Why target urate in PD?

A recent confluence of evolutionary, laboratory, epidemiological and clinical data has identified urate or one of its determinants as a promising target in the development of neuroprotective therapy for PD. These findings have prompted the clinical development of a urate-elevating strategy for disease modification.

Urate (a.k.a. uric acid, though the anionic form urate actually predominates at neutral pH) is the end product of purine metabolism in humans (see diagram below). It circulates at high concentrations in humans and apes due to a series of mutations of the UOx gene late in hominoid evolution (Oda et al., 2002)  UOx encodes urate oxidase, which converts urate to allantoin in most, if not all, other mammalian species (Figure 1).

Figure 1

An inferred selective advantage of the urate elevation resulting from UOx mutation in our ancestors led to the hypothesis and then demonstration in 1981 that urate possesses antioxidant properties (Ames et al., 1981) The emergence of the oxidative stress hypothesis of PD and other neurodegenerative diseases in the 1980s prompted consideration of urate as an endogenous neuroprotectant. In the 1990s post-mortem studies lent support to this contention in reporting that relevant brain regions in Parkinson and Alzheimer diseases had lower urate content than did respective controls (Church and Ward, 1994; Hensley et al, 1998).   More recently, urate has been found to be neuroprotective in cellular models of the dopaminergic neuron degeneration in PD (Duan et al., 2002; Haberman et al., 2007; Guerreiro et al., 2009).

The initial urate-PD link prompted a series of prospective epidemiological investigations of urate and PD risk with all demonstrating that healthy subjects with higher blood urate levels were less likely to develop PD (as indicated in the graphic approximation below; Figure 2, upper panel) (Davis et al., 1996; de Lau et al., 2005; Weisskopf et al.,. 2007; Chen et al.,. 2009).  Our epidemiology group, led by Alberto Ascherio of the Harvard School of Public Health, noted that for the largest of these PD cohorts this inverse relationship between plasma urate and PD risk became even stronger after excluding from the analysis subjects who developed PD within four years of baseline urate measurement. This observation argues against the possibility that early (preclinical) PD leads to a lower urate level, supporting instead an effect of urate or its determinants on the development of PD (Weisskopf et al, 2007). Similarly, people who consume diets that raise urate levels are at lower risk of PD (Gao et al., 2008) as are those diagnosed with gout, a form of arthritis triggered by high urate concentrations that exceed the limits of solubility in joint fluid (Alonso et al., 2007; De Vera et al., 2008).

These consistent epi data linking higher urate to a reduced risk of PD prompted our hypothesis that amongst people who’ve already developed PD, higher urate is predictive of slower disease progression. To test this hypothesis Alberto and I, together with Ira Shoulson, David Oakes and other investigators of the Parkinson Study Group, conducted secondary analyses of two completed PD clinical trial databases that contained incidentally measured blood urate values, as well as rigorously collected disease progression outcome data. In the PRECEPT study we found that higher but still normal serum urate concentrations at baseline were predictive of slower rates of disease progression, measured both clinically and by brain scans (quantifying loss of dopamine transporter binding sites in striatum) (Schwarzschild et al., 2008).

The other trial known as DATATOP was actually completed decades earlier, but like PRECEPT had enrolled some 800 subjects with early PD and followed them for two years, recording as the primary outcome measure the time to disability warranting the start of dopaminergic medication therapy.  As in the PRECEPT cohort, baseline concentrations of serum urate amongst DATATOP subjects were predictive of a slower rate of clinical disability progression. Moreover, urate in CSF collected at baseline (but measured last year after two decades of freezer storage) also showed a predictive relationship between higher urate concentrations and slower rates of decline (Ascherio et al., 2009). Together these clinical data-mining investigations established higher levels of urate as a molecular predictor not only of a lower rate of developing PD, but also of a lower rate of its clinical progression amongst people already diagnosed with the disease (as indicated in the graphic approximation below; Figure 2, lower panel).

