パーキンソンの病気―最近の進歩

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Introduction

Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by the loss of dopaminergic neurons and accumulation of Lewy’s bodies leading to imbalance in the levels of dopamine. PD is the second frequent neuro disorder following Alzheimer’s disease. Symptoms of PD include tremors, bradykinesia, muscle stiffness, impaired posture and gait, loss of movement, changes in speech, changes in writing, thinking difficulties, constipation, depression, sleep problems, changes in blood pressure, smell dysfunction and pain and fatigue. The levels of norepinephrine at neuron ends, which control many automatic functions of the body are also affected, leading to non-movement features.¹ It is a slowly progressing neurodegenerative disorder with no exact cause identified, with symptoms similar to other neurodegenerative diseases such as multiple system atrophy, progressive supranuclear palsy, striatonigral degeneration. This makes it difficult to identify PD at an early stage.^{2, 3}

Approximately 10 million people worldwide live with PD. The cost of PD is estimated to be close to $52 billion every year in the United States alone with nearly one million expected to be living with Parkinson's disease by 2020. PD is generally diagnosed above the age of 60, with 1% of the population diagnosed during their 60s or later.^{4, 5}

The symptoms of PD are classified as motor and non-motor symptoms, with symptoms getting progressively worse as the disease develops.

Motor Symptoms are the symptoms most strongly associated with the progression of PD. Motor symptoms include dyskinesia, dystonia, shuffling gait and micrographia.⁶
Non-motor Symptoms include a loss in the sense of smell, sleep disorders and gastrointestinal issues such as constipation, all of which can occur years before the first stage of PD.^7,8

Progression of PD

PD progresses in five stages, with non-motor and motor skills degenerating rapidly with the progression to the next stage.

Stage 1: Initially there are mild symptoms that do not affect normal life. Examples include tremors, changes in posture, and movement symptoms occurring on one side of the body.

Stage 2: Movement symptoms begin to progress to both sides of the body, with visible changes in gait and walking. Symptoms begin to affect daily routines, making them more difficult and time-consuming.

Stage 3: The movements become slower and there is more frequent loss in balance. While the patient is still able to live on his own, daily tasks such as eating become significantly impaired by PD.

Stage 4: Standing becomes difficult with patients requiring support of a walker. Symptoms are very severe, and patients cannot live alone.

Stage 5: This is the most advanced stage of PD, with little or no leg function. The patient experiences frequent hallucinations and delusions, and requires round-the-clock care.⁹

Pathophysiology

PD is characterized by a loss in dopaminergic neurons in the substantia nigra pars compacta, located in the midbrain. The pathological hallmark of PD is the aggregation of α-synuclein in the form of Lewy bodies and Lewy neurites, the underlying mechanism of which involves the following:

Mitochondrial dysfunction
Defective protein clearance mechanisms
Neuroinflammation

Structure of α-synuclein

α -synuclein is a presynaptic neuronal protein encoded by gene SNCA. The SNCA gene encodes a 140 amino acid protein which in aqueous solution is present as stable tetramers that resist aggregation. The protein does not have a defined tertiary structure. It is mostly unfolded, and is called as natively unfolded protein.

α -synuclein protein is composed of three distinct regions (Fig.1):

An amino terminus with 1–60 amino acid residues, containing apolipoprotein lipid-binding motifs, predicted to form amphiphilic helices conferring the propensity to form α-helical structures on membrane binding.
A central hydrophobic region with 61–95 amino acid residues, so-called NAC (non-Aβ component) which confers the β-sheet potential.
A carboxyl terminus that is highly negatively charged, and is prone to be unstructured.

Fig. 1. Schematic representation of human α-synuclein depicting: (source)

(a) SNCA gene structure, (b) mRNA, and (c) protein domains.

