Table 4.

Criteria for determining candidate agents for clinical trials in HD.

Evidence type	Neuroprotective candidate attribute
Preclinical criteria	Experimental evidence of a neuroprotective action using an established neuroprotective model at physiological drug doses Independent replication of the neuroprotective action in the same model and at the same dose Replication of the neuroprotective action in at least one other model at a physiological dose Replication of the neuroprotective action in neural tissue, preferably mature neurons or glia, at a physiological dose Independent replication of the neuroprotective action in the specified neural tissue at the same site and in the same animal at the same dose (e.g., replication of a rat striatal neuron finding in a rat striatal neuron model, rather than in rat cerebellar granule cells) Evidence in an accepted animal model for HD (e.g., transgenic mice, quinolinate rat model, etc., their limitations notwithstanding) Evidence of multiple neuroprotective actions that have been demonstrated as above A greater overall neuroprotective positive “valence” (the number of neuroprotective actions minus the number of neurodegenerative actions demonstrated for the agent of interest [e.g., an agent with 3 distinct neuroprotective actions and 1 neurodegenerative action might be assigned a positive valence of 3 − 1 = 2 (recognizing at the present time that different actions may someday be demonstrated to have differentially weighted correlation coefficients with neurodegenerative progression)])
Clinical criteria	Clinical evidence suggestive of delayed progression (e.g., lack of progression in chorea and dementia over 5 years, lack of deterioration in UHDRS TFC score after 5 years in a patient rigorously diagnosed for HD, absence of change in MRI caudate volume over 5 years in a patient rigorously diagnosed for HD, etc.) Evidence of a more benign disease course than expected for patients in a case series or clinical trial (particularly if symptomatic effects of the drug can be controlled for)

These are putative criteria for assessing the probability that an agent will demonstrate a translational neuroprotective effect in an HD clinical trial. Since the predictive utility of these factors remains to be demonstrated, an equal weighting may be assigned to each criterion. It is likely that the more criteria an agent meets, the greater the likelihood that it will yield significant results in a clinical neuroprotective trial in HD. Abbreviations: HD Huntington’s Disease; μM micromolar; mg milligram; ml milliliter; mM millimolar; MMSE Mini-Mental State Examination; MRI magnetic resonance imaging; TFC Total Functional Capacity; UHDRS Unified Huntington’s Disease Rating Scale (adapted from Lauterbach et al. [13]).