In HD field identifying biomarkers (in addition to the number of GAG repeats) may predict age of onset and disease progression. Recently easily accessible predictors, coming from peripheral leucocytes and plasma, are receiving attention.
We got informative preliminary results on DNA damage response (DDR) and the telomeres shortening in peripheral leucocytes, along with circulating micro-RNAs and small nucleolar RNAs. All these biomarkers will longitudinally (3 years) be studied in pre-manifests, HD patients, and matched controls, and will be integrated through a biostatistics approach to measure their predictive potential. Moreover, some evidences on DDR in peripheral leucocytes from pre-manifests (it increases over time and collapsed, although at higher than normal levels, once the symptoms appeared; it is absent in healthy subjects and it is potentially reversible) supports its use as quick and handy drug-screening approach to explore treatment repurposing before disease onset.
Recently, the discovery of brain lymphatic vessels [1] and the new role of microglia and astrocytes on survival and metabolism of neurons is changing our idea of the pathogenesis of neurodegenerative diseases. There is now strong evidence that the mechanism leading to neuron death is substantially influenced by the expression of the mutant protein by non-neuronal cells (microglia-astrocytes, non-cell autonomous pathogenesis) [2]. Since microglial cell are regulated and regulate lymphocytes [3] we reasoned that peripheral lymphocytes stress might be a mirror of microglia-astrocytes-neuron stress.
We wish to detect the earliest pathogenic process in HD and to translate it in reliable assays. This approach unveils measurable parameters in pre-manifests escaping the clinical detection. There are multiple applicative potentials: a) characterizing the different conditions (pre-manifest and overt disease); b) using DDR of PBMC and plasma non-coding RNAs as biomarkers to monitor the progression of pathogenic events leading to manifest disease; c) generate a simple and reliable model incorporating the above biomarkers to predict the disease onset and to define a temporal window in which the patient could be effectively treated; d) making available a liable-to-changes biomarker to monitor the effectiveness of treatments, especially in pre-manifest people; e) finding peripheral patterns that may mirror brain dysfunctions and represent potential therapeutic targets. In this context, a minimally invasive procedure to obtain samples and relatively simple analytical assays are desirable, and currently not available, as biomarkers for trials and care in pre-manifest individuals.
The above point "d" (the in-vitro assays with approved drugs to be repositioned in pre-manifest and patients with HD) will have a significant impact in clinical practice. This pilot step will be implemented testing the effect of a panel of candidate drugs on the DDR, that was shown to be clearly detectable in pre-manifest HD (negligible in healthy subjects), and potentially reversible with targeted treatment. Moreover, a personalized approach may be envisioned if different drugs will prove to be active in cells derived from different pre-manifests. This approach will possibly result in a portfolio of candidate drugs for pilot trials especially in pre-manifest HD. This experimental setting is based on the drug repositioning approach (i.e. finding a new indication for existing drugs), which in turn relies on the concept that a single drug can interact with multiple targets: off-targets in the disease for which the drug was developed may turn to be effective in counteracting pathogenic loops in other disorders [4]. Repurpusing is a consolidated strategy for cutting the timeline and costs of drug development [5-7].
1.Louveau, A. et al. Structural and functional features of central nervous system lymphatic vessels. Nature 523, 337-341 (2015).
2.Ilieva, H., Polymenidou, M. & Cleveland, D. W. Non-cell autonomous toxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187, 761-772 (2009).
3.Almolda, B., González, B. & Castellano, B. Are Microglial Cells the Regulators of Lymphocyte Responses in the CNS? Front. Cell. Neurosci. 9, 440 (2015).
4.Medina-Franco, J. L., Giulianotti, M. A., Welmaker, G. S. & Houghten, R. A. Shifting from the single to the multitarget paradigm in drug discovery. Drug Discov. Today 18, 495-501 (2013).
5.Dolgin, E. Nonprofit disease groups earmark grants for drug repositioning. Nat. Med. 17, 1027 (2011).
6.Reed, J. C. et al. The NIH¿s role in accelerating translational sciences. Nat. Biotechnol. 30, 16-19 (2012).
7.Nosengo, N. Can you teach old drugs new tricks? Nature 534, 314-316 (2016).