Regenerative Drugs for Parkinson’s Disease
Posted in Regeneration Series on 30th Sep 2014
- No drug yet has convincing data to prove that it has neuroprotective properties in PD.
- Many agents show promise in the laboratory and are undergoing Phase 2 evaluation of clinical efficacy.
- Repositioning of agents already licensed for use in man avoids major safety and tolerability concerns.
- The existence of a wide range of agents, with diverse mechanisms all related to our latest understanding of PD neuro-degeneration, provides hope that one or more of these may translate to a clinically useful therapy.
While neuro-“regeneration” is conceptually distinct from neuro-protection, from the perspective of therapeutic development in Parkinson’s disease, progress indicating any effect in slowing, stopping or reversing neurodegeneration would be warmly welcomed. Any mechanism through which an agent may protect against neuronal degeneration, might similarly allow endogenous repair processes to resume, therefore there is no attempt to distinguish between these concepts here.
There have been several major disappointments in this field in recent years. Creatine, Coenzyme Q10 and Cogane all showed promise as potential disease modifying agents in PD but all failed when formally evaluated in large phase 2 trials. Our enthusiasm for the next generation of candidates must thus be tempered by these disappointments and necessitates closer scrutiny of the evidence supporting potential efficacy before the major financial investment is made to embark on further very expensive, large scale trials. The agents that are currently at various stages in the “PD regenerative pipeline” include;
Some large epidemiological studies have suggested a slightly lower risk of PD among individuals treated with brain penetrating dihydropyridine calcium antagonists such as isradipine.1 However similar benefits are associated with the non-brain penetrating amlodipine, and this association has been questioned as simply reflecting that patients prescribed these drugs are exposed to a specific pattern of health care, a behaviour which has greater relevance for PD risk then the exposure to the agent itself.2 However credence is given from laboratory work showing that nigrostriatal cells have calcium dependent pacemaking activity which is highly energy demanding that can be blocked by this class of drugs.3 Furthermore, in mouse models of PD, isradipine protects against dopaminergic cell death from either the MPTP or 6-hydroxy dopamine mitochondrial toxins.4 There are, as yet, no data regarding the efficacy of this drug in transgenic animals or animals exposed to alpha synuclein preformed fibrils, currently considered to represent closer models of the neurodegenerative process of PD.5
Thus far, the clinical trial data in patients with PD shows that the 10mg dose of the drug is well enough tolerated with respect to blood pressure lowering, although the evidence of beneficial effects (~1 point advantage in the total Unified Parkinson’s disease rating scale (UPDRS) score after one year) is modest and did not reach statistical significance.6 Whether this effect size is of clinical importance is debatable, however these data have already been considered sufficiently strong to secure $23m funding from NIH to take this agent to a phase 3 trial.
Epidemiological studies also suggest that higher levels of plasma uric acid are associated with a slower rate of progression of PD.7,8 Again, while intriguing, this does not confirm that this association is in any way causal; perhaps individuals with higher CNS dopamine levels gain greater (dopamine-mediated) pleasure from uric acid rich foods/wines. Nevertheless, there are also some supportive data from the study of in-vivo animal models of PD that uric acid may have neuroprotective properties.9 Uric acid itself is rapidly metabolised in the gut however oral administration of inosine, the precursor to uric acid, can successfully increase plasma and CSF uric acid levels.10
In a pilot clinical trial, patients with low levels of serum urate at baseline were recruited and randomised to receive low or medium doses of inosine or placebo for two years.11 Most participants continued with their allocated drug for six months, however the number of participants had fallen by 50% at one year and only a small minority were still exposed to inosine/placebo beyond one year, although there appeared to be only a small risk of causing gout or kidney stones. Overall, the difference in the rate of worsening based on change in total UPDRS score per year indicated only a very slight advantage (~1 point) in the higher dose inosine treated group only, and careful consideration must be taken to decide whether this magnitude of signal of effect justifies the major further investment currently being sought.
Intra-putaminal Glial cell derived neurotrophic factor (GDNF)
In 2003, an open label trial of intra-putaminal GDNF infusion in PD patients reported positive clinical and radiological outcomes, however a subsequent double blind trial could not replicate these beneficial effects.12,13 Prolonged debate followed regarding differences in the methods used to administer the GDNF in the double blind trial that may have explained this discrepancy. However further concerns emerged regarding the significance of a) anti-GDNF antibodies and b) cerebellar toxicity, observed in some laboratory animals treated with prolonged GDNF infusion.14 Enthusiasm has been further dampened by the subsequent lack of beneficial effect of Cogane, an orally active GDNF inducer, and neurturin – a GDNF analogue delivered via gene therapy vector.15,16
Nevertheless, inspired by the original results and long term follow up of patients in the open label trial, the team in Bristol, UK are recruiting further patients to a further double blind trial to revisit and clarify the potential of intra-putaminal administration of GDNF.
