Search continues for biomarkers to aid Huntington’s research

Huntington’s disease has suffered its fair share of setbacks in the last few years. Encouraging early-stage work focusing on techniques to monitor and measure disease progression might help push research efforts forwards once again.

Three studies published in the Journal of Huntington’s Disease this month report on work to establish biomarkers for the disease. Reliable and sensitive biomarkers that can track a patient’s disease, as well as help evaluate new therapies, are sorely needed in this intractable neurological condition. However with the pipeline thin, new candidates are also in high demand.

Objective markers

With disease-modifying therapies for Huntington’s clearly in the industry’s crosshairs, there is certainly a need for objective markers of disease progression. This is particularly true for patients who have yet to develop symptoms, as they can be functionally indistinguishable from subjects acting as controls in any study.

Most large Huntington's studies done to date have used rating scales to measure a patient’s progress. For example Pfizer and Medivation’s Horizon study of dimebon, a trial that ultimately failed, primarily used two rating scales – the MMSE (mini–mental state examination) and CIBIC-plus (ADCS CGIC), a scale used to assess behaviour, cognition and function. NeuroSearch used the Huntington’s scale, UHDRS motor assessment, for its later studies of Huntexil, trials that also failed amid some controversy.

While these scales can provide insight into a patient’s ability to function, less subjective techniques to measure disease progression and a drug’s effectiveness would greatly aid researchers.

With this in mind, researchers at Lund University in Sweden and UCL in London evaluated inflammatory markers. While the disease is not traditionally thought of as an inflammatory disorder, immune changes can be observed in Huntington's patients before the onset of obvious symptoms. This raised the possibility that inflammatory markers in plasma could be used to track disease progression.

The researchers evaluated the potential of inflammatory biomarkers identified in previous studies, and investigated whether other markers associated with innate immunity might serve as biomarkers of disease progression in Huntington’s. Plasma levels were studied of several proteins involved in inflammation and innate immunity, including complement proteins, APPs, S100 proteins and apolipoproteins, in two separate cohorts including healthy controls, patients yet to manifest symptoms and early and later-stage subjects.

Of the many inflammatory markers studied, only C-reactive protein was found to be reduced in early Huntington’s disease. Several markers previously described as altered in Huntington patients, such as clusterin, complement component 4, complement component 9 and alpha-2 macroglobulin did not differ between healthy patients and those with the disease. While some of the other inflammatory markers measured correlated with clinical measures, none was shown to be significantly altered in both of the cohorts tested.

Neuroimaging

Ultimately, this large study did not yield any obvious inflammatory markers that might be useful in Huntington’s. A second paper yielded more promise – it sought to identify progression markers using neuroimaging measures, more obvious candidates because of their clear relevance to the pathology of the disease. The paper summarised findings from a wealth of longitudinal imaging studies in the literature, focusing on the most widely available imaging modalities: structural MRI, functional MRI and PET.

The authors identified longitudinal imaging of caudate volume using structural MRI as one of the most promising biomarkers for future trials. Measurement is reliable and reproducible, and the structure is disproportionately affected by the disease, they wrote.

PET is also promising, they said, although it is more expensive and less widely available, and might not be as sensitive to longitudinal change, while it has the advantage of being able to target specific molecules.

“Overall, neuroimaging shows real promise for characterising the progression of Huntington's and may be qualified to assess drug efficacy in clinical trials of putative disease-slowing compounds in the future. As imaging metrics are an indirect measure of neuronal activity/health [and] cannot be assumed to relate directly to clinical progression, other measures will be needed alongside them, eg, total functional capacity and/or quality-of-life scales, particularly in clinical trials of early manifest individuals who are likely to be the most suitable population for many of these trials,” the authors concluded.

Underlying process

A third paper, by researchers from the University of Auckland in New Zealand and University of Manchester in the UK, focused on attempts to elucidate the processes that underlie neurodegeneration in Huntington’s.

The genetic defect that drives the disease is inherited or caused by a spontaneous mutation in the HTT gene. This alters the structure of the huntingtin protein and initiates a cascade that ultimately causes dementia. The researchers used a technique called two-dimensional gel electrophoresis to identify changes in protein expression associated with the neurodegeneration in two brain regions. Post-mortem human tissue from seven well-characterised Huntington’s patients and eight controls was studied.

The authors found 29 altered proteins, 20 of which to their knowledge had not been associated with the pathogenesis of Huntington’s before. However, all functional families implicated had previously been linked to other neurodegenerative diseases, they wrote.

The proteins identified play roles in cell stress responses, apoptosis, metabolic regulation linked to type 2 diabetes, the ubiquitin proteasome system, or protein trafficking/endocytosis. The researchers propose that HTT mutations lead to or cause functional impairment of these pathways. Simultaneous restoration of their functions by targeted pharmacotherapy could ameliorate the signs and symptoms of the disease, they concluded.

“These studies provide a unique illustration of the interlinked disease processes that underpin/contribute to the pathogenesis of neurodegeneration in a genetically mediated disorder of protein structure, and provide a signpost towards the design of new therapeutic interventions,” they wrote.

Commercial interest

All of these papers were written with a view to a future that holds potential disease-modifying compounds. Unfortunately, following the failures of the last couple of years, the late-stage pipeline holds few hopes (Therapeutic focus – Two steps back for Huntington’s disease, April 11, 2013).

However, interest can be found at the big commercial drug developers. Only last month Roche struck a research deal with Isis to work on antisense-based projects, while Teva bought the assets to NeuroSearch’s failed Huntexil last year (Isis looks another partner as big pharma looks for sense in antisense, April 10, 2013). 

With more sophisticated tools in hand to measure the disease, and the drugs that these collaborations might yield, hopefully the future hold more promise.

To contact the writer of this story email Amy Brown in London at AmyB@epvantage.com or follow @AmyEPVantage on Twitter

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