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Abstract

The understanding of the pathobiology of Parkinson's disease (PD) is evolving, based largely on genetic discoveries. Despite a rich pipeline of potential therapies addressing aspects of the underlying biology of the disease, there is currently no available disease-modifying therapy for PD. In this short commentary, we review the status of the relevant pipeline and highlight areas where alternative or complementary approaches could also be advanced to the stage of clinical trials, with the ultimate goal of providing meaningful clinical benefit to patients and their families. The further evolution of biomarkers, cellular and animal models of the disease and delivery methods will be crucial to this end.

Plain language summary

The understanding of the background of Parkinson's disease (PD) is evolving, based largely on genetic discoveries. Despite numerous potential therapies addressing aspects of the underlying biology of the disease, there is currently no available therapy able to modify PD clinical course. In this short commentary, we review the status of the relevant therapeutic trials landscape and highlight areas where alternative or complementary approaches could also be advanced to the stage of clinical studies, with the ultimate goal of providing meaningful clinical benefit to patients and their families. The further evolution of biomarkers, cellular and animal models of the disease and delivery methods will be crucial to this end.

Keywords

Parkinson's disease disease-modifying therapy biomarkers cellular model animal model alpha-synuclein glucocerebrosidase

Introduction

The Parkinson's disease (PD) clinical therapeutic pipeline is robust. While many programs in development address important symptomatic needs, nearly half focus on disease-modifying therapies. Strategies target a range of possible biology associated with PD pathogenesis, with several progressing into mid and later clinical testing phases.¹

Here, we highlight opportunities in the clinical therapeutic pipeline for PD where emerging concepts and biological insight may offer future promise. Given the many avenues to explore, we elected to focus on approaches targeting disease pathobiology, such as those emerging from genetic and other studies. To provide a more thoughtful focused commentary, we have not included approaches such as trophic or cell-based therapies that aim to provide a general protective environment to cells of the nervous system or seek to restore or replace missing cellular function. We also do not address approaches targeting neurotransmitter systems for symptomatic relief which are vital for patients but beyond the scope of this short commentary (Table 1).

Table 1.

Current status of the PD therapeutic pipeline and areas where alternative or complementary approaches could be applied.

In the pipeline	Commentary	Alternative approaches
Targeting Alpha-Synuclein	Relevant for most PD patients
Passive Immunization	Multiple ongoing efforts, some have failed; pending more definitive results
Active Immunization	Few approaches, more needed
Anti-aggregation with small molecules	Only one compound in clinical trials, more similar approaches needed	Targeting liquid phase separation
Targeting interactions with lipids	Promising area of research, one ongoing trial	Promising results in preclinical models
		Targeting transmission through effects on receptors/relevant pathways
Reducing production through intrathecal ASO or small molecule	Intrathecal ASO approach promising, based on success in other neurodegenerative diseases; small molecule may also inhibit other proteinopathies	siRNAs, shRNAs, AAV-mediated approaches, Alternative routes of delivery of nucleic acids, random screening efforts to identify other small molecules that inhibit AS production
		Specifically enhancing AS clearance through PROTAC or AUTOTAC
Targeting Cellular Degradation Systems	May be relevant for co-pathologies
C-Abl kinase inhibitors	Results pending
		Macroautophagy stimulation through small molecules acting on mTOR-dependent or -independent pathways
		Enhancement of Chaperone-Mediated Autophagy
		Enhancement of proteasomal activity
		Enhancement of lysosomal clustering or acidification
Targeting Vesicular Recycling	May be relevant for iPD more generally	Pharmacological chaperones stabilizing retromer function
Targeting GBA1-GCase	Most relevant for GBA-PD
Enzyme Replacement through AAV-mediated intracisternal delivery of GBA1 gene or aided by MRI-focused ultrasound	Pending results for AAV approach, MRI-focused ultrasound approach demonstrated safety and feasibility	Alternative routes of delivery of GBA1 gene or GCase
Substrate Reduction	Major trial failed
Small molecule chaperones	Ambroxol trials most advanced	High-throughput screening efforts for similar compounds without inhibitory activity
Targeting LRRK2	Most relevant for LRRK2-PD
Reducing LRRK2 levels through intrathecal ASO	In early stages	siRNAs, shRNAs, AAV-mediated approaches, Alternative routes of delivery of nucleic acids; Reducing LRRK2 levels through increased clearance with LRRK2 PROTAC
Inhibiting kinase activity through type I kinase inhibitors	Results awaited	Allosteric modulation through inhibition of GTPase activity or dimerization; type II kinase inhibitors; enhancers of PPM1H phosphatase
Targeting Neuroinflammation	Relevant to most PD cases
General peripheral immunosuppression through azathioprine	Proof of principle
Human recombinant GMCSF, as inducer of T-regulatory immune cell responses		More targeted approaches for addressing specific adaptive immune responses to AS
Inhibition of innate immunity through targeting of NLRP3 inflammasome or other microglial pro-inflammatory pathways		Targeting of NF-kB; selective TNF-alpha inhibition; complement inhibition; TLR2 inhibition (with additional effects on AS clearance, possibly also transmission)
Fecal Transplantation	Encouraging results from phase 2 study	Antibiotic treatment may also be considered
Targeting Mitochondrial, Oxidative and Metabolic Health	Relevant perhaps to a subset of PD cases
Anti-oxidants	Have largely failed
Increasing mitochondrial biogenesis	One PPAR-γ agonist failed	Other PPAR-γ activators in development; enhancement of PGC-1α; direct delivery of healthy mitochondria
Targeting mitochondrial dynamics: Drp1 inhibitor in clinical development		More approaches enhancing mitochondrial fusion or inhibiting fission
Enhancing mitophagy: Inhibitor of USP30, an inhibitor of mitophagy, in clinical development		Other compounds to activate mitophagy, such as PINK1, PRKN enhancers
	Promoting mitochondrial health, reducing oxidative stress: Nrf2 activation a possible target	DMF used in MS an attractive candidate; other Nrf2 activators
	Other methods to improve mitochondrial health	Targeting calcium overload; enhancing AMPK; targeting cardiolipin
GLP-1 agonists	Conflicting results from trials

Alpha-synuclein-directed therapy

Overwhelming genetic, neuropathological, biochemical, animal model and biomarker data connect the presynaptic alpha-synuclein (AS) protein, and particularly its aberrant conformations, to PD.² The advent of the AS Seeding Amplification Assays (SAAs)³ has further brought AS to the forefront as a valid therapeutic target.

Targeting of aberrant AS could involve many approaches, from reducing its production to inhibiting specific aberrant species or specific intramolecular interactions, up to promoting its clearance. The current pipeline is rich with many ongoing clinical trials, mostly using passive and active immunization, which should act mainly by removing extracellular species. Notably, two approaches with ready-made antibodies with preference to aberrant AS conformations failed to meet primary endpoints in Phase 2 clinical trials for early PD.^4,5 Subsequent editorials have debated the validity of these approaches and whether pessimism may be premature.^6,7 In fact, the development of one of the two aforementioned antibodies, prasinezumab, is continued, based on encouraging results in the original report and further analyses of the generated data.^5,8,9 Encouraging target engagement data have also been reported with active immunization with the UB-312 peptide.¹⁰ It would be nice to see more of these active immunization approaches in the clinic, given issues of cost and ease of administration.

Compared to immunization approaches, there are relatively fewer approaches with small molecules. Curiously, there is only one ongoing trial with a pure anti-aggregation compound, emrusolmin (previously Anle 138b),¹¹ which was discovered through an in vitro screening as an inhibitor of Prion and AS oligomers.¹² The theoretical advantage of this approach is that it only attacks presumably deleterious AS species (notwithstanding the pinning down of their exact nature), leaving intact the protein's physiological functions. Furthermore, such compounds may bind to and neutralize deleterious aggregated conformations of other proteins, such as Αβ or Tau, which may be important in view of the mounting evidence of co-pathologies. It would therefore be important to see more anti-aggregation compounds in the pipeline, such as those based on Epigallocatechin gallate (EGCG) or other structures.¹³ A related approach currently tested in the clinic, through the compound Minzasolmin, of inhibiting earlier steps of AS misfolding, by displacing membrane-associated oligomers,^14,15 seems to have failed according to a recent press release. A recently discovered pathway of protein aggregation that is thought to be relevant for proteinopathic neurodegenerative diseases is that of liquid phase separation, in which aggregate-prone proteins condensate within liquid droplets. AS can follow this pathway, and a recent publication paves the way for targeting this through small molecules, such as claramine.¹⁶

The AS pipeline is also relatively sparse in compounds indirectly influencing AS, through an action on intramolecular interactions. The interaction of AS with lipids at the membrane is receiving increasing scrutiny as a target for therapeutic intervention. Along these lines, an interesting approach that has reached the clinic, is that of inhibiting stearoyl-CoA desaturase (SCD), leading to a reduction of unsaturated fatty acids (FA).¹⁷ Lowering unsaturated fatty acid levels by slowing the lipase-mediated lipid degradation process has also been proposed as an alternative therapeutic approach,¹⁸ while selective pharmacological phospholipase A₂ inhibition also modulated FA interaction with AS, leading to its rapid proteasomal degradation.¹⁹ These studies overall suggest that modulation of the lipid environment may be a targetable strategy for alleviating AS-mediated neurotoxicity, and warrants more attention.

Given the likely importance of AS cell-to-cell transmission, it is important to also consider alternatives, beyond antibodies, that could specifically target this process. Along these lines, Kim et al.²⁰ and Dutta et al.,²¹ amongst others, have shown that selective inhibition of Toll-like Receptor 2 (TLR2) in neurons and glia inhibits AS transfer, as well as inflammatory and neurodegenerative effects in animal models. Interestingly, TLR2 inhibition by a novel small molecule also promoted neuronal autophagic degradation of AS.²² Thus, TLR2 targeting could have therapeutic potential from multiple angles, from an anti-inflammatory, pro-degradation and anti-propagation standpoint. More approaches targeting neuron-to-neuron and neuron-to-glia AS transmission are needed, pending a better understanding of the underlying mechanisms.²³

Inhibition of AS production appears like a rather straightforward method of decreasing the overall burden of AS, including its aberrant species. Although it does carry the potential risk of excessively interfering with the normal function of AS, neurotoxicity has not been demonstrated with AS lowering in experimental models.²⁴ The approach of using intrathecal antisense oligonucleotides (ASO), after being successfully implemented in preclinical models, including the non-human primate,²⁵ is currently being tested in a Phase 1 study. Other similar approaches could include siRNA or miRNA-mediated AS lowering, potentially through AAV-mediated viral transduction.²⁶ Such approaches could include systemic peripheral injections of relevant brain-penetrant AAVs which would ensure better biodistribution and potentially less CNS neurotoxicity compared to direct brain or intrathecal injections. Alternatively, such AS-targeting nucleic acid-based treatments could be aided by improved methods of delivery, such as the intranasal route, or conjugation with brain-penetrant peptides or polymers that would allow systemic delivery. These approaches have been successfully applied in preclinical models of synucleinopathies (reviewed in²⁷). A promising related avenue is that of utilizing the CRISPR/Cas9 gene editing technology to downregulate or even eliminate AS expression, and this has been achieved in a relevant neuronal iPSC model, with resultant inhibition of AS seeding.²⁸ In the current pipeline, there are few approaches with small molecules specifically targeting AS production, apart from buntanetap, which is being tested in a phase 3 trial (with encouraging results reported in a company press release) and has the advantage of also reducing APP, and therefore Αβ production, as well as Tau. Random screening approaches or rational design targeting specific regulatory elements that control AS transcription/translation can lead to the discovery of novel compounds that lower AS levels, such as Sunecleozid, with therapeutic potential.²⁹

Ingenious methods for the targeted clearance of specific protein targets have been recently developed through the construction and application of specific chimeric constructs that contain elements that bind selectively proteins of interest, such as AS, and target them for proteasomal (PROTAC) or autophagic (AUTOTAC) degradation; these have been successfully applied in cellular and even animal synucleinopathy models^30,31 and could find their way to the clinic.

