Search for Biomarkers Crucial to Neurodegenerative Disease Therapeutics and Diagnostics

Search for Biomarkers Crucial to Neurodegenerative Disease Therapeutics and Diagnostics

Kalorama Information offers related market research titles withProteomics Markets(research and clinical markets), Proteomics Research MarketsandThe Global Market for Biomarkers.

The debilitating neurodegenerative diseases Alzheimer’s and Parkinson’s have vexed healthcare in terms of both therapy and definitive antemortem diagnosis. The localized nature of the diseases in the central nervous system (CNS) makes the development of in vitro diagnostic (IVD) tests difficult. An incomplete understanding of the causes behind the diseases from a systems biology standpoint has also stalled clinical diagnostics development, even when CNS samples such as cerebrospinal fluid (CSF) are available. The incentive to develop marketable clinical assays has also been diminished to an extent by a lack of curative therapies for neurodegenerative diseases; clinicians are less apt to request or use a lab test to direct decision making for a disease without curative therapies. Still, clinical value exists for diagnostics able to detect pre-symptomatic onset of Alzheimer’s and Parkinson’s and inform earlier implementation of palliative care and neuroprotective therapy. Outside of clinical applications, lab diagnostics for the neurological diseases are in demand for life sciences research and clinical trials. Research use assays can assist in the characterization of neurodegeneration-associated biomarkers to improve understanding of cellular disease pathways and explore potential drug targets.

Assay development for Alzheimer’s and Parkinson’s diseases is ongoing at various stages from biomarker discovery, biomarker validation, and assay development. Nervous system or neurological biomarkers are covered in the Kalorama Information reports Proteomics Research Markets and The Global Market for Biomarkers; the latter report highlighted nervous system biomarkers as the second-fastest growing segment in the clinical and research biomarkers markets. Researchers have heavily targeted Alzheimer’s Disease (AD) diagnostics development using CSF samples and even skin samples. One study in Mexico took skin biopsies from patients with Alzheimer’s, Parkinson’s and non-Alzheimer’s dementia as well as similarly aged healthy patients and used immunohistochemistry (IHC) tests to assay levels of tau protein. The biomarker was found to be significantly elevated in the skin samples of Alzheimer’s and Parkinson’s patients; alpha-synuclein protein was also found to be elevated in the samples of Parkinson’s patients. Skin samples are theorized to be feasible proxies for brain tissue because of the samples’ common origin in embryonic development.

Another study identified protein kinase C epsilon (PKCe) as a biomarker for AD with reduced levels observed in AD patient skin samples. Development-stage therapeutics company Neurotrope is interested in a PKCe modulator as a potential treatment for AD patients. While CSF biomarker tests for AD are further along in development, skin biopsy tests would be much more widely implementable in healthcare.

Kalorama Information previously covered the market potential of AD assays. Amarantus Bioscience has targeted the market for investigational or research use only (IUO/RUO) AD assays for use in clinical trials and drug development activities. The market for such tests for AD was estimated by Amarantus at $150 million. The company offers a blood-based assay as a non-invasive alternative to CSF-based AD tests. The Lymphocyte Proliferation (LymPro) assay is able to differentiate AD individuals from other forms of dementia and healthy individuals by measuring the expression of CD69 protein during stimulated lymphocyte mitosis or cell division. In AD individuals, CD69 expression is down regulated compared to healthy individuals and those with other forms of dementia. The lymphocyte cell surface CD69 markers are measured using flow cytometry. In the test, peripheral blood lymphocytes are used as surrogates for neurons that theoretically exhibit the same cell cycle dysfunction. 

Biopharmaceutical clinical trials are also turning to the proteomic tool kit for highly sensitive, specific and flexible assays. One biomarker services company, Proteome Sciences, offers a multiplex panel assay for the absolute quantitation of 9 AD biomarkers. The method uses clinical plasma samples, high-performance liquid chromatography (HPLC), and triple quadrupole mass spectrometry (MS) in selected reaction monitoring (SRM) mode. The targeted mass spec analysis is able to determine absolute quantities of AD protein biomarkers in plasma samples through the relative abundance of associated peptide fragments and the use of tandem mass tags (TMT) reagents or isotope-labeled peptide internal standards. Proteome Sciences’ test targets a different application within the clinical trial market than Amarantus’ assay; the TMT-SRM assay is intended to stratify patients rather than provide initial AD diagnosis.

Assays of tau proteins and beta amyloid in CSF are still widely used in AD therapeutics clinical trials. While products such as Amarantus’ LymPro seek to deliver improved assay specificity to AD, other research has sought to improve assay selectivity of biomarkers. Researchers at Merck have seized upon MS to meet evolving protein analysis demands, selecting immunoaffinity microflow LC-triple quad MS to identify different isoforms of tau biomarkers arising from post-translational modification. Immunoassays do not provide the specificity necessary to identify tau modifications that potentially influence disease progression.

Thermo Fisher has applied its own immunoenrichment triple quad MS approach for low-abundance blood proteins to the discovery and monitoring of AD biomarkers. Researchers have used Thermo’s multiplexed mass spectrometric immunoassay (MSIA)-SRM assays for the quantitation of aberrant ceruloplasmin (affects homeostasis of free copper and results in AD-associated protein degradation and aggregation) and apolipoprotein E (promotes AD-associated beta amyloid fibril formation).

The biomarker research space for Parkinson’s Disease does not feature as much activity as in AD biomarker research, possibly as Parkinson’s Disease has a much lower prevalence than AD. Parkinson’s Disease (PD) is estimated at around 500,000 in the United States as the second most common neurodegenerative disease (behind dementia). The number of AD cases in the United States is estimated at over 5 million.

 A number of PD biomarkers have been investigated including alpha-synuclein, Charnoly body, coenzyme Q10, mitochondrial-ubiquinone-NADH oxidoreductase, melatonin, and metallothioneins. Phosphorylated alpha-synuclein has been proposed as a PD biomarker assayable from skin biopsies. Novel PD biomarkers are still very much in demand for assay development and may be identified through differential analysis of metabolites and other pathway proteins between PD patients and healthy patients. Researchers may be able to associate the characteristic PD odor noticed by a select few individuals to one or more secreted biomarker identifiable through LC-MS analysis or other laboratory methods.