Figure 2 Based on these convergent data and the availability of an existing strategy to elevate urate in humans via oral administration of inosine (a precursor of urate; see metabolic pathway diagram above) (Spitsin et al., 2001), we have established a non-commercial IND (Investigational New Drug) development plan that targets urate elevation in pursuit of an indication for slowed clinical progression in PD.  With approval from the FDA and grant support from the LEAPS program of the Michael J. Fox Foundation (link)we have begun a phase II randomized, placebo-controlled trial of oral inosine to test its ability to safely elevate urate levels in the serum and CSF of subjects with early PD, and to optimize clinical trial design features for a possible phase III study focused on efficacy for disease modification. The trial, named SURE-PD (for its abbreviated title, Safety of URate Elevation in Parkinson Disease) has begun enrolling subjects and is currently open at 8 of 11 planned clinical sites in the US (link).

Mechanistic Studies

Urate as a neuroprotectant: Further laboratory studies should investigate the neurobiology and therapeutic potential of the urate-PD association observed in humans.  Antioxidant, metal chelator and other potential direct mechanisms by which urate may confer neuroprotection in models of PD should be explored, along with urate interactions with the candidate genetic and environmental influences on the neurodegeneration of PD

Alternative hypotheses: The possibility that urate itself is an endogenous neuroprotectant that can reduce the risk of developing, as well as slow the progression of PD is compelling. However, causality is not the only hypothesis that can explain the available data.  Intriguing alternatives worth investigation include that:

• urate pathway metabolites other than urate may protect neurons from degeneration in PD, with higher urate simply serving as a marker of increased flux through purine pathways (e.g., as shown in metabolic pathway diagram above). Alternative (non-urate) candidate neuroprotectants in this metabolic cascade include:
  • adenosine: well known to modulate neurotransmission and neuronal cell death through adenosine A1 and A2A receptors
  • inosine: may be protective either directly on intracellular kinase cascades (Irwin et al.,. 2006) or adenosine receptors (Gomez and Sitkovsky, 2003), or indirectly through metabolic conversion to downstream metabolites. Of note neurorestorative therapy with inosine is being developed for stroke and spinal cord injury patients (link)
  • hypoxanthine: though hypoxanthine itself is not a known modulator of neurodegeneration, deficiencies of hypoxanthine-guanine phosphoribosyltransferase (HPRT) produce a hypodopaminergic biochemical phenotype in mice and humans without overt dopaminergic neuron degeneration (Visser et al., 2002). The basis of this pathophysiological association between purine metabolism and dopamine deficiency in Lesch-Nyhan disease (HPRT deficiency) remains an unsolved mystery that may hold clues to the urate-PD link.
  • allantoin: recently suggested to mediate neuroprotection by inosine in a rat model of PD (Terpstra et al., 2009). Though the relevance to humans is unclear (given our lack of enzymatic generation of allantoin from urate) such studies highlight the value of understanding the relationships between purine metabolites in PD as well as its models.
• non-metabolic urate determinants rather than urate or its precursor/metabolites may be the basis of urate-PD associations. For example, urate transporters such as URAT1 and GLUT9 may influence brain concentrations of PD toxins/protectants while incidentally determining urate levels.

Questions

• Does equipoise exist for the current, safety-focused phase II clinical trial of inosine to elevate urate in PD?
  • Or should clinical development be less cautious, for example:
    • advancing directly to a phase III efficacy trial (given that inosine is widely consumed and available as a nutritional supplement and has been deemed largely safe in phase II trials to elevate urate in multiple sclerosis)?; or
    • raising urate above 8 mg/dL (considered the upper limit of ‘normal’, and the current maxium target level in SURE-PD).
  • Or should clinical development be more cautious, given that:
    • pre-clinically: demonstrations of neuroprotective benefit of urate have thus far only been reported for cell culture (not in vivo) models; and that
    • clinically urate is only a potential neuroprotectant, whereas it is a known contributor to gout and uric acid kidney stones, and is also a possible contributor to cardiovascular disease.
• If in fact equipoise exists for a urate-elevating trial in PD, might there be another urate-elevating strategy (other than simply providing the precursor inosine) that should be pursued first or concurrently?
• How does urate confer protection against neurodegeneration?
• How might urate interact with known genetic and environmental influences on parkinsonism?
• What alternative explanations (other than a direct protective effect of urate) should be considered for the urate-PD associations?