Monthly Research Review – May 2019

~ Simon

 

At the end of each month the SoPD writes a post which provides an overview of some of the major pieces of Parkinson’s-related research that were made available during May 2019.

The post is divided into seven parts based on the type of research:

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials
  • Clinical trial news
  • Other news
  • Review articles/videos

 

So, what happened during May 2019?

In world news:

8th May – A British teenager, Isabelle Holdaway (below), aged 17, was reported to be the first patient ever to receive a genetically modified phage therapy to treat an antibiotic-resistant infection (Click here to read the research report and click here to read the press release).

9th May – The Reserve Bank of Australia acknowledged an unfortunate spelling error (“Responsibil_ty”) on 400 million new $50 notes. There is currently $2.3 billion of these notes in circulations (Click here to read more about this).

May 24 – British Prime Minister Theresa May announced her resignation as Conservative leader, effective 7 June 2019.

30th May – Physicists reported that they have teleported a computer circuit instruction – known as a quantum logic operation – between two separated ions (electrically charged atoms), providing an example of how quantum computer programs could carry out tasks in future large-scale quantum networks (Click here to read more about this, and click here to read the press release).

In the world of Parkinson’s research, a great deal of new research and news was reported:

In May 2019, there were 828 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (3742 for all of 2019 so far). In addition, there was a wave to news reports regarding various other bits of Parkinson’s research activity (clinical trials, etc).

The top 5 pieces of Parkinson’s news

1. An anti-fungal approach to LRRK2?

Oxford University researchers has published a Parkinson’s UK funded study demonstrating the importance of Parkinson’s-associated LRRK2 in lysosomal biology (a novel interaction between LRRK2 & vATPase a1 subunit) & that an anti-fungal treatment called clioquinol could be re-purposed for Parkinson’s ( to read more about this).

2. Isradipine has no impact

The results of the STEADY-PD III clinical trial evaluating Isradipine in Parkinson’s have been announced. Isradipine is calcium channel blocker that is used in the treatment of hypertension, and the results of this 3 year study suggest that the drug has no impact on the course of Parkinson’s. This is disappointing, but it’s how we respond to disappointment that defines us (Click here to read more about this).

3. Bipolar disorder and Parkinson’s

Analysis of the Taiwan National Health Insurance Research Database suggests individuals with bipolar disorder have an increased risk of developing Parkinson’s (HR=6.78, 95% confidence interval 5.74–8.02) ( to read more about this and click here to read the press release).

4. A brain wave about brain waves

Researchers report that scalp EEG measures of beta beta waveform shape over the sensorimotor cortex distinguishes between people with Parkinson’s on & off medication, as well as PwPs off medication from controls. A safe, non-invasive biomarker for PD? ( to read more about this).

5. A better bet on beta agonists

Further fodder for the β2AR agonist/antagonist debate has been published. Analysis of Danish medical recordes finds β2AR agonist use associated with reduced Parkinson’s risk (& antagonist use = increased PD risk). BUT the association of agonists mediated by smoking. “The association of β2AR antagonists indicates reverse causation, with Parkinson’s symptoms triggering their prescription rather than β2AR antagonists causing PD. Thus, current epidemiologic data do not support a causal link between β2AR agonists & antagonists and PD risk” ( to read more about this).

Basic biology news

  • Researchers identify a novel Fyn-mediated signaling mechanism that amplifies NLRP3 neuroinflammation in Parkinson’s (Click here to read more about this).
  • A powerful new tool – a fully automated image acquisition & four-dimensional tracking of morphological changes within individual cells in organotypic cultures from rodent & human primary tissues (for at least 3 weeks! – to read more about this).
  • A new manuscript on bioRxiv provides high-resolution functional landscape of midbrain dopamine neurons. Such work could aid efforts in cell replacement therapy for Parkinson’s ( to read more about this).
  • Researchers have developed the HANABI (HANdai Amyloid Burst Inducer) device, which is a fully automated tool for accurately detecting α-synuclein aggregation in cerebrospinal fluid using ultrasonication. A useful new tool for Parkinson’s? ( to read more about this and click here for the press release).
  • Researchers report that Vitamin B12 inhibits Parkinson’s-associated alpha synuclein fibrillogenesis (dose-dependent manner), delays conversion of α-syn to β-sheet, disassemble preexisting fibrils, & reduced toxicity ( to read more about this).