Synuclein family of proteins consist of 3 forms namely α, β, δ among which only α-synuclein is predominant as compared to other forms. α -synuclein differs structurally from the NAC region. On binding to lipids such as phospholipids, and other negatively charged lipids, it forms α-helical structures.Under a prolonged period of incubation, it produces β-sheet-rich amyloid-like structure which aggregates resulting in different forms such as unfolded monomers, soluble oligomers, protofibrils, and high molecular weight insoluble fibrils. (Fig.2)

Fig. 2. formation of α-synuclein oligomers enriched in β-sheet structures (source)

α -synuclein possesses two low complexity domains and undergoes liquid–liquid phase separation. α -synuclein in the presence of a molecular crowder, which is promoted further by various PD-associated conditions. This was addressed by using Simple Modular Architecture Research Tool (SMART) and IUPred2 algorithms which exposed that α -synuclein droplets undergo a liquid to solid-like transition, leads to hydrogel formation that comprises fibrillar aggregates and oligomers. α -synuclein forms liquid droplets even within cells and consequently transforms into solid-like aggresomes, which is regulated by microtubules. These events collectively establish that phase separation acts as an initial step towards α -synuclein aggregation associated with PD pathology.¹⁰

Degradation of α-synuclein (protein clearance) occurs through Ubiquitin-Proteasome System, Molecular chaperones involving Heat shock proteins or Autophagy lysosomal pathway as represented by Fig.3.

Fig. 3. Protein clearance pathway (source)

α-synuclein, in association with tubulin proteins such as tau proteins, plays a key role in cytoskeletal dynamics. During the misfolding of α -synuclein, tau proteins are hyperphosphorylated resulting in neuroinflammation and neurotoxicity.^{11, 12}

Dopamine

α-synuclein is known to regulate the production of dopamine through interaction with tyrosine hydroxylase Phenylalanine or tyrosine, which is the precursor for Dopamine synthesis via sequential reactions catalyzed mainly by phenylalanine hydroxylase (PH), tyrosine hydroxylase (TH), and DOPA decarboxylase. It can also be synthesized from tyramine via a minor pathway by CYP2D6. Dopamine is effectively degraded into the main inactive metabolites DOPAC and homovanillic acid (HVA) via a series of reactions mediated predominantly by the enzymes monoamine oxidase (MAO), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), and ADH. The dopamine metabolism and clearance mechanism is presented in Fig.4.

Fig. 4. Metabolic pathway of dopamine synthesis and clearance (source)

Risk factors for the onset of PD

Many factors could trigger the onset of PD, ranging from environmental conditions, genetic factors or the type of gut microbes existing in the person’s intestine. The loss of nigrostriatal dopaminergic innervation causes PD. Other risk factors could include gender (men are more susceptible to PD than women) and age (most patients diagnosed with PD are over the age of 60).^{13, 14}

Genetic Risk Factors

Researchers have identified a few specific genes that could be attributed to the development of PD; however, they are very rarely seen, such as in cases where many members of the family are diagnosed with PD. There are specific genes, however, which can increase the chances of PD.¹⁵

Missense mutation in α-synuclein (A53T) encoded by the SNCA/PARK1 gene, mutations in the N-terminal of α-synuclein including A30P, E46K, H50Q, G51D and A53E and mutations of LRRK2/PARK8 gene have been identified in PD.
Other changes include PTEN-induced putative kinase (PINK) 1, a mitochondrial protein kinase; mutations in PINK1 could also lead to autosomal PD.
Mutations of DJ-1, encoded by the PARK7 gene, have been linked with early onset of recessive PD. DJ-1 is responsible for many neuroprotective roles, such as acting as an antioxidant and regulating the actions of cell survival related genes. Furthermore, DJ-1 has the capability to assist in the degradation of certain misfolded proteins.
Mutations of the Vacuolar protein sorting 35 (VPS35) gene is associated with the late-onset PD.
Glucocerebrosidase (GBA1) gene mutations, encoding gluco-cerebrosidase 1 (gcase 1) is a common genetic risk factor for PD, which has been associated with Lysosomal Storage Disease, a disease caused when the body lacks certain proteins to facilitate the breakdown of specific lipids, which can lead to neurogenerative damage in the brain.
Mutation of Mitochondrial DNA resulting in mitochondrial damage due to age has been found in PD patients.¹⁶

Environmental risk factors

Environmental factors that could increase the likelihood of PD include head injury, exposure to pesticides, herbicides, Polychlorinated Biphenyls etc.