GM1 ganglioside is an important component of neuronal membrane signalling and has been shown to have neuroprotective effects in the toxin based animal models of PD.17,18 In a double blind delayed start designed trial, early use of GM1 (administered as iv loading injection followed by twice daily subcutaneous injection) had clear acute symptomatic effects (~5 point improvement on the motor subsection of the UPDRS).19 Individuals allocated to receive GM1 after a 24 week delay also had comparable symptomatic improvement but did not catch up with the benefits seen in the early start group during the two year exposure period. After cessation of the drug, all patients slowly deteriorated but again those individuals treated earlier had a modest advantage at all subsequent time points over the next two years. There is therefore ongoing interest in the potential of GM1 as both a symptomatic as well as a potential neuroprotective drug in PD.
Excessive levels of iron have been identified in the substantia nigra of PD patients correlating with disease severity.20 Deferiprone is a licensed treatment for iron chelation, known to cross the blood brain barrier.21 In a further delayed start design trial, deferiprone reduced levels of iron in the SN seen using T2* MRI, associated with a two point improvement in the UPDRS motor subscore.22 This effect size is clinically important although these data cannot yet be interpreted as neuroprotection given that it remains possible that there is some interaction between iron chelation and dopaminergic treatment. A further pilot trial is ongoing. (Clinical trials.gov NCT01539837).
Exenatide is an agonist for the Glucagon-like peptide 1 receptor (GLP-1), the stimulation of which leads to an increase in insulin release and proliferation of pancreatic beta islet cells.23 It is licensed for the treatment of type 2 diabetes mellitus. In vitro studies have suggested additional neurotrophic actions and in vivo studies have shown neuroprotective effects on dopaminergic cells in the toxin based animal models of PD.24,25,26,27 Exenatide has also been shown to have beneficial effects on noradrenergic and serotonergic systems with positive behavioural effects in animals indicating potential relevance for non-motor symptoms of PD such as memory and mood disturbance.28,29
In a small open label trial, administration of exenatide by twice daily subcutaneous injection for 12 months was accompanied by a five point advantage on the motor subsection of the UPDRS together with a similar improvement in cognitive performance.30,31 These advantages persisted 12 months after cessation of exenatide, however given the open label trial design, these results must be interpreted with caution unless/until they are replicated in a double blind trial.
Pioglitazone is a licensed treatment for type 2 diabetes mellitus, and acts to improve insulin resistance via an action on the peroxisome proliferator activated receptor gamma (PPARŒ≥) receptor. In the laboratory it has been shown that this agent reduces the expression of pro inflammatory cytokines by reactive microglia.32 In the non-human primate MPTP model of PD, pioglitazone was found to reduce the loss of dopaminergic neurons and preserve motor function.33
As a result of these observations, a phase 2 trial of pioglitazone in 216 patients with PD is underway but as yet there are no efficacy data in humans with PD. However, despite the robust laboratory data supporting study of pioglitazone in tandem with intriguing mechanistic links between pioglitazone, mitochondrial function and PD, a potential association between pioglitazone and a small increased risk of bladder cancer has recently been discovered; in a meta-analysis it was calculated that this amounted to approximately five cases of bladder cancer for every 100,000 person years of pioglitazone treatment.34 Careful scrutiny of clinical trial data regarding any benefit on PD progression will be required before any conclusion can be drawn in evaluating the acceptability of this level of risk.
Alpha synuclein vaccination
Given that we know that excessive levels of (even normal) alpha synuclein are sufficient to cause PD, the concept of using vaccination has arisen, to try and lower these levels.35 The major problem has been identifying whether and how a peripherally administered antibody can access the central nervous system and target a predominantly intracellular protein, and have sufficient selectivity for alpha synuclein and no other synucleins. In a transgenic mouse over-expressing human alpha synuclein, such an antibody has been shown to successfully lower alpha synuclein aggregation in neuronal cell bodies even after peripheral administration.36,37 This has led to the initiation of two safety trials in small numbers of either healthy individuals (Clinicaltrials.gov/ NCT02095171) or patients with early PD (Clinicaltrials.gov/NCT01885494). Similar attempts are underway to try and lower beta amyloid levels as a treatment for Alzheimer’s disease.
The GBA gene encodes the enzyme glucosylceramidase (GCase), and homozygous or compound heterozygous mutations in this gene are the cause of Gaucher’s disease. Carrying a single GBA mutation has been shown to be the commonest genetic risk factor for PD.38 There is a reduction in the activity of GCase in brain tissue from PD and DLB patients (with or without GBA mutations).39 This enzyme is thus a potentially very important target for the treatment of PD. Ambroxol hydrochloride is a small molecule that protects GCase from thermal denaturation and boosts the function of GCase through upregulation of the transcription factor TFEB.40 It is licensed for use in humans and is present in many cough syrups as it also has a role as a mucolytic. It can cross the blood brain barrier.41 Laboratory data therefore lend strong support to taking this agent into phase 1 clinical trial in PD patients.