  • Researchers report that Anetholtrithion – a drug used since 1696 – does not act as an unspecific antioxidant molecule, but rather unexpectedly it decreases mitochondrial reactive oxygen species production. Implications for Parkinson’s? ( to read more about this).
  • Parkinson’s-associated LRRK2-G2019S mutant acts through regulation of SERCA activity to control ER stress in astrocytes. It impairs ER Ca2+ homeostasis, which ultimately determines cell survival ( to read more about this).
  • Researchers report that lipid alterations in membranous compartments promoted by brain aging (& in Parkinson’s-like model) may have an effect on α-synuclein aggregation & segregation in abnormal multimeric structures ( to read more about this).
  • Fingolimod (an immunomodulating drug) may reduce oxidative stress (via inhibiting PI3K/AKT/GSK-3β pathway & reducing p65 phosphorylation), decreasing NLRP3 inflammasome activation, & ultimately reducing microglia activation-induced neuronal damage ( to read more about this).
  • New report suggests mitochondrial lipid composition is altered with Parkinson’s-associated PARKIN deletion & with age in the mouse brain ( to read more about this).
  • Researchers report that not only do Alzheimer’s amyloid fibres exhibit an intrinsic near-infrared signal, but they also demonstrate how this could be used for non-invasive & contrast-agent-free imaging. Implications for Parkinson’s? (Click here to read more about this).

  • Oral administration of epigallocatechin-3-gallate (EGCG; 100 mg) reduces the cognitive impairment in the aging rats and decreased Aβ plaques, but EGCG could not be detected in brain tissues of young control rats, suggesting BBB permeability matters ( to read more about this).
  • New bioRxiv manuscript reports LMX1A & LMX1B genes are assoicated with autophagy regulatory – could explain the protective roles of these genes have in adult dopamine neurons. Implications for Parkinson’s? ( to read more about this).
  • Fbox07 (or PARK15) is a gene associated with Parkinson’s. German researchers report that Fbxo7 is essential for the support of the axon-myelin unit & long-term axonal health. Schwann cells were particularly sensitive to Fbxo7 deficiency ( to read more about this).
  • Parkinson’s-assocaited LRRK2 contributes to the alpha synuclein pre-formed fibrils-mediated oxidative stress pathways. The results suggest that microglial LRRK2 may contribute to the pathogenesis of PD via altered oxidative stress signaling ( to read more about this).
  • Researchers have designed & synthesized an amido-bridged nucleic acids-modified antisense oligonucleotide (AmNA-ASO) that targets Parkinson’s-assocaited alpha synuclein.

  • Administration of AmNA-ASO rescued a PD mouse model ( to read more about this).
  • New research suggests that the initial step in Parkinson’s-associated PARKIN recruitment & activation in mitophagy requires protein ubiquitylation by MITOL/March5 with subsequent PINK1-mediated phosphorylation ( to read more about this).
  • New data connects seemingly divergent views of Parkinson’s-associated alpha synuclein protein function. Researchers report functional interaction between alpha synuclein and VAMP2 is necessary for α-syn–induced synaptic attenuation ( to read more about this).
  • Loss of Parkinson’s-associated PARKIN in mice reduces lung tumor development by blocking p21 degradation. Could this partly explain why the incidence of lung cancer is negatively associated with the development of PD? ( to read more about this).
  • Metabolomics work in a mouse model of Parkinson’s points towards adenosine deaminase (ADA) as a potential therapeutic target. ADA inhibitors protected against neurodegeneration in MPTP model of PD ( to read more about this).
  • Herpes simplex virus type 1 catalyzes the aggregation of Alzheimer’s-associated amyloid β-peptide ( in vitro & in vivo). Implications for Parkinson’s? ( to read here more about this).

