Toward a Salivary Biomarker for Huntington Disease

Medscape: What was the motivation behind your study, and what were the objectives?

Dr Corey-Bloom: Our overall motivation was to try and identify peripheral biomarkers for HD. In this study, we were specifically trying to assess whether salivary Htt levels can serve as a biomarker for HD and disease burden.

The pathogenesis of HD is associated with expression of the mutant Htt protein, which is ubiquitously expressed throughout the body. The Htt protein is the most significant molecular target for disease-modifying therapies, and several therapeutic approaches that target its production, processing, or turnover are under development or approaching clinical trials.

Medscape: Can you briefly touch on the need for biomarkers in neurodegenerative disorders?

Dr Corey-Bloom: Peripheral biomarkers are greatly needed in the field of neurodegenerative disorders for several reasons: to anticipate onset of disease symptoms, to monitor disease progression, and to track potential therapeutic effects. One of the most relevant biomarkers for HD is the disease protein itself: Htt. However, measurement of Htt in the brains of patients is not possible, and cerebrospinal fluid measurement is highly invasive.

Medscape: Has any prior research explored the potential of peripheral Htt as a biomarker of disease risk?

Dr Corey-Bloom: Prior research exploring the potential of peripheral Htt as a biomarker for HD is limited. Massai and colleagues[2] applied an enzyme-linked immunosorbent assay (ELISA) using commercially available antibodies to quantify Htt levels in peripheral blood mononuclear cells from patients with HD; Weiss and colleagues[3] used time-resolved Förster resonance energy transfer immunoassay to quantify mutant and total Htt protein levels in leukocytes from patients with HD. Of course, levels can vary depending on the blood cell type; large starting volumes (50 mL) are often required, and blood drawing is an invasive technique that requires trained personnel.

Medscape: What were the results of your study?

Dr Corey-Bloom: In the current study, we measured Htt protein levels in saliva from HD gene-positive individuals (n = 36) and age- and sex-matched healthy control participants (n = 52) using ELISA and Western blot methods. Full-length soluble Htt protein levels detected by Western blot analysis were decreased in saliva samples from HD patients compared with the control participants.

In contrast, ELISA using antibodies recognizing amino acids 802-940 of human Htt protein revealed significant increases in Htt expression in saliva from patients with HD compared with control participants. Furthermore, salivary Htt levels were higher in symptomatic patients with HD than in presymptomatic or transitional patients.

Medscape: What are the clinical implications of your findings in terms of screening, diagnosis, and treatment?

Dr Corey-Bloom: This study is part of a larger study to identify the major forms of Htt protein in saliva, determine whether salivary Htt can distinguish patients with HD from healthy controls, and determine whether salivary Htt levels correlate with clinical data. It is still early days, but we are excited that we can indeed measure Htt protein in saliva, and it looks as if Htt levels in saliva are higher in patients with HD than in matched normal controls.

If this finding holds up, we may be able to use salivary Htt to anticipate onset of disease symptoms, monitor HD progression, and even track potential treatment effects in a noninvasive fashion.


SOURCE: Medscape Neurology


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