There can be some enthusiasm for the agents that currently represent the major focus as neuroprotective / neuroregenerative agents in PD. However, as yet none have emerged with robust double blind data to demonstrate a major neuroprotective effect in patients with PD.
Ongoing work to develop more useful animal models of PD neurodegeneration, and to develop a reliable biomarker that can be used to judge effects in humans with PD will be enormously helpful. Furthermore, while it is hoped that the identification of a disease modifying agent in PD will be of use in individuals with established disease, other initiatives are underway to try and identify “at-risk” populations who might be more responsive to treatments that require a relatively intact cellular architecture.
These issues and further work to understand PD pathogenesis remain of vital importance, but from a pragmatic perspective there is an urgency to efficiently confirm or exclude beneficial effects of those agents with the strongest supportive data without undue delay. To this end, there are considerable efforts to streamline and “de-risk” this process through the linked clinical trials initiative.42 The challenges are great but with the breadth and depth of the efforts being made to overcome these challenges, it is reasonable to be optimistic.
- Pasternak B, Svanstrom H, Nielsen N, et al. Use of calcium channel blockers and Parkinson’s disease. J Epidemiol. 2012;175:627–35.
- Marras C, Gruneir A, Rochon P, et al. Dihydropyridine calcium channel blockers and the progression of parkinsonism. Ann Neurol. 2012;71:362-9.
- C. Chan, Guzman, N. Jaime, E, et al. Rejuvenation’ protects neurons in mouse models of Parkinson’s disease. Nature. 2007;447:1081-6.
- Ilijic E, Guzman JN, Surmeier DJ. The L-type channel antagonist isradipine is neuroprotective in a mouse model of Parkinson’s disease. Neurobiol Dis. 2011;43:364–71.
- Luk KC, Kehm V, Carroll J, et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science. 2012;338:949-53.
- Parkinson Study Group. Phase II safety, tolerability, and dose selection study of isradipine as a potential disease-modifying intervention in early Parkinson’s disease (STEADY-PD). Mov. Disord. 2013;28:1823–31.
- Gao X, Chen H, Choi HK, et al. Diet, urate, and Parkinson’s disease risk in men. Am J Epidemiol. 2008;167:831-8.
- Shen C, Guo Y, Luo W, et al. Serum Urate and the Risk of Parkinson’s: results from a meta-analysis. Can J Neurol Sci. 2013;40:73-9.
- Chen X, Burdett TC, Desjardins CA, et al. Disrupted and transgenic urate oxidase alter urate and dopaminergic neurodegeneration. Proc Natl Acad Sci. 2013;110:300-5.
- Chen X, Wu G, Schwarzschild MA. Urate in Parkinson’s disease: more than a biomarker? Curr Neurol Neurosci Rep. 2012;12:367-75.
- The Parkinson Study Group SURE-PD. Inosine to Increase Serum and Cerebrospinal Fluid Urate in Parkinson Disease. JAMA Neurol. 2013;71:141-50.
- Gill SS, Patel NK, Hotton GR, et al. Direct brain infusion of glial cell line-derived neurotrophic factor in Parkinson disease. Nat Med. 2003;9:589-95.
- Lang AE, Gill S, Patel NK, et al. Randomized controlled trial of intraputamenal glial cell line-derived neurotrophic factor infusion in Parkinson disease. Ann Neurol. 2006;59:459-66.
- Hovland DN, Boyd RB, Butt MT, et al. Six-month continuous intraputamenal infusion toxicity study of recombinant methionyl human glial cell line-derived neurotrophic factor (r-metHuGDNF in rhesus monkeys. Toxicol Pathol. 2007;35:1013-29.
- Investigation of Cogane (PYM50028) in Early-stage Parkinson’s Disease (CONFIDENT-PD). Clinical trials.gov. Available: http://clinicaltrials.gov/ct2/show/NCT01060878. Accessed 2014
- Marks WJ, Bartus RT, Siffert J, et al. Gene delivery of AAV2-neurturin for Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol. 2010;9:1164-72.
- Schneider JS, Kean A, DiStefano L. GM1 ganglioside rescues substantia nigra pars compacta neurons and increases dopamine synthesis in residual nigrostriatal do- paminergic neurons in MPTP-treated mice. J Neurosci Res. 1995;42:117-23.
- Schneider JS, Pope A, Simpson K, et al. Recovery from experimental parkinsonism in primates with GM1 ganglioside treatment. Science. 1992;256:843-6.