  • Researchers screen over 2,500 compounds & identify a new Parkinson’s-associated α-synuclein inhibitor, called 3-[(3-methoxyphenyl)carbamoyl]-7-[(E)-2-phenylethenyl]-4,7-dihydropyrazolo [1,5-a]pyrimidine-5-carboxylic acid (or just “compound 2”). Compound 2 not only inhibited the misfolding & aggregation of α-syn, protected protected against α-syn toxicity, but also has a more specific binding site (compared to positive controls). Interesting use of mass spectrometry to discover α-syn aggregation inhibitors ( to read more about this).
  • Mice with no Regulator of G protein signaling 6 (RGS6) protein reported to recapitulate key hallmarks of Parkinson’s, including dopamine cell loss, reduced levels of striatal dopamine, motor deficits, & α-synuclein accumulation ( to read more about this).
  • New research finds Peli1 is a critical mediator in the regulation of microglial activation & neuroinflammation-induced death of dopaminergic neurons in both models of Parkinson’s & postmortem tissue, suggesting Peli1 as a novel therapeutic target ( to read more about this).
  • Effects of MUL1 & PARKIN on the circadian clock, brain & behaviour in fly models of Parkinson’s ( to read more about this).
  • Researchers report that mice deficient in NF-κB/c-Rel protein (c-rel-/- mice) exhibit a progressive Parkinson’s pathology with non-motor & motor symptoms & a Braak-like pattern of brain ascending α-synuclein depositions ( to read more about this).
  • New insights into how Parkinson’s-associated PINK1 & PARKIN function in anti-viral innate immune response. In addition to mitophagy, PINK1 regulates RIG-I by inhibiting TRAF3 degradation, & inhibits the association of YAP1 & IRF3 ( to read more about this).

 

Disease mechanism

  • A low-dose treatment of Maraviroc – inhibitor of CCR5 & a FDA–approved drug for HIV treatment – has been found to reduce the infiltration of T Cells into the brain & protect a primate model of Parkinson’s, improving locomotor activities ( to read more about this).
  • Researchers have a manuscript on bioRxiv suggesting that physiologically available small molecule heme minimizes toxicity of Parkinson’s-assocaited alpha-synuclein oligomers by inducing a conformational distortion ( to read more about this).
  • New manuscript on bioRxiv reports that the endogenous bile acid – tauroursodeoxycholic acid (TUDCA) – prevents neurotoxic (A1) polarization of astrocytes & pro-inflammatory polarization of microglia in Multiple Sclerosis model ( to read more about this).
  • Researchers report that colonic inflammation is associated with changes in Parkinson’s-associated alpha synuclein expression (reduced) & phosphorylation (increased) in the myenteric plexus of small primates ( to read more about this and click here to read the press release).
  • Researchers report that 2nd generation mixed-lineage kinase-3 (MLK3) inhibitor CLFB-1134 protects against neurotoxin-induced model of Parkinson’s ( to read more about this).
  • New research reports the direct interaction of NLRP3 inhibitor MCC950 with the Walker B motif within the NLRP3 NACHT domain. NLRP3 inhibitors are being developed for the treatment of Parkinson’s, and a better understanding of the mechanisms of inhibition will allow for improved drug design ( to read more about this).
  • A manuscript on bioRxiv supports the finding that the NACHT domain of NLRP3 is the molecular target of diarylsulfonylurea inhibitors (like MCC950 – to read more about this).
  • Researchers report that chronic mild gut inflammation (caused by 0.5% dextran sodium sulfate) accelerates brain neuropathology & motor dysfunction in alpha-synuclein mutant mouse model of Parkinson’s ( to read more about this).

  • Researchers suggests loss of Parkinson’s-associated PARKIN function in mice leads to cortico-striatal presymptomatic disarrangement which may predispose an imbalance of striatal outflow accompanying symptomatic PD ( to read more about this).
  • Loss of PARK9 function disrupted lysosomal Calcium homeostasis, increased cytosolic Calcium & impaired lysosomal exocytosis. Activation of transient receptor potential mucolipin 1 (TRPML1) increased lysosomal exocytosis & prevented α-syn accumulation (Click here to read more about this)
  • Oxyresveratrol exerts ATF4- & Grp78-mediated neuroprotection against endoplasmic reticulum stress in models of Parkinson’s. Oxyresveratrol suppressed mutant A30P oligomer formation in vitro. Would be interesting to see this tested in vivo ( to read more about this).
  • Researchers have a manuscript on BioRxiv with evidence suggesting that gum disease-associated gingipain R1 is present in Parkinson’s blood (41 controls vs 40 PD patients). Should COR388 also be tested in PD? ( to read more about this & click here to read a previous SoPD post on this topic)
  • Researchers report drug-like small molecules that interact with native Parkinson’s-assocaited alpha synuclein can impact a variety of its pathological processes ( to read more about this).
  • Mutations in ATP13A2 have been associated with Parkinson’s. New research suggests that ATP13A2 may be modifying the lipid digestion capacity &/or the redistribution of lipids in these subcellular organelles ( to read more about this).