Therapy directed to cellular degradation systems

Given that intracellular clearance mechanisms are known to be affected in neurodegenerative disease states, possibly even instigating or perpetuating the process, while they also malfunction with aging, their enhancement may represent a viable therapeutic strategy. Considering co-pathologies in the context of PD and other neurodegenerative diseases, such strategies could enable clearance of multiple pathogenic protein conformations.³² A caveat is that in each neurodegenerative disease the clearance pathways may be perturbed at different steps, and therefore strategies targeted to each disease state may still be required.³³

The relevant current pipeline includes only agents acting as c-Abl kinase inhibitors, which however have pleiotropic actions beyond alleviation of macroautophagy inhibition conferred by c-Abl. We believe that strategies to generally stimulate macroautophagy have therapeutic potential, based on ample preclinical data (reviewed in.³⁴ Rapamycin, the classical mTOR inhibitor, was effective in removing seeded AS aggregates in an inducible neuronal cell model,³⁵ and derivatives thereof, with less side effects and better brain penetration, could be attractive candidates. An mTOR-independent strategy with the disaccharide Trehalose was beneficial in synucleinopathy models, including non-human primates.³⁶ Either mTOR-dependent or -independent strategies could be used, in fact in recent work in an Alzheimer's Disease (AD) mouse model the best results were achieved with their combination.³⁷ A more recent relevant promising strategy involves improving lysosomal acidification through lysosomal nanoparticles, thus leading to improved overall lysosomal function and amelioration in animal synucleinopathy models.³⁸ A related potential therapeutic approach is that of activation of the lysosomal proton channel TMEM175 through synthetic chemicals, leading to enhanced lysosomal acidification and function and reduction of AS aggregation; this is especially important considering the genetic link of TMEM175 to PD, established through GWAS.^39,40 Enhancing the clustering of lysosomes around the microtubule organizing center (MTOC) and thus improving autophagic flux is another recent strategy that was effective in promoting cellular AS aggregate clearance. Several compounds with lysosomal-clustering activity were identified; importantly, they acted further downstream in the autophagy pathway, thus minimizing the potential for side effects.⁴¹

A separate, selective autophagy pathway, Chaperone-Mediated Autophagy (CMA) has been closely linked to AS and PD pathobiology and yet no relevant approaches exist in the current pipeline. Most notably, CMA is an important pathway for monomeric AS degradation, it is impaired in PD, and overexpression of its rate-limiting step, the lysosomal transmembrane protein Lamp2a, protects from AS-induced toxicity in cell culture and in vivo models (reviewed in³⁴). Recent data suggest that CMA is impaired in AD brains and animal models, that APP and Tau are CMA substrates, and that CMA enhancement through various small molecules, including the well-known anti-diabetic drug metformin⁴² alleviate AD neuropathological and behavioral phenomena in relevant experimental animal models.^43,44 Thus, pharmacological enhancement of CMA emerges as a possible therapeutic avenue, especially in the context of co-pathologies.

The proteasome has been neglected as a target in the PD pipeline, despite evidence that it may be responsible for clearing select deleterious oligomeric AS species, and in turn being inhibited by them, creating a vicious cycle,⁴⁵ or that it may be the main pathway for intrinsic rodent AS degradation in vivo.⁴⁶ It would be important to see therapeutic strategies promoting general proteasomal function in the clinic, given similar successful preclinical studies in the field of Alzheimer's Disease (AD); for example, brain-penetrant peptides promoting proteasomal function led to amelioration of pathological phenotypes in AD mouse models,⁴⁷ while the beneficial effects of resveratrol, the well-known SIRT1 activator, in similar models were attributed in part to its proteasomal-inducing activity.⁴⁸

Therapy directed to the vesicular recycling pathway

The vesicular recycling pathway related to endosomes and their trafficking between the cell membrane, lysosomes and the Golgi apparatus, is especially important for the function of lysosomes and the synapse. There is ample evidence that genetic defects in this pathway may lead to PD, through alterations in lysosomal and synaptic function.⁴⁹ There is very little in the pipeline regarding targeting these pathways in PD. An approach that could be fruitful in this space is that of improving the VPS35-dependent retromer function, involved in recycling endosomes to the Golgi apparatus.⁵⁰ Starting from an approach originally developed in the AD field,^50,51 Eleuteri et al.⁵² have identified a pharmacological chaperone, named 2a, able to stabilize retromer function and protect against AS-mediated neurotoxicity in a relevant synucleinopathy mouse model; interestingly, neuroprotection may be mediated through the indirect effect of promoting CMA.