Gut microbiome: The association between impaired gastrointestinal mobility and high PD-specific pathology is poorly understood. However, from recent studies it is known that gut microbiota is required for many neurological functions, such as motor function, microglia function, and α-synuclein pathology.

Braak's Hypothesis explains the reason why non-motor symptoms are typically the first to emerge. The medulla is responsible for involuntary actions, such as sneezing, and olfactory bulb is responsible for the sense of smell. Braak's Hypothesis states that PD originates in these parts of the brain and progresses to the substantia nigra over time. A pathogen which causes sporadic PD could enter the body through nasal tract or may be present in the gut (Prevotellaceae bacteria is relatively high in patients with PD). Once it has entered the nasal tract, it is swallowed, causing Lewy pathology in the nasal as well as digestive tract. The pathogen then proceeds from the nasal cavity to the olfactory bulb or through the vagal nerve, finally causing Lewy pathology in the brain which results in PD.¹⁷

Oxidative stress theory states that antioxidants present in the brain need to be broken down and oxidized. The antioxidants create oxidative stress, which has been found to be significantly higher in patients with PD. In PD, there is a deficiency of dopamine (DA), which is an inhibitory neurotransmitter. This stimulates a chain of reactions leading to the opening of neural gates responsible for the control of Ca++ ions. The Ca++ ions spill out of the neuron, damaging mitochondria and creating further oxidative stress in the brain, making DA neurons more susceptible to neurodegeneration.¹⁸

According to some, Cortisol, a hormone responsible for stress, can be associated with gait deficit in PD patients.¹⁹

Diagnosis

Imaging is used to confirm clinical diagnosis of symptoms such as muscular rigidity, rest tremor or postural instability.

Single photon emission computed tomography [SPECT], also known as DaTscan, is used to assess the density of presynaptic dopaminergic terminals. This technique differentiates PD from disorders that exist in the absence of presynaptic dopaminergic terminal deficiency.
Positron Emission Tomography (PET) scan assesses the presynaptic dopaminergic integrity and accurately identifies the monoaminergic disturbances in PD.
The standard Magnetic Resonance Imaging (MRI) has a marginal role in the diagnosis of PD. However high and ultra high field (7 Tesla) MRI combined with advanced techniques such as Diffusion Tensor Imaging (DTI), is used for early diagnosis of PD.
Currently, there are no approved tests for the detection of α-Synuclein in the Cerebrospinal fluid or blood and scientists are working to find a way for use of α-Synuclein as a biomarker.²⁰

Biological marker	Tracer used	Technique
Metabolism of levodopa	¹⁸F-dopa	PET
Presynaptic dopamine transporter	¹¹C-CFT, ¹⁸F-CFT, ¹¹C-RTI-32, ¹⁸F-FP-CIT, ¹¹C-methylphenidate	PET
Presynaptic dopamine transporter	¹²³I-β-CIT, ¹²³I-FP-CIT, ¹²³I-altropane, ^99mTc-TRODAT-1	SPECT

Table 1: Imaging strategies for the assessment of presynaptic nigrostriatal terminals

Fig. 5. Scan of brain; Control vs. Parkinson patients (source)

Management of PD

Therapeutic options for treating Parkinson’s disease include pharmacotherapeutic interventions involving drug or drug combinations as well as non-pharmacotherapeutic interventions involving surgeries, neurostimulations etc.