  • PPAR-γ agonist pioglitazone reduces microglial proliferation & NF-κB activation in the substantia nigra in a rat model of Parkinson’s ( to read more about this).
  • Low dose FTY720 (fingolimod) improves behavior, increases BDNF & myelin markers, & reduces alpha synuclein pathology in a model of Parkinson’s (GM2 +/− mice –  to read more about this).
  • Researchers demonstrate that the gap junction protein connexin-32 (Cx32) is centrally involved in the preferential uptake of Parkinson’s-associated alpha synuclein oligomeric assemblies in neurons & oligodendrocytes. Cx32 inhibition blocks a-syn uptake ( to read more about this and click here to read the press release).

 

Clinical research

  • New research suggest that color discrimination does not simply relate to dementia but points towards higher order perceptual deficits which may predict visual hallucinations in Lewy body disorders (eg. Parkinson’s – to read more about this).
  • 30 people with bilateral Parkinson’s & 15 controls underwent neuromelanin-sensitive imaging: “the characteristics of disease progression …support post-mortem data showing asynchrony in the loss of neuromelanin-containing versus TH+ nigral cells” ( to read more about it).

  • Genetics researchers & colleagues have a manuscript on BioRxiv utilising multiple datasets to uncover putative gene expression & splicing mechanisms driving Parkinson’s GWAS signals ( to read more about this).
  • Researchers report that GBA & APOE ε4 associate with sporadic Dementia with Lewy Bodies in a European GWAS (involving 828 DLB cases & 82035 controls – to read more about this).
  • An analysis of inflammatory mediators in peripheral blood cells (from 33 PD subjects & 33 controls) provides evidence for functional dysregulation of the sVCAM1-VLA4 axis in Parkinson’s. sVCAM1 levels correlated with disease stage & motor impairment ( to read more about this).
  • Using magnetoencephalographic (MEG) recording, Taiwanese researchers find abnormalities in motor programming, response inhibition, & frontal inhibitory modulation in 12 people with Parkinson’s (compared to 13 controls –  to read more about this).
  • An observational study from Brazil finds 14 out of 23 Gaucher disease patients present at least 1 non-motor feature of Parkinson’s (daytime sleepiness was the most frequent –  to read more about this).
  • Researchers report that early significant caudate dopaminergic denervation was found in half of the cases in PPMI. Baseline bilateral caudate involvement was associated with increased risk of cognitive issues, depression & gait problems (Click here to read more about this).
  • Researchers use the Protein Misfolding Cyclic Amplification (PMCA) method to assess Parkinson’s-associated alpha synuclein aggregates in gut biopsies. 10/18 PD cases were positive, only 1/11 controls. Rectum biopsies are not useful ( to read more about this).
  • Plasma data from 150 people in the Harvard Biomarkers Study (PD=50; other neurodegenerative diseases=50; control=50) suggests a multi-tiered blood-based proteomic screening method for detecting neurodegeneration & then further distinguishing Parkinson’s ( to read more about this).
  • Interesting report about the presence of L-dopa-induced dyskinesias in atypical Parkinson’s-syndromes (such as multiple system atrophy & progressive supranuclear palsy – click here to read more about this).
  • The rationale, design & methods for the EXosomes in Parkinson’s Disease (EXPAND) Study – exploring the cargo of exosomes isolated from the blood serum in order to identify candidate biomarkers for PD ( to read more about this).

  • Interesting case study – synergistic alterations in lysosomal functions & mitochondrial biogenesis, associated with a mitochondrial genetic defect in patient derived PARK2-Parkinson’s fibroblasts. PARK2 cells senesce sooner than controls ( to read more about this).
  • Researchers have a manuscript on bioRxiv that describes a clinical phenotype, detectable at baseline in a subset of individuals with Parkinson’s, that is associated with accelerated development of postural instability ( to read more about this).
  • You have heard of the placebo response in Parkinson’s? Well now there is the nocebo response in PD! A systematic review & large meta-analysis suggests that it is a thing & it should be considered in the design & interpretation of future clinical trials ( to read more about this).
  • People with non-tremor-dominant Parkinson’s have less alpha synuclein protein in their brain derived exosomes (collected from blood) than people with tremor-dominant PD, who have less of it than people with essential tremor or healthy controls ( to read more about this).
  • The PRoBaND clinical consortium report that the main determinants of variation in the L-dopa response in early Parkinson’s are age & motor severity. A limited L-dopa response is associated with faster motor progression ( to read more about this).
  • Alzheimer’s-associated beta amyloid deposits are NOT associated with cognitive impairment in Parkinson’s. Based on 115 subjects with PD (normal cog = 23; MCI = 76; PDD = 16) & florbetaben PET imaging ( to read more about this).
  • Detection of orthostatic hypotension (OH) using ambulatory blood pressure monitoring (ABPM) in Parkinson’s finds that selected ABPM parameters, such as # of hypotensive episodes & the presence of awakening hypotension, may be used to screen patients for OH ( to read more about this).
  • Mitochondria function associated genes contribute to Parkinson’s risk & later age at onset. The data suggests that therapeutics targeting mitochondrial bioenergetics & proteostasis (distinct from mitophagy) could be beneficial 4 treating early stages of PD ( to read more about this).

