Many potentially effective agents and approaches have gone by the wayside during clinical assessment, because of poorly designed trials that aggregated populations that varied in their underlying disease pathogenesis, hence diluting any therapeutic effects. Thus, designing a trial to assess the therapeutic response of cell implantation in any given disorder requires a detailed understanding of the pathogenesis and natural history of that disorder, so as to understand its phenotypic heterogeneity, and thus its optimal inclusion criteria and control populations. Yet even for diseases whose genetic bases and natural histories are reasonably well-understood, establishing the relative benefit of a cell therapeutic may prove difficult. As a case in point, the childhood leukodystrophies, which would seem exceedingly attractive targets for cell therapy, and yet have become especially difficult diseases for which to design definitive clinical trials, given the rarity of these conditions, their phenotypic heterogeneity, and our limited understanding of their natural histories and prognoses. Indeed, as exciting as these new strategies of cell therapy might be, and as strong as the preclinical animal data may be in suggesting their potential efficacy,
