility of these markers for determining a treatment response.
Particularly exciting was the ability of serum NFl to predict the clinical course of disease. Similar to other assays, absolute values vary between patients. That means it is not useful to hang your hat on one value. Serum NFl levels remain stable in individual subjects when measured over time. In patients with neurodegenerative disease the values increase significantly above values seen in non-diseased people. NFl values increase and plateau in some species. That is contrasted to levels that continue to rise in other species. An efficacious treatment will result in NFl values that decrease. What we heard was that NFl would be clinically useful if there are detectable changes (decrease) in levels following exposure to a therapeutic agent.
To move these markers forward in human disease there needs to be an effective therapeutic to test (in motor neuron diseases). They propose using NFl in phase-2 human trials to reduce sample size and most promising, using serum NFl as a pharmacodynamic biomarker. They found the potential utility of serum pNfH more “nuanced”. It didn't add prognostic value to readily available clinical parameters and serum NFl. The bottom line was that serum NFl, but not serum pNfH, may be considered a clinically validated prognostic biomarker for human ALS. And NFl may have value as a potential pharmacodynamic biomarker that should be incorporated into ongoing and future phase-2 drug trials. Again, they await an effective treatment for ALS.
What can we horse owners and veterinarians take from this work? We don’t know until we look at a sample size that can be statistically meaningful. We are accepting serum samples from horses with possible PNE (the veterinarian must complete the PNE examination form). We will determine the levels of NFl before and after a treatment. The NFl values will be reported the day after we receive the sample. Give us a call for details on this exciting program!
The CLIFS notes on neurofilaments
A neurofilament makes up part of the cytoskeleton that is specific to neurons. Neurofilaments are similar to cytoskeletal elements in other cells, but they are made up of a different set of proteins. They are found in the axons, the long extensions of neurons that transmit nerve impulses away from the cell body toward other cells.
A neurofilament is an intermediate filament that is made up of at least two of the three different types of specialized protein subunits. These three types are called Neurofilament light (NFl), Neurofilament medium (NF-M) and Neurofilament heavy (pNfH); each neurofilament consists of NFl and either NF-M or pNfH. When neurons or axons degenerate, neurofilament proteins are released into the blood or cerebrospinal fluid. Immunoassays of neurofilament proteins in cerebrospinal fluid and plasma can thus serve as indicators of axonal damage in neurological disorders.