Gazing into the future: Parkinson's disease gene therapeutics to modify natural history Kathleen A. Maguire-Zeiss a , Timothy R. Mhyre a , Howard J. Federoff b, ⁎ a Department of Neuroscience, Georgetown University, 3970 Reservoir Road, NW, Washington, DC 20007, USA b Georgetown University Medical Center, 4000 Reservoir Road, NW, Washington, DC 20007, USA Received 15 June 2007; revised 19 September 2007; accepted 24 September 2007 Available online 11 October 2007 Abstract PD gene therapy clinical trials have primarily focused on increasing the production of dopamine (DA) through supplemental amino acid decarboxylase (AADC) expression, neurotrophic support for surviving dopaminergic neurons (DAN) or altering brain circuitry to compensate for DA neuron loss. The future of PD gene therapy will depend upon resolving a number of important issues that are discussed in this special issue. Of particular importance is the identification of novel targets that are amenable to early intervention prior to the substantial loss of DAN. However, for the most part the etiopathogenesis of PD is unknown making early intervention a challenge and the development of early biomarker diagnostics imperative. © 2007 Elsevier Inc. All rights reserved. Etiopathogenesis in the future Parkinson's disease (PD) was first described by James Parkinson in “An Essay on the Shaking Palsy” and currently affects over one million Americans (Parkinson, 1817). The cardinal clinical features are largely motoric and include trem- ors, rigidity, slow decreased movements, as well as problems with gait and balance. Less appreciated are non-motoric symptoms including constipation, daytime somnolence, depres- sion, dementia and cardiovascular autonomic dysfunction. These non-motoric features may represent useful clinical benchmarks for initiating early therapeutics prior to the overt motoric symptoms. Neuropathologically, later in the disease, PD cases display universal loss of substantia nigral dopaminergic neurons (DAN) and striatal projections resulting in dopamine deficiency and motor control deficits owing to dysfunction of the basal ganglia. The disease is also typified by increased microglial activation and the presence of intracytoplasmic proteinacous inclusions known as Lewy bodies in the few surviving DAN and in other non-dopaminergic neurons. Despite these consistent clinical symptoms and signs and invariant loss of DAN the etiology of PD is unknown but hypothesized to be multivariate consisting of genetic, toxicant and environmental insults (Maguire-Zeiss and Federoff, 2003). The convergent pathobiologic model of PD posits that these disparate initiators converge on a common pathway of presynaptic injury and finally cell death (Maguire-Zeiss and Federoff, 2003). Implicit in this model is the identification of potential shared therapeutic targets regardless of distinct disease initiators. Identification of these shared targets as well as capabilities to monitor inter- vention will impact future patient therapeutics. PD is both a familial and sporadic disease. Genetic mutations, duplications and triplications account for less than 10% of all PD cases leaving the greatest number idiopathic and thus difficult to diagnosis prior to overt symptoms. Genes correlated with PD include α-synuclein (Park-1, Park-4), LRRK2 (Park-8), parkin (Park-2), PINK1 (Park-6), and DJ-1 (Park-7)(Paisan-Ruiz et al., 2004; Polymeropoulos et al., 1996; Polymeropoulos et al., 1997; Valente et al., 2001; Valente et al., 2004). α-Synuclein was the first gene associated with PD and mutations within this gene (A53T, A30P, E46K) lead to an early onset clinically severe phenotype (Polymeropoulos et al., 1997; Polymeropou- los, 2000; Zarranz et al., 2004). Furthermore, triplication of the α-synuclein locus (Park-4) was reported in one Iowa family with early onset PD (Singleton et al., 2004; Singleton et al., 2003). This is of particular interest since it implicates α-synuclein gene dosage and/or the regulation of wild-type α-synuclein protein Available online at www.sciencedirect.com Experimental Neurology 209 (2008) 101 – 113 www.elsevier.com/locate/yexnr ⁎ Corresponding author. E-mail address: hjf8@georgetown.edu (H.J. Federoff). 0014-4886/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.expneurol.2007.09.030