Similarly, the short lifespan of mice complicates modeling diseases in which different compartments become dysfunctional at different stages. For instance, peripheral nervous system (PNS) involvement complicates many of the hereditary human leukodystrophies, but often tends to be less apparent in mice, whose short lifespans can inaccurately minimize the role of less-rapidly evolving PNS disease. For disorders such as Niemann-Pick, Krabbe disease, adrenoleukodystrophy and the mucopolysaccharidoses, all of which include significant PNS pathology, effective treatment strategies will need to include systemic enzyme replacement, or the broad dispersal of enzymatically wild-type cells throughout peripheral nerves (Hawkins-Salsbury et al., 2015). As a result, the combination of intracerebral hGPC grafts with systemic enzyme replacement will likely be necessary to achieve durable therapeutic benefit for those disorders affecting both the CNS and PNS. More broadly, this issue suggests caution in relying too heavily on mouse avatars of these disorders, lest that reliance lead to the systematic over-estimation of therapeutic response, based upon the tendency of investigators to favor simple and clearly-defined models for diseases that are rarely simple.