  • Researchers report coexistence of Lewy body disease pathologies in a small proportion of frontotemporal lobar degeneration cohort; having implications for clinical & neuropathologic diagnoses, plus the identification of biomarkers ( to read more about this).
  • The screening of 21 cytokines & growth factors in the dorsomedial prefrontal cortex of 16 cases of progressive supranuclear palsy (&16 control brains) suggests increased cortical interleukin-2 levels & a shift in the peripheral T cell population in PSP ( to read more about this).
  • Peripheral mitochondrial function (in fibroblasts) correlates with clinical severity in idiopathic Parkinson’s; small study, but may lay a foundation for better stratification of patients ( to read more about this).
  • Researchers report a dramatic increase in catechol-O-methyltransferase (COMT) & lower levels of DNA methylation in induced pluripotent stem cell-derived dopamine neurons from people with PARKIN (PARK2)-associated Parkinson’s ( to read more about this).
  • Parafoveal thinning of inner retina is associated with visual dysfunction in lewy body diseases, like Parkinson’s. This could be a sensitive & clinically relevant imaging biomarker PD ( to read more about this).

  • Small study (10 participants) finds that Exergaming – video game-based training with augmented virtual reality – is feasible & has potential to improve dexterity in individuals with Parkinson’s ( to read more about this).
  • Researchers report an evolution of prodromal Parkinson’s & dementia with Lewy bodies manifestations (similar to that predicted by pathological staging models) – based on prospective observations with predicted intervals as long as 20 yrs ( to read more about this).

 

New clinical trials

  • An interesting new clinical trial being conducted in Ontario has been registered. It will be exploring the physiological benefits of high-intensity interval training for individuals with Parkinson’s (Click here to read more about this).
  • A new Phase I clinical trial has been registered by Enterin Inc. investigating their Squalamine-based ENT-01 compound for the treatment of Parkinson’s Dementia (Click here to read more about this).

  • Neuropore announced the initiation of a Phase I clinical trial in healthy volunteers of their autophagy-promoting compound, NPT520-34 – a therapeutic candidate being developed to treat Parkinson’s & Amyotrophic Lateral Sclerosis. NPT-520-34 inhibits PI3K-AKT-mTor pathway, promotes autophagy, & reduced protein aggregates ( to read more about the trial and to read the press release).
  • Neuropore also announced that their partner UCB has initiated a multicenter Phase Ib clinical trial of UCB0599 in Parkinson’s. UCB0599 is an orally bioavailable, brain barrier penetrant small molecule alpha-synuclein misfolding inhibitor ( to read more about this).

  • New clinical trial has been registered for JM 010 (a combination of buspirone & zolmitriptan) for Parkinson’s with L-dopa induced dyskinesias. Called the ASTORIA study (“A Study in Parkinson’s Disease in paTients With mOderate to seveRe dyskInesiA” – Click here to read more about this).
  • New clinical trial has been registered testing whether 1-week of rifaximin treatment is able to restore the gut microbiota in a long-term manner in people with Parkinson’s (Click here to read more about this).
  • The plan for the NMS-Nab Study (Nabilone – a synthetic cannabinoid – for non-motor symptoms of Parkinson’s) – a mono-centric phase II, randomized, placebo-controlled, double-blind, parallel-group, enriched enrollment withdrawal study – has been published ( to read more about this).