GBA1-directed therapy

As the most common PD genetic risk factor, pathogenic heterozygote GBA1 mutations linked to PD (GBA-PD) reduce the activity of the lysosomal enzyme glucocerebrosidase (GCase) which degrades glucosylceramide (GlcCer) into glucose and ceramide. In turn the reduction of GCase activity may trigger AS accumulation, which may lead to disruption of GCase trafficking, creating a vicious cycle. Additional interrelated putative pathogenic mechanisms include accumulation of GCase substrates, lysosomal dysfunction, inflammation and endoplasmic reticulum (ER)-associated stress due to the misfolded mutant. There is a debate whether a loss or gain of function accounts for neurodegeneration, although most findings suggest the former.⁵³

Accordingly, proposed treatment approaches attempt to increase GCase activity, reduce its substrates through synthesis inhibition or improve the folding and trafficking of GCase through pharmacological small-molecule chaperones.

The mainstay of treatment for Gaucher disease (GD), with biallelic GBA1 mutations, is enzyme replacement therapy (ERT), which, however, does not traverse the blood-brain barrier (BBB). To circumvent this issue in the case of GBA-PD, a clinical trial is under way using, in combination with ERT, MRI-guided focused ultrasound in order to disrupt the BBB.⁵⁴ Future approaches could include tagging GCase with peptides that would enable BBB traversal.⁵³ A more direct approach is that of gene therapy delivering GCase to the brain, as currently in an ongoing clinical trial with intracisternal delivery of PR001, an AAV9 vector encoding for GCase. Newer AAV strains which offer BBB penetration and widespread brain transduction through systemic injection could be a promising future approach. Another interesting approach for augmenting GCase levels could be through the use of histone deacetylase inhibitors that prevent GCase proteasomal degradation.⁵⁵

The substrate reduction approach has had a setback with the failure of the MOVES-PD study, evaluating Venglustat, a brain penetrant glucosylceramide synthase inhibitor (GZ/SAR402671), in GBA-PD.⁵⁶ This failure occurred despite evidence for target engagement, suggesting that GlcCer and more generally GCase substrate accumulation might not represent an effective therapeutic target for GBA-PD.

Given the uncertainty regarding the pathogenicity of GBA-PD gain or loss of function, the concept of applying small molecule chaperones is attractive, and is currently being tested in a number of clinical trials. Ambroxol, a repurposed drug, is the most advanced at the moment and has shown evidence of target engagement in the cerebrospinal fluid.⁵⁷ More efforts are needed to uncover new GCase stabilizing compounds without inhibitory activities, and methods of high-throughput screening may prove instrumental in this regard.⁵⁸ The variability in the pathogenicity of the various mutants also needs to be considered, and it is possible that treatments will have to be tailored to the properties of the individual mutant conformations.

LRRK2-directed therapy

Mutations in the leucine-rich repeat kinase (LRRK2) gene lead to autosomal dominant PD through a presumed gain of function involving the kinase domain of the protein, leading to enhanced phosphorylation of its main substrates, Rab GTPases, with consequent alterations in vesicular trafficking. The current pipeline includes approaches to reduce levels or kinase activity of LRRK2. There are some safety concerns related to such approaches based on potential systemic effects of lowering LRRK2 activity.⁵⁹ Another important issue is whether such strategies could also be applied, beyond LRRK2-PD, to idiopathic PD (iPD), given evidence of increased LRRK2 activity in this setting as well. Accordingly, most current clinical trials include iPD participants. Interestingly, a recent study suggests that a biomarker of LRRK2-dependent centrosomal function in peripheral cells may be used to stratify iPD patients responsive to such therapies.⁶⁰

Regarding reduction of LRRK2 levels, a direct approach currently in the clinic is that of inhibiting LRRK2 synthesis through an intrathecal ASO. Indicatively, a prior study used this strategy successfully in an AS mouse model.⁶¹ As mentioned in the case of a similar approach for AS, related methods could in the future be applied to the same end (miRNA, siRNA via AAV transduction). The strategy of using a specific PROTAC for selective protein degradation, as already mentioned for AS, is currently in a phase I clinical study, based on the successful development of such brain-penetrant compounds which substantially reduce cellular LRRK2 levels.⁶²

Regarding inhibition of pathogenic LRRK2 activity, two classical or type I kinase inhibitors competing with ATP for binding to the ATP-binding pocket within the kinase domain are currently in clinical trials, based on strong preclinical data.⁶³ Results of these studies, especially the more advanced DNL-141/BIIB-112 compound, are eagerly awaited. Allosteric modulation of kinase activity could also be considered. This could be achieved, for example, through inhibition of the LRRK2 GTPase domain, however very few small molecules that inhibit GTPase activity have been reported.⁶⁴ Interestingly, vitamin B12 has been identified as an allosteric modulator of LRRK2 activity though inhibition of its dimerization, and cell-permeant peptides designed to inhibit dimerization may also act as LRRK2 activity inhibitors.⁶⁵ Therefore, engineered peptides that gain access to the brain or compounds with similar activity could be envisioned as future therapies. Another strategy could be the development of type-II kinase inhibitors,⁶⁶ although these may be less effective against mutant forms.⁵⁹ Another interesting approach could be the development of enhancers of the activity of PPM1H phosphatase, which dephosphorylates Rab proteins, thus acting as a crucial regulator of LRRK2 signaling.⁶⁷

Therapy directed to neuroinflammation

There is increasing evidence for the involvement of both innate and adaptive immunity mechanisms in PD pathogenesis.⁶⁸ Accordingly, there are quite a few anti-inflammatory/immunomodulatory approaches in the current pipeline.^69,70 A proof of principle study uses the general immunosuppressant azathioprine, with does not traverse the ΒΒΒ, in order to assess whether suppression of peripheral inflammation may be sufficient to provide clinical benefits.⁷¹ In a more specific approach targeting adaptive immunity, two phase 1 studies are investigating the use of human recombinant granulocyte-macrophage colony-stimulating factor (GMCSF), which induces T-regulatory immune cell responses.⁷² If indeed adaptive immune mechanisms, and in particular T cell responses, are important in PD pathogenesis, an intriguing thought, is whether drugs currently in use against Multiple Sclerosis could be repurposed for PD. In fact, fingolimod, a sphingosine-1-phosphate receptor antagonist, which inhibits T cell migration to the central nervous system, was protective in certain PD toxin-based animal models, although its effect was attributed to inflammasome inhibition in microglia.⁷³ It would be nice to see more directed approaches targeting the specific immunomodulatory events that are linked to PD pathogenesis, in particular the presumed specific activation of particular T cell subsets in response to AS peptides,⁷⁴ although this will require an improved understanding of the underlying biological processes.

Inhibition of innate immunity, more specifically of microglial activation, is also a current focus in the pipeline. Most approaches target the central sensor of inflammation in microglia, the NLRP3 inflammasome, based in part on data from neurotoxin-based animal models.⁷⁵ With the same aim of inhibiting microglial activation, the repurposed drug Montelukast, a leukotriene antagonist which was effective in a neurotoxin-based PD animal model,⁷⁶ has been used in a small open label phase 2 trial with encouraging results.⁶⁹ The relevant pipeline also includes NE3107, that binds to and inhibits extracellular signal-regulated kinase (ERK)-mediated pathways in macrophages/microglia, AKST4290, an antagonist of CCR3, a chemokine receptor expressed on leucocytes and activated microglia and astrocytes, and BHV-8000, a dual selective inhibitor of TYK2/JAK1, aiming at curtailing the relevant pro-inflammatory signaling pathways.⁶⁹

Several additional approaches mainly targeting aberrant inflammatory microglial/astrocytic activation could be envisioned for future trials; for example, NF-κB inhibition, as it appears to represent a central node in detrimental innate immune activation in the context of PD models.^77,78 TLR signaling is also a valid therapeutic target, especially TLR2, as its inhibition may have other beneficial effects beyond attenuation of neuroinflammation, as mentioned earlier. Somewhat counterintuitively, TLR4 activation is associated with neuroprotection in a Multiple System Atrophy transgenic mouse model, due to the enhanced clearance of AS.⁷⁹ Tumor Necrosis Factor (TNF) signaling has long been proposed as a therapeutic target, and its inhibition could represent a valid approach if selectivity to pro-inflammatory effects is achieved.⁸⁰ In fact, the administration of anti-TNF therapy in inflammatory bowel disease (IBD) correlated with a significant decrease in the occurrence of PD.⁸¹ Complement activation may occur in the context of PD, and a recent study suggests that modulation of astrocytic C3 in a PD animal model is neuroprotective,⁸² which is quite interesting, given the emergence of anti-complement therapeutics in neurological diseases.

Considering the role of gut microbiota in inflammation, current efforts in the pipeline using fecal microbiota transplantation or antibiotics could be considered within the anti-inflammatory space. Notably, a phase 2 trial with a single fecal microbiota transplantation in patients with mild to moderate Parkinson's disease (GUT-PARFECT) reported encouraging results.⁸³

Therapy directed to mitochondrial, oxidative, and metabolic health

Environmental, genetic and pathological evidence has long linked mitochondrial dysfunction to at least some forms of PD offering a range of possible targets for therapeutic intervention.⁸⁴ Attempts so far to mitigate mitochondrial dysfunction and potentially slow PD-associated neurodegeneration have mostly targeted oxidative stress with various antioxidants (e.g., coenzyme Q10, glutathione, urate elevation) but have largely failed or shown uncertain benefit in clinical testing.⁸⁴ Reasons for this lack of success are not clear but may include limited ability for agents to achieve sufficient brain exposure or that the intrinsic kinetics of redox processes in the cell may simply act too fast or be too tightly regulated for any delivered molecule to adequately influence. We may also simply not know exactly when, where or who to target with these approaches.⁸⁵ More potent ways to address mitochondrial impairment, such as targeting mechanisms that regulate overall mitochondrial health and quality are therefore needed.⁸⁶

Increasing biogenesis of new, healthy mitochondria is one approach with much attention focused on targeting key regulators such as peroxisome proliferator-activated receptor gamma (PPAR-gamma) and PPAR-gamma coactivator 1alpha (PGC-1alpha).⁸⁷ Unfortunately, trials of pioglitazone, a PPAR-gamma agonist, showed little benefits for PD.⁸⁸ Newer PPAR-gamma agonists are in development (for example⁸⁹) as well as approaches that target PGC-1alpha, such as TQS-168 currently in early clinical testing for amyotrophic lateral sclerosis.⁹⁰ More recently, increasing appreciation of the role that mitochondrial-derived vesicles play in regulating mitochondrial quality control suggests the possibility of therapeutically delivering healthy mitochondria or mitochondrial components directly to at-risk cells.^91,92

Mitochondrial fusion and fission, a process important for dynamically responding to a variety of cellular stressors⁸⁶ may play roles in PD pathogenesis.⁹³ Therapeutically, targeting the key proteins involved in mitochondrial fission and fusion such as dynamin-related protein 1 (Drp1) and mitofusins (Mfn1 and Mfn2) might offer protective benefits if sufficiently selective and safe compounds can be developed.⁹⁴ Intriguingly, at least one therapeutic, ASHA-091, which targets Drp1 is reportedly in development for PD and other conditions (https://www.ashatherapeutics.com/pipeline).

Mitophagy is key for removal of dysfunctional mitochondria and appears to increase with brain aging in some cell populations including PD-vulnerable dopamine neurons.⁹⁵ Impairment in mitophagy, as is supported by PD-associated mutations in PRKN and PINK1, may therefore contribute to some forms of PD and is an area of increasing therapeutic interest.⁹⁶ Based on promising preclinical studies, at least one approach is now in early human testing to inhibit USP30, a deubiquitylating enzyme that blocks mitophagy.⁹⁷ Efforts to therapeutically activate parkin and PINK1, and thus potentially enhance mitophagy, are also emerging and worth continued progression into clinical testing.^98,99

Enhancing overall mitochondrial defenses and resilience can also offer promise. Targeting the NF-E2 p45-related factor 2 (Nrf2) transcriptional pathway activates a range of protective mechanisms including those linked to mitochondrial function and health.¹⁰⁰ Availability of approved medications targeting this pathway such as dimethyl fumarate for multiple sclerosis might offer repurposing opportunities for PD based on preclinical data in a range of neurodegeneration models.¹⁰¹ Calcium is important for maintaining dopamine neuron pace-making activity but may also increase mitochondrial stress and subsequent neurodegeneration.¹⁰² While testing of the calcium channel blocker isradipine failed to show benefit in a large phase 3 trial, further analysis suggests there may still be potential with improved attention to drug pharmokinetic properties or dosing.^103,104 Other targets with growing therapeutic potential for improving mitochondrial health in PD and other neurodegenerative disorders include AMP-activated protein kinase (AMPK), a key cellular energy sensor¹⁰⁵ that has also recently been implicated in mediating the anti-aging effects of caloric restriction.¹⁰⁶ Targeting the critical mitochondrial lipid cardiolipin, which supports mitochondrial membrane stability¹⁰⁷ may also offer neuroprotective benefits with compounds already in development for neurodegenerative diseases such as ALS.¹⁰⁸

Finally, bolstering metabolic processes linked to mitochondrial function has been another area of particular interest, with much focus on use of GLP-1 receptor agonists driven by a growing foundation of preclinical support.¹⁰⁹ Multiple clinical trials of GLP-1 receptor agonists, including exenatide, liraglutide and lixisenatide have painted an intriguing but unfortunately complicated picture of possible benefits for PD, with the latest large phase 3 study of exenatide being negative.^110–113 Theories fueling possible neuroprotective rationale for targeting GLP-1 receptors in neurodegenerative diseases are many,¹¹⁴ but current clinical trial data offer limited to no clarity on this question.

As more understanding emerges of the role mitochondrial impairment plays in the pathogenesis of PD, it is likely that we will see entry into clinical testing of therapies with ever greater mechanistic specificity. Moreover, mitochondria sit at an interface with several other neurodegenerative pathways which may reveal additional therapeutic targets, such as links to cGAS-STING¹¹⁵ or NLRP3 inflammasome signaling.¹¹⁶ A recent study suggesting PINK1 may act as an autoantigen and trigger of possible adaptive immune responses in PD¹¹⁷ demonstrates the complex connections between mitochondria and other neurodegenerative processes. Critical for future success of any of these approaches (or at least more informative clinical testing) will be the development of meaningful biomarkers of mitochondrial function and oxidative stress, with some intriguing possibilities emerging from imaging tracer development.¹¹⁸ Such measurement tools will not only support more informed clinical trials but also help better define PD patient populations most likely to benefit from mitochondria-directed therapy.

Conclusion

It is obvious that the current PD pipeline contains diverse disease-modifying therapeutic approaches, but that it could be further enriched (Figure 1). As “one size does not fit all”, different therapeutic strategies may likely be needed for particular biological subtypes of PD or particular biological stages, as initiating factors may be different from those sustaining or propagating the disease. Sex-specific factors may also be important, as the disease may biologically differ in males and females.¹¹⁹ Thus, biomarker-based stratification will be critical to match the specific target population with a particular pharmacological/biological intervention. An important and emerging case-in-point are studies in the prodromal stage of synucleinopathies based on the AS SAA.¹²⁰ In such a population, for example, it would make sense to prioritize strategies directed against AS. This means that a future PD pipeline will need to not only exhibit an expanded range of strategies, as well as informative target engagement biomarkers, linked to our increasing knowledge of underlying biological mechanisms, but also reflect a more precise targeting of key disease subtypes enriched with new measurement tools. This more than anything represents in many ways the main “gap” in the current PD pipeline but one that if filled could greatly accelerate progress in delivering better treatments for patients.

Figure 1.

General bullet points regarding approaches targeting PD pathobiology.

Footnotes

ORCID iDs

Christos Koros

Brian Fiske

Leonidas Stefanis

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Christos Koros and Leonidas Stefanis have received funding from the Michael J. Fox Foundation for their participation in the PPMI Study.

Brian Fiske is a Co-Chief Scientific Officer at The Michael J. Fox Foundation for Parkinson's Research.

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Gaps in the Parkinson's disease therapeutic clinical pipeline: A focus on approaches targeting disease pathobiology

Abstract

Plain language summary

Keywords

Introduction

Alpha-synuclein-directed therapy

Therapy directed to cellular degradation systems

Therapy directed to the vesicular recycling pathway

GBA1-directed therapy

LRRK2-directed therapy

Therapy directed to neuroinflammation

Therapy directed to mitochondrial, oxidative, and metabolic health

Conclusion

Footnotes

ORCID iDs

Funding

Declaration of conflicting interests

References