Pharmacotherapeutic interventions

The most prevalent treatment for PD is highly symptomatic.. The available treatments involve increasing the level of dopamine in the neuronal endings as proposed below:

Levodopa is designed to replace the dopamine.
Dopamine agonists, categorized into ergot and non-ergot derivatives, stimulate dopamine system by binding to the dopaminergic receptors.
Monoamine Oxidase B (MAO-B) inhibitors act by inhibiting the enzyme MAO-B that is involved in dopamine metabolism thus preserving endogenous dopamine.
Catechol-O-methyl transferase (COMT) inhibitors act by preventing the breakdown of dopamine by COMT
Anticholinergics act as antagonists at cholinergic receptors and reduce the neurotransmitter acetylcholine activity.²¹

Disease modifying therapy

Disease modifying therapy for treatment of PD involves inhibition of misfolding and/or aggregation of α-synuclein.

Decreasing the rate of α-synuclein synthesis or increasing its clearance is an approach for reducing α-synuclein burden. Reduction of α-synuclein synthesis by silencing SNCA through small hairpin RNA and antisense oligonucleotides is under study.
α-synuclein degradation through ubiquitin–proteasome system and autophagy–lysosomal pathway, can be addressed by using a small-molecule inhibitor, USP14, which has been successful in both in vitro and in vivo models.
Interaction between LRRK2 and α-synuclein has opened up a new area of study for LRRK2- targeted therapies which could benefit patients with idiopathic PD. However, in the absence of preclinical models, it could be very challenging.
Therapeutic agents such as Calcium ions that rescue vulnerable neurons.

Such trials have not been successful so far because of following challenges:

Clinical heterogeneity of the population.
Patient selection.
Lack of an adequate preclinical model of sporadic PD.
Lack of a disease biomarker to identify preclinical PD.
Identification of a time frame to apply disease-modifying therapies.

Repurposed drugs

Repurposed drugs involves examination of existing drugs for new therapeutic purposes so as to provide quick results in a cost effective manner. Existing drug development approaches include extensive efforts towards identifying mechanism of action of new drug candidates which result in agents or drugs, considered to be ‘non-specific’ when more than one unrelated enzyme or protein is affected at similar concentrations. Based on this principle repurposed drugs are recent emergents in treating diseases such as PD. FDA approved repurposed drugs are being tested for treating PD.²²

Mechanisms of potential therapies for repurposed drugs:

Iron-targeting agents generally involves chelation therapy; such an approach is under study by ApoPharma which started a clinical trial titled Conservative iron chelation as a disease-modifying strategy in Parkinson's disease (FAIRPARKII). This trial, is in phase 2 (ClinicalTrials.gov Identifier: NCT02728843).²³
Calcium channel blockers such as Isradipine are being tested by the University of Rochester and Northwestern University. University of Rochester has currently completed phase 3 while Northwestern University has completed Phase 2 trials for studying the efficacy of Isradipine in treating Parkinson disease. (ClinicalTrials.gov Identifiers: NCT02168842; NCT00909545).²⁴
Michael Alan Schwarzschild, a neurologist, in collaboration with The Parkinson Study Group; Michael J. Fox Foundation for Parkinson's Research; University of Rochester; National Institute of Neurological Disorders and Stroke (NINDS) are in phase 3 focusing on Inosine, a urate precursor and potential antioxidant. (ClinicalTrials.gov Identifier: NCT02642393).²⁵
University College, London is in phase 3 focusing on glucagon-like peptide 1 (GLP1) agonist, exenatide named Exenatide PD3 to be administered once weekly over a period of two years (ClinicalTrials.gov Identifier: NCT04232969).²⁶

Fig.6 represents the proposed mechanisms for cellular therapies and small molecules.

Fig. 6. cellular therapies in PD (source)

Non-pharmacotherapeutic interventions

Symptomatic motor therapy using viral vector-mediated targeted delivery of genes encoding proteins involved in dopamine production such as aromatic-l-amino acid decarboxylase, or basal ganglia network modulation such as glutamate decarboxylase, are under study.

Dopaminergic cells derived from human pluripotent stem cells, which may be either human embryonic stem cells or induced pluripotent stem cells, are regarded as cellular therapies for PD and are currently facing challenges on account of ethical issues.