 

Clinical trial news

  • A single-arm, open-label clinical study of Istradefylline – an analog of caffeine – finds improved gait issues in people with Parkinson’s suffering from freezing of gait, improving quality of life ( to read more about this).
  • Neurocrine Biosciences & Voyager Therapeutics announce Phase I clinical trial results for VY-AADC in people with Parkinson’s at the AAN 2019 Annual Meeting. Posterior delivery trajectory resulted in 54% coverage of the putamen & reduced infusion time ( to read more about this).

  • Neurocrine Biosciences also presented Phase III data demonstrating that Opicapone added to Levodopa resulted in a significant & sustained increase in ON time without dyskinesias in people with Parkinson’s. 60% experienced >1hr increase in total ON time ( to read more about this).
  • The results of the Phase I/II clinical trial involving intrathecal administration of IONIS-HTTRx into 46 people with Huntington’s have been published. A similar approach was being proposed for Parkinson’s ( to read more about this).
  • Living Cell Technologies Limited have provided a 24 months post implant update on their Phase I/IIa clinical trial of NTCELL® for Parkinson’s. 4/18 participants who received 80 capsules show benefits (UPDRS III) in the OFF state ( to read more about this).

  • ParkinSong! A controlled clinical trial of singing-based therapy for Parkinson’s. Researchers report that song intervention significantly improved vocal intensity, maximum expiratory pressure, & voice-related quality of life ( to read more about this).
  • A 4-week single-blinded, randomised controlled clinical trial of trunk-specific rehabilitation training decreased the forward trunk flexion severity and increased postural control in people with Parkinson’s ( to read more about this).
  • Brazilian researchers report that 16 weeks of strength training improves the respiratory muscle strength & quality of life of elderly with Parkinson’s. 28 subjects randomized into 2 groups: control=16 participants & strength training group=12 participants ( to read more about this).
  • IRLAB Therapeutics announced the completion of recruitment for its Phase II study with IRL790 in people with Parkinson’s with dyskinesia. 74 participants, 28 day treatment. Top line results expected in 10 weeks (Click here to read more about this and click here to read more about the trial).

  • Posthoc analysis of clinical trial data of NC001, an oral formulation of nicotine, suggests that this treatment significantly reduced falls & freezing of gait in people with Parkinson’s over 10 weeks of treatment. No difference in UPDRS II & III ( to read more about this).
  • The final results of the GREENFIELD observational study have been published. This study was exploring motor & non-motor outcomes in patients with advanced Parkinson’s treated with levodopa/carbidopa intestinal gel ( to read more about this).

 

Other news

  • The Michael J Fox Foundation held a LRRK2 summit recently – bringing together experts from academia and industry – to share the current state of progress. They also provided a nice summary of the event (Click here to read more about this).

  • There is also a really interesting discussion of Parkinson’s clinical trials-related matters involving Walter J. Koroshetz (NINDS director) & Michael J Fox foundation CEO Todd Sherer – “the data that comes from this trial and the other trials is incredibly important” ( to read more about this).
  • Centogene has launched a 2 year Parkinson’s study. The ‘Rostock International Parkinson’s Disease Study’ (ROPAD) – in cooperation the University of Luebeck – will enroll approximately 10,000 participants worldwide, to study a cohort with a broad genetic background. Participants with LRRK2 mutations will have the option to undergo further clinical assessment in a supplementary study, ‘LRRK2 International Parkinson’s Disease Project (LIPAD)’, & may also be offered participation in future clinical studies with study partner Denali therapeutics ( to read more about this and click here to see the ROPAD website).

  • The French clinical research network for Parkinson’s (NS-Park) has created a national patient registry to A) report medical activity to ministry, B) facilitate pre-screening 4 clinical trials, C) provide a source 4 epidemiology studies ( to read more about this).
  • Medopad & Tencent have begun a clinical trial in London of an artificial intelligence program that aims to diagnose people with Parkinson’s (also planning to target multiple sclerosis & psoriasis –  to read more about this).
  • French biotech TreeFrog Therapeutics raises over €7M ($7.8M) in Series A financing to transition the company’s C-Stem™ technology to cGMP standards by 2021. Objective of a first-in-man clinical trial in 2024. Parkinson’s is on their list ( to read more about this). And watch this video to see what Treefrog are working on:
  • Live biotherapeutics company 4D Pharma announced that they will have a poster presentation of their lead Parkinson’s candidates, MRx0005 & MRx0029 at the Neuro4D conference (Frankfurt, 13-14th May – to read more about this).
  • Prevail Therapeutics – a gene therapy biotech is seeking to go public to help fund development of a broader set of AAV gene therapies for GBA-associated Parkinson’s, but the perspective provides a lot of interesting information about the company. For example, it suggests that Prevail submitted an IND application for their lead program PR001 to the U.S. FDA in May 2019, with the hope of initiating a Phase I/II clinical trial for PR001 in GBA-associated Parkinson’s. PR001 utilizes an AAV9 vector to deliver codon-optimized DNA encoding wild-type GCase for GBA-associated Parkinson’s. The intended route of administration for PR001 is via injection into the intra cisterna magna – a ventricular space above the spinal canal containing CSF. The company believes that PR001, when administered via injection into the CSF, will broadly transduce the cells of a patient’s CNS & produce sufficient GCase to restore healthy lysosomal function & neuronal survival, thereby slowing the progression of GBA-associated Parkinson’s ( to read more about this and click here to read the perspective).

  • Casma Therapeutics has received a grant from the Michael J Fox Foundation to support the development of their Parkinson’s drugs program focused on compounds that activate the calcium channel TRPML1 ( to read more about this).
  • The NIH has awarded researchers at the Cleveland Clinic a 5 year, US$3 million grant to conduct a multi-site clinical trial to study the long-term effects of aerobic exercise on slowing the progression of Parkinson’s ( to read more about this).
  • French biotech AmyPore has picked up EU funding to help it progress a peptide drug that it says has potential in treating both Alzheimer’s & Parkinson’s. The peptide (AmyP53) targets gangliosides ( to read more about this and click here and here to read more about the research behind this biotech company).

 

Review articles/videos

  • Basically everything you need to know about the role of DJ-1 in the mechanism of pathogenesis of Parkinson’s ( to read more about this).
  • Researchers suggest that “Vitamin B12 supplementation could be considered as an adjuvant approach to improve cholinergic transmission and, potentially, motor & cognitive function in patients with Parkinson’s” ( to read more about this).
  • Interesting analysis/discussion of barriers & facilitators to diagnosing & managing apathy in Parkinson’s. “Future research must aim to identify apathy specific treatments, both pharmacologic & non-pharmacologic” ( to read more about this).
  • An encouraging discussion of progress being made in cell transplantation for Parkinson’s, involving Prof Roger Barker, Prof Malin Parmar, Dr Claire Henchcliffe & Prof Jun Takahashi at the recent G-FORCE meeting (Click here to read more about this and watch more videos):
  • “Antibodies against alpha‐synuclein” Sounds like a political movement, but it is a review of different alpha synuclein antibody approaches for research, diagnosis & potential therapeutic use in synucleinopathies like Parkinson’s ( to read more about this).
  • And yet more on alpha synuclein – a review on the “Progress of immunotherapy of anti-α-synuclein in Parkinson’s” ( to read more about this).
  • “The human LRRK2 gene, coding for a multidomain/multiactivity enzyme, acts as a pleiotropic disease locus – with tentacles extending into leprosy, inflammatory bowel disease, & Parkinson’s” – an interesting lecture ( to read more about this).
  • Interesting video presentation (from the recent AAN meeting) of some data on Parkinson’s-associated LRRK2 & GBA genetic variant carriers by Dr Tanya Simuni (Click here to watch the video).
  • A doctor with young-onset Parkinson’s – a new youtube channel:
  • Researchers & colleagues provide a useful review discussing the current literature reporting a role of lipids in Parkinson’s-associated alpha synuclein misfolding & neurotoxicity in various synucleinopathy disorders ( to read more about this).
  • An open access review of all the various ways Parkinson’s-associated alpha‐synuclein protein can be cleared from the intracellular & extracellular environments ( to read more about this).
  • In this new review, researchers dive deep into alpha-synuclein function, aggregation & pathology, & then consider the role of the microbiota might play in Parkinson’s ( to read more about this).
  • “Failure to report the results of clinical trials threatens the public’s trust in research and the integrity of the medical literature, and should be considered academic misconduct” ( to read more about this).
  • A useful overview of what is in the pipeline for Parkinson’s clinical trials by Prof Simon Lewis of the University of Sydney:
  • A useful review exploring how alpha-synuclein is cleared from the cells ( to read more about this).
  • Interesting overview of the development of NLRP3 inhibitors for various conditions including Parkinson’s – “There may be other inflammasomes playing a role under certain conditions, and we just don’t know about them yet” ( to read more about this).
  • Interesting review of how Parkinson’s-associated alpha synuclein & Alzheimer’s-associated Tau might be spreading. It includes a systematic comparison of the various mechanisms involved – “In contrast to prion diseases, in AD & PD there is still no definitive evidence for horizontal transmission of tau or alpha synuclein pathologies, as these proteins have not been shown to be infectious”; “From an anatomical point of view, alpha synuclein and tau appear to spread from and to different locations, in patterns that are relatively predictable” ( to read more about this).
  • Prof Roger Barker of the University of Cambridge on the major trends in Parkinson’s research:

 

  • A useful review of the DNAJC protein family of heat shock proteins & how they relate to Parkinson’s ( to read more about this).
  • A good read on the challenges (read: opportunities) in central nervous system drug discovery ( to read more about this).
  • The latest edition of Clinical Trial Highlights for Parkinson’s (Click here to read more about this).
  • An interesting review the current preclinical & clinical evidence supporting kinase-targeting agents (Exenatide, inosine, nilotinib & lithium) as potential disease-modifying therapies for Parkinson’s ( to read about this).
  • A man on a mission. Nobel Prize winner Prof Randy Schekman is leading a new initiative to understand PD. Funded by the Sergey Brin Family Foundation, “Aligning Science Across Parkinson’s” (or ASAP) is focusing on the basic biology of the condition ( to read more about this and click here for the ASAP website).

  • Interesting primer of antisense oligonucleotides. Parkinson’s gets a mention, highighting efforts to develop antisense oligos for LRRK2 & alpha synuclein ( to read more about this).
  • Interesting overview of the research backing the novel glucagon‐like peptide‐1 receptor agonist, NLY01 (similar to Exenatide) being developed by Neuraly for Parkinson’s ( to read more about this).
  • A nice review of how Dipeptidyl Peptidase-4 Inhibitors (like Linagliptin) could be useful potential treatments for brain conditions, like stroke & Parkinson’s ( to read more about this).
  • A useful review of Rab GTPases as physiological substrates of Parkinson’s-associated LRRK2 Kinase ( to read more about this).
  • An excellent review of the mechanisms by which the ketone body D-β-Hydroxybutyrate may improve various pathologies of Parkinson’s ( to read more about this).

 

* * * * * * * * * * * *

And there it is, just some of the highlights from May 2019 – another very busy month of Parkinson’s research. Hopefully there will be bits and pieces of interest for everyone in the list. Much of the material used here was collected from the Science of Parkinson’s Twitter feed (and there is a lot more posted there each day).

Any thoughts/feedback would be greatly appreciated (either in the comments below, or contact me directly).

And now: on to June!

 

EDITOR’S NOTE: The information provided by the SoPD website is for information and educational purposes only. Under no circumstances should it ever be considered medical or actionable advice. It is provided by research scientists, not medical practitioners. Any actions taken – based on what has been read on the website – are the sole responsibility of the reader. Any actions being contemplated by readers should firstly be discussed with a qualified healthcare professional who is aware of your medical history. While some of the information discussed in this post may cause concern, please speak with your medical physician before attempting any change in an existing treatment regime.

In addition, many of the companies mentioned in this post are publicly traded companies. That said, the material presented on this page should under no circumstances be considered financial advice. Any actions taken by the reader based on reading this material is the sole responsibility of the reader. None of the companies have requested that this material be produced, nor has the author had any contact with any of the companies or associated parties. This post has been produced for educational purposes only.

Published by Simon

I am the Director of Research at Cure Parkinson's. Before that I was working as a Parkinson's research scientist at the University of Cambridge where I conducted both clinical- and lab-based research on Parkinson's. I have worked in the Parkinson's research field for over 15 years - both academically and in biotech ventures. All of my views/opinions expressed here are solely my own, and may not reflect the views of my employer or associated parties.

One thought on “Monthly Research Review – May 2019”

  1. Simon, you continue to amaze me – your capacity to review, classify and summarize vast quantities of research literature is truly astounding. And you do it month after month!
    If I really set myself to it, it takes me over 1/2 a day to digest your monthly summary. And even after that, I’m always left with a stack of “must read” citations, saved for rainy days or long flights.
    Please know that some of us PwP’s truly rely on your blog as our primary window on the world of PD research.
    I am ever grateful to you for your dedication and perseverance.

    Like

    Reply

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