- Schneider JS, Gollomp SM, Sendek S, et al. A randomized, controlled, delayed start trial of GM1 ganglioside in treated Parkinson’s disease patients. J Neurol Sci. 2013;324:140-8.
- Sian-Hulsmann J, Mandel S, Youdim MB, et al. The relevance of iron in the pathogenesis of Parkinson’s disease. J Neurochem. 2011;118:939-57.
- Sohn YS, Breuer W, Munnich A, et al. Redistribution of accumulated cell iron: a modality of chelation with therapeutic implications. Blood. 2008;111:1690-9.
- Devos D, Moreau C, Devedjian JC, et al. Targeting chelatable iron as a therapeutic modality in Parkinson’s disease. Antioxid Redox Signal. 2013;0:1-16.
- Parkes DG, Mace KF, Trautmann ME. Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone, GLP-1. Expert Opin Drug Discov. 2013;8:219-44.
- Perry T, Lahiri DK, Chen D, et al. A novel neurotrophic property of glucagon-like peptide 1: a promoter of nerve growth factor-mediated differentiation in PC12 cells. J Pharmacol Exp Ther. 2002; 302:881-8.
- Perry T, Haughey NJ, Mattson M, et al. Protection and reversal of excitotoxic neuronal damage by glucagon-like peptide-1 and exendin-4. J Pharmacol Exp Ther. 2002;302:881-8.
- Bertilsson G, Patrone C, Zachrisson O, et al. Peptide hormone exendin-4 stimulates subventricular zone neurogenesis in the adult rodent brain and induces recovery in an animal model of Parkinson’s disease. J Neurosci Res. 2008;86:326-38.
- Kim S, Moon M, Park S. Exendin-4 protects dopaminergic neurons by inhibition of microglial activation and matrix metalloproteinase-3 expression in an animal model of Parkinson’s disease. J Endocrinol. 2009;202:431-9.
- Rampersaud N, Harkavyi A, Giordano G, et al. Exendin-4 reverses biochemical and behavioral deficits in a pre-motor rodent model of Parkinson’s disease with combined noradrenergic and serotonergic lesions. Neuropeptides. 2012;46:183-93.
- Foltynie T, Aviles-Olmos I. Exenatide as a potential treatment for patients with Parkinson’s disease: first steps into the clinic. Alzheimers Dement. 2014;10:S38-46.
- Aviles-Olmos I, Dickson J, Kefalopoulou Z, et al. Exenatide and the treatment of patients with Parkinson’s disease. J Clin Invest. 2013;123:2730-6.
- Aviles-Olmos I, Dickson J, Kefalopoulou Z , et al. Motor and Cognitive Advantages Persist 12 Months After Exenatide Exposure in Parkinson’s Disease. J Parkinsons Dis. 2014
- Carta AR, Pisanu A. Modulating microglia activity with PPAR-ϒ agonists: a promising therapy for Parkinson’s disease? Neurotox Res. 2013;23:112-23.
- Swanson CR, Joers V, Bondarenko V, et al. The PPAR-ϒ agonist pioglitazone modulates inflammation and induces neuroprotection in parkinsonian monkeys. J Neuroinflammation. 2011;8:91.
- Ferwana M, Firwana B, Hasan R, et al. Pioglitazone and risk of bladder cancer: a meta-analysis of controlled studies. Diabet Med. 2013;30:1026-32.
- Olanow CW, Brundin P. Parkinson’s Disease and Alpha Synuclein: Is Parkinson’s Disease a Prion-Like Disorder? Mov Disord. 2013;28:31-40.
- Masliah E, Rockenstein E, Adame A, et al. Effects of alpha-synuclein immunization in a mouse model of Parkinson’s disease. Neuron. 2005;46:857-68.
- Masliah E, Rockenstein E, Mante M, et al. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011;6:e19338.
- Duran R, Mencacci NE, Angeli AV, et al. The glucocerebrosidase E326 K variant predisposes to Parkinson’s disease, but does not cause Gaucher’s disease. Mov Disord. 2013;28:232-6.
- Gegg ME, Burke D, Heales SJ, et al. Glucocerebrosidase deficiency in substantia nigra of Parkinson disease brains. Ann Neurol. 2012;72:455-63.
- Schapira AH, Gegg ME. Glucocerebrosidase in the pathogenesis and treatment of Parkinson disease. Proc Natl Acad Sci. 2013;110:3214–5.
- McNeill A, Magalhaes J, Shen C, et al. Ambroxol improves lysosomal biochemistry in glucocerebrosidase mutation-linked Parkinson disease cells. Brain. 2014;137:1481-95.
- Brundin P, Barker RA, Conn P, et al. Linked clinical trials–the development of new clinical learning studies in Parkinson’s disease using screening of multiple prospective new treatments. J Parkinsons Dis. 2013;3:231-9.
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