Transplantation of mesencephalic fetal dopaminergic neurons into the striatum of patients with PD has also been observed to improve motor symptoms and reduce the disorders in movement.²⁷

Recent advancements

Immunotherapies targeting α-synuclein are a new focus for clinical testing. Since the introduction of levodopa, there are major advances in the field of PD treatment. Disease modifying therapies with chemical entities along with regenerative approaches such as stem cells and gene therapies, are significant improvements that have taken place in recent times.²⁸

On the whole, curative therapy for PD involves disease halting mechanism, restorative therapy, and neuroprotective agent with different methods involved in each approach. A schematic presentation of such approaches is presented in Fig.7.

Fig. 7. Schematic representation of curative therapies

Surgical intervention

Surgical treatment of Parkinson’s disease has made significant progress over the past 70 years, however, its effectiveness is limited to motor symptoms which include bradykinesia, rigidity, tremor and medication-induced dyskinesia. There has been rapid progress in surgical interventions varying from the lesioning procedure to the more recent deep brain stimulation and other techniques such as optogenetics, magnetogenetics, and sonogenetics. A general representation of progress in surgical approaches is presented in Fig.8.²⁹

Fig. 8. Schematic representation of surgical approaches for PD treatment

New drugs undergoing trials

The clinical trial data presented below gives an idea of the status of new drugs that are likely be launched in the near future. (Table 1)

Phase 3 studies

Sponsors / Collaborators	Drug name	Phase	Date of start to estimated end date
Pharma Two B Ltd.	P2B001	Phase 3	January 29, 2018 to February 28, 2021
Sunovion	APL-130277	Phase 3	August 31, 2015 to March 1, 2023
Takeda Pharmaceuticals	TVP-1012 (Rasagiline)	Phase 3	February 3, 2015 to September 29, 2016

Phase 1 and Phase 2 studies

Sponsors / Collaborators	Drug name	Phase	Date of start to estimated end date
Immunotherapy
Hoffmann-La Roche with Prothena Biosciences Limited	RO7046015 ( prasinezumab )	Phase 2	June 27, 2017 to April 17, 2026
Biogen	BIIB054	Phase 2	January 10, 2018 to June 21, 2021
Astrazeneca with Covance MMS Holdings, Inc Catalent	MEDI1341	Phase 1	October 17, 2017 to January 19, 2021
Lundbeck with Genmab	Lu AF82422	Phase 1	July 25, 2018 to December 2020
United Neuroscience Ltd. With Centre for Human Drug Research, Netherlands Worldwide Clinical Trials	UB-312	Phase 1	August 29, 2019 to June 30, 2021
Small molecule
Neuropore Therapies Inc. With Celerion	NPT520-34	Phase 1	May 5, 2019 to October 9, 2019
Neuropore Therapies Inc. With UCB S.A. - Pharma Sector	NPT200-11	Phase 1	July 2015 to February 2016

Table 2. On-going clinical studies for new drugs^{32, 33}

*In 2017 Takeda pharmaceuticals submitted a New Drug Application (“NDA”) to the Ministry of Health, Labour and Welfare in Japan for rasagiline mesylate (TVP-1012). No information is available on its approval.

Failed trials

A few clinical trials that failed during phase 3 are given below:

Acorda Therapeutics, in 2017, terminated its phase 3 clinical trial with Oral adenosine A2,a receptor antagonist advanced as an adjunctive treatment to levodopa in Parkinson’s disease patients to reduce OFF time, that is, motor fluctuations. The trial was terminated due to side effects such as sepsis, agranulocytosis, and also no/high white blood cell counts.³⁰
Merck, in 2013, terminated its phase 3 clinical trial of Preladenant as the prevalent neurological disorder failed to beat that of placebo.³¹

Start-ups

Many start-up companies are currently working on alleviating PD, a few of which are listed below.

Neuraly, a startup biotech company, announced in 2018, its intent to pioneer the development of disease-modifying agents for neurodegenerative disorders such as Alzheimer’s and Parkinson disease by using NLY01, a potent, brain-penetrant long-acting Glucagon-like peptide-1 receptor (GLP-1R) agonist, which is now in phase 2 (NCT number NCT04154072).^{34, 35}
Prevail Therapeutics received $50 million in funding from Surveyor Capital and AbbVie Ventures in 2019, to develop novel gene therapy involving AAV vector for the treatment of Parkinson’s disease.³⁶
Cerevel Therapeutics was launched by Bain Capital and Pfizer in 2018 to develop drugs for central nervous system disorders. It includes Tavapadon which is in phase 3 for treating Parkinson disease (NCT number NCT04223193).^{37, 38, 39}

Patents

A patent search was conducted to identify innovative approaches adopted by researchers for diagnosis / treatment of PD.

Diagnosis

US2020128801AA: from university-industry cooperation group of Kyung Hee University titled Information providing method for diagnosing Parkinson’s disease deals with measurement of metabolite produced by the Proteus mirabilis strain, and α -synuclein in a biological sample.⁴⁰
EP3587597A1: from MD Healthcare Inc titled Method for diagnosing Parkinson's disease through bacterial metagenome analysis deals analyzing an increase or decrease in the content of extracellular vesicles derived from specific bacteria by bacterial metagenomic analysis.⁴¹

Treatment

Drug

US2020002323A1: from GlaxoSmithKline titled compounds deals with novel compounds that inhibit LRRK2 kinase activity, along with their preparation, composition and use to treat or prevent Parkinson's disease.⁴²
US20200046667A1: from Impel Neuropharma Inc titled Respiratory tract delivery of levodopa and dopa decarboxylase inhibitor for treatment of Parkinson's disease deals with a dry pharmaceutical composition for respiratory tract delivery for treatment of Parkinson's disease or Parkinson syndrome.⁴³
US2016022573A1: from Neuroderm Ltd. titled Method for treatment of Parkinson's disease deals with a method of parenteral administration of a composition comprising carbidopa and levopoda, and oral administration of a catechol-O-methyl transferase (COMT) inhibitor such as entacapone or tolcapone.⁴⁴

Gene therapy

US20190282639A1: from American Gene Tech Int Inc. titled Viral vectors for treating Parkinson’s disease deals with lentiviral vector system for expressing a lentiviral particle. The system includes a therapeutic vector, an envelope plasmid and one helper plasmid wherein the lentiviral particle is for inhibiting PARP expression in neuron cells and is useful for treating Parkinson's disease.⁴⁵

Cell transplantation

US2020063098AA: from Ultra-Microrigin Biomedical Technology Co., Ltd. titled Use of n-butylidenephthalide in dopaminergic progenitor cell transplantation deals with use the same to enhance the therapeutic effect in Parkinson's disease.⁴⁶
EP3591039A4: from S Biomedics titled Method for isolating dopamine neurons and pharmaceutical composition for treating Parkinson’s disease, containing dopamine neurons isolated using same deals with method for separating dopaminergic neural cells and a pharmaceutical composition comprising the dopaminergic neural cells for treatment of Parkinson's disease, wherein method of separation comprises a step of separating TPBG-positive dopaminergic neural cells.⁴⁷

Conclusion

Parkinson’s disease poses a big challenge to researchers due to individual patient heterogeneity as well as its progressive nature. The knowledge of genetic risk factors arising from LRRK2 (leucine rich repeat kinase 2), and mutations in the GBA gene etc. are laying the foundation for the development of precision medicine. New therapeutic targets and more accurate diagnostic agents are being developed to identify precisely the root cause of the disease. In treatment, there is a shift from symptomatic treatment to disease modifying treatment with more focus on reducing the spread of α-synuclein pathology. Special focus is being directed towards neuroprotection and also development of agents to enhance neuronal survival. Possible causes such as immunomodulation and gut microbiome are also gaining research attention.

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