Given the number of potential ways in which to interfere with LRRK2 dysfunction, it is rather early to discuss which drugs might be best developed to treat LRRK2-related PD. There are some obvious issues that may stand in the way of the assessment and development of any drug, however, and it is worth discussing those issues with the goal of identifying key experiments in the field that should be performed with a long-term view that LRRK2 is "druggable."
With the development of any drug, the first step in assessing the efficacy of the drug is to test it in a suitable animal model. To date, there are more than ten mouse models carrying different LRRK2
-transgenes driven by different promoters (reviewed in [68
]). Disappointingly, these models have not yet fully recapitulated all the clinical features seen in a PD patient. Although some DA neuronal death is observed in some of these models, the loss is not progressive and is rather limited with mild motor deficits. However, it has been reported that acute expression of mutant LRRK2 using viral vectors does replicate the DA neuronal cell loss seen in PD [51
]. These models might be helpful in that they provide an opportunity to assess the acute application of inhibitors and might be the first level of testing novel agents with transgenic animals used for longer-term experiments, possibly using phenotypes other than DA neuronal cell loss if these can be shown to be reliable.
There are some general limitations in the development of all LRRK2 drugs. First, the potential therapeutic agent should be able to cross the blood-brain barrier (BBB). As discussed in Targeting LRRK2 kinase and GTPase activity
, the most promising candidate assessed biochemically and in in vitro
models is LRRK2-IN1. When tested in vivo
, however, it was shown that LRRK2-IN1 does not affect the phosphorylation of S910 and S935 of LRRK2 in the mouse brain, but that it does abolish phosphorylation of S910/S935 in the kidneys, indicating that LRRK2-IN1 has poor BBB permeability [62
]. These data suggest that future LRRK2 inhibitors need to have distinct properties to overcome the current lack of BBB penetration.
A corollary of this issue is that poor penetration of LRRK2 therapeutic agents across the BBB could cause an inadvertent accumulation of the agents in peripheral tissues. This could raise a potentially important toxicity problem, as, for example, it was recently shown that knocking down LRRK2 in mice had deteriorating effects on kidneys [69
]. It would therefore be important to monitor the function of organs in which LRRK2 is highly expressed, particularly with regard to kidney and lung function. LRRK2 is also highly expressed in B cells, so immunological function should be assessed.
Another major problem in the development of LRRK2 drugs is the selectivity of the therapeutic agents. Even selective LRRK2 medications could have significant off-target effects if used at high concentrations for an extended period. For example, it is well-established that no kinase inhibitor is exclusively selective to a single kinase [71
]. If the concentration of the inhibitor is high enough, it could inhibit other structurally similar kinases and cause multiple side effects, a particular problem for extended use.
Assuming LRRK2 drugs were on hand, one difficult question would be when it would be most appropriate to start treatment. One the one hand, it would be logical to initiate prophylactic treatment in early adulthood in mutation carriers before the development of classic PD symptoms. In this case, appropriate therapy could potentially prevent or delay neuronal degeneration. One the other hand, mutations in the LRRK2 gene have incomplete penetrance and variable age at onset. Therefore, treatment of carriers could lead to long-term treatment of individuals who will not necessarily express the disease phenotype in their lifetimes, which presents both ethical and financial hurdles. This might then lead to the alternative view that any therapy should be restricted to individuals who have parkinsonism. It is also relevant that some of the motor aspects of PD are treatable, if imperfectly, by levodopa and by surgical approaches such as deep brain stimulation, so a LRRK2-based strategy would have to have proven benefit compared to current treatments. Efficacy, measurement of the progression of PD symptoms and the safety of treatments over extended periods will have to be considered in the development of LRRK2 therapeutic regimens.
Another reasonable question is whether therapeutics based on LRRK2 could also be beneficial for sporadic PD. Ultimately, this question cannot be answered without a therapeutic agent in hand, and in all likelihood this agent would be one that has proven benefit in LRRK2 cases. If one had an appropriate compound, however, it would be possible to address the hypothesis whether LRRK2 PD and sporadic PD are mechanistically linked, so it is worth thinking about the probability that this hypothesis would be supported.
On the one hand, LRRK2 is a defined subset of PD where, as we have discussed, there is even some question whether all mutations work in the same way. This would suggest that LRRK2 mechanisms would be relevant only for LRRK2 PD, perhaps even for single mutations. On the other hand, LRRK2 cases are similar clinically, and sometimes pathologically, to sporadic PD; therefore, it is possible that the underlying mechanisms are similar. In further support of the idea that LRRK2 may play a role in sporadic PD, there is a signal around the LRRK2
locus in GWAS in sporadic PD that is not accounted for by specific LRRK2
]. Although the genetic basis of this association is unclear, one interpretation is that changes in the regulation of WT LRRK2 account for some of the lifetime risk of PD. By extrapolation, this would support the idea that LRRK2 is mechanistically linked to sporadic disease and would predict that LRRK2 therapies should be tried in idiopathic disease.
Recently, LRRK2 has been associated with an increased risk in some cancers, in particular melanoma [72
]. PD patients with G2019S mutations have a threefold increased risk of developing melanoma before the onset of PD [72
]. Whether a kinase inhibitor of LRRK2 would have any impact on cancer is very difficult to predict, but might be considered a potential extra target for drug development.
A biomarker of LRRK2 is needed to answer several of the above questions. Demonstration that a given drug has the desired effect in humans, that is, shows engagement of the target, will be crucial for deciding whether a given treatment has actually tested the underlying hypothesis. Furthermore, having a proximate biomarker for pathological LRRK2 activity would also be helpful in deciding whether the protein is involved in sporadic PD. What such a biomarker would look like is uncertain, although the action of LRRK2 kinase on a target protein is an obvious possibility. Development of these types of markers is eagerly awaited.