Monthly Research Review – January 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 January 2019.

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

  • Basic biology
  • Disease mechanism
  • Clinical research
  • New clinical trials (Oooh, new section for 2019!)
  • Clinical trial news
  • Other news
  • Review articles/videos

 

So, what happened during January 2019?

In world news:

January 1st – All works published in 1923 (except sound recordings) lost copyright and entered the public domain in the United States. You may do what you like with Sigmund Freud‘s “The Ego and the Id”, Kahlil Gibran’s “The Prophet”, and of course: “The Charleston”.

 

 

 

 

January 3 – The Chinese probe Chang’e 4 became the first human-made object to land on the far side of the Moon.

(This is actually Chang’e 3, but it’s a nice pic!)

January 11th – Researchers at the University of Michigan demonstrated a new approach to 3D printing. It is based on lasers and simply the lifting of shapes from a vat of liquid. And it is 100 times faster than conventional 3D printing processes! It is rather amazing (Click here to read the research report and click here for the press release).

 

 

 

25 January – AlphaStar, a new artificial intelligence algorithim by Alphabet’s DeepMind subsidary, defeated professional players of the real-time strategy game StarCraft II in ten rounds out of eleven (I don’t even know what StarCraft II is, but this terrifies me).

30th January – The temperature in the city of Chicago hit a daytime high of -24C (-11F ?!?!?). It then dropped to a low of -28C overnight (I repeat: ?!?!?).

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

In January 2019, there were 694 research articles added to the Pubmed website with the tag word “Parkinson’s” attached. 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. The Australian Parkinson’s Mission:

Without any doubt the most exciting bit of Parkinson’s research news this month (possibly year!). The Australian Government has announced the initiation of a $30+ million, 5 year clinical trial programme that will be focused around a large multi-arm clinic trial. This is a fantastic way to kick off 2019 (Click here to read the press release, click here to visit the APM website, and click here to read a SoPD post on this topic).

2. Exciting exosomes:

researchers demonstrate the use of brain-derived exosome-based biomarkers as objective measures of target engagement using serum from the exenatide Phase II clinical trial in Parkinson’s. Basically the researchers analysed ‘exosomes’ – these are small brain cell-derived sacks or ‘vesicles’ – found in the blood samples of Parkinson’s participants in the Exenatide Phase II clinical study, and they found that the treatment (the diabetes drug exenatide) had augmented insulin signaling inside the exosome. Implications are huge! May provide an potentially objective measure of target engagement from a simple blood sample ( to read more about this, and click here to read a SoPD post on this topic).

3. Bacteria in the brain

Not immediately Parkinson’s related, but it could have important implications for PD – biotech firm Cortexyme & international collaborators report porphyromonas gingivalis – a bacteria involved with inflammation of the gums – is present in the brain of people with Alzheimer’s. Mice infected with P. gingivalis begin to exhibit Alzheimer’s features, and a bacterial protease inhibitor (called COR388) rescues mouse model ( to read more about this). Interestingly, COR388 has already completed a Phase I clinical trial (Click here to read more about this).

4. A gut feeling

Researchers discovered that gut bacteria produce an enzyme called tyrosine decarboxylase. This enzyme efficiently converts levodopa – the treatment of Parkinson’s – into dopamine, even in the presence of tyrosine (a competitive substrate) and decarboxylase inhibitors. The investigators also found that high levels of this enzyme compromised levels of levodopa entering the blood system of people with Parkinson’s. The results bring into question the role of microbial metabolism in drug availability in Parkinson’s ( to read more about this).

5. Prognosis and clinical subtypes

An analysis of a retrospective cohort study of 111 individuals with autopsy-confirmed Parkinson’s suggests that clinical subtypes at the time of diagnosis could be used to estimate disease course, which may be useful in providing a more accurate prognosis in individual patients in the clinical setting (Click here to read more about this).

 

Basic biology news

  • Researchers find that both normal & mutant (G2019S) forms of Parkinson’s-associated LRRK2 interact with the translocase of outer mitochondrial membrane (TOM) complex subunits – an additional role for LRRK2 in mitochondrial function ( to read more about this).
  • Presenilins-associated rhomboid-like protein (PARL) is a protease in the inner membrane of mitochondria which is associated with Parkinson’s. Now researchers have found a new role 4 it in the maintenance of the respiratory chain in the CNS ( to read more about this and click here to read the press release).
  • Researchers have published the crystal structure of the WD40 domain dimer of Parkinson’s-associated LRRK2 protein. The data “suggest the potential utility of LRRK2 kinase inhibitors in treating PD patients with WD40 domain mutations” ( to read more about this).

  • Researchers have a manuscript on BioRxiv suggesting that neuro-inflammation in Parkinson’s & peripheral nerve damage due to inflammation in T1R (Leprosy) may share overlapping mechanisms of pathogenicity ( to read more about this).
  • Not Parkinson’s related, but researchers screened 1000s of compounds for molecules that interfere the prion protein interaction with Alzheimer’s-associated beta amyloid. An old antibiotic that decomposes into a polymer appears to work ( to read more about this and click here to read the press release).
  • Also not Parkinson’s related, but you have to wonder… Researcher report that gut-derived IgA+ plasma cells access the brain in multiple sclerosis mouse model & repress neuroinflammation in an IL-10-dependent manner ( to read more about this and click here to read the press release).
  • Again, not Parkinson’s related but intravenous injection of C. albicans cells (pathogenic yeast; common member of the human gut flora) causes a localized cerebritis, accumulation of activated microglial/astrocytes AND Alzheimer’s-associated β-amyloid around the yeast cells. C. albicans are “able to penetrate the mouse blood brain barrier & establish a transient cerebritