Huntington’s disease (HD) is an autosomal dominant, adult-onset neurodegenerative disease. The motor, cognitive and psychiatric manifestations appear in early adulthood and progress to significant functional disability and, ultimately, death. The characterisation of the mutant gene allows predictive testing of individuals at risk for HD and hence the identification of asymptomatic gene carriers.
Current therapies for HD provide control of some of the major troublesome signs and symptoms (chorea, psychosis, depression). However, these treatments are only “symptomatic”, meaning that they ameliorate the clinical features of the illness, but the benefits are only temporary and disappear when the treatment is stopped. Unfortunately, no current therapy has shown to interfere with the underlying natural history of the disease, slowing or halting its progression.
EHDN’s ultimate goal is to facilitate the development of therapeutic strategies for curing the disease or, as an alternative, for slowing or stopping its progression. By having a genetic conclusive diagnostic marker, HD provides a clear and unequivocal opportunity for pursuing this ambitious objective, allowing for pre-symptomatic or very early symptomatic interventions.
The designation most commonly applied to a treatment that postpones or slows the progression of a neurodegenerative disease is “neuroprotective”. However, this concept is controversial and restrictive, because it describes a mechanism of action rather than a consequence of an intervention. Other similar mechanistic concepts include “neuro-rescue” (refers to the salvage of dying neurones) and “neuro-restoration” (refers to increasing the numbers of neurones by techniques such as cell implantation or nerve growth factor infusion).
A broader term that has gained a wider acceptance by the scientific community is the “disease-modifying” effect. This implies halting or delaying the neuronal loss and therefore slowing or stopping the progression of neurological symptoms, and ultimately modifying the clinical course of the disease.
When applied to HD, the “disease-modifying” concept may describe an intervention that favourably interferes with the genetic aetiology or neuronal pathogenesis and forestalls the disease onset (in pre-symptomatic gene carriers) or slows functional decline (in patients with manifest HD).
A number of potential disease-modifying agents have recently been identified through basic research and are currently under investigation in pre-clinical trials. There is also a huge effort aimed at conducting “disease-modifying” trials in HD patients. Thus, the present time constitutes a crucial moment to define the best way for designing trials with these specific outcomes, since methodological problems may increase their cost and render them ineffective.
The design of these trials raises many questions:
- Which populations should be studied and for how long?
- How should treatment effects be measured in terms of primary and secondary endpoints?
- Are surrogate markers available to assess disease-modifying outcomes?
Based on the fact that there is a knowledge gap in the present topic, the Neuroprotective Therapy Working Group has defined as main objectives:
- to improve knowledge on how to select pharmacological agents to enter clinical development stages;
- to improve knowledge on how to design and conduct clinical trials to demonstrate a disease-modifying effect in HD and make recommendations for future trial designs;
- to stimulate and facilitate the design, conduction and analysis of disease-modifying trials in HD;
- to make information available to scientists and the general public;
- to stimulate collaboration with partners in research and pharmaceutical industry.
To this end, the Working Group will elaborate comprehensive consensus reviews on methodological aspects which can help design and conduct clinical trials of putative disease-modifying treatments for HD more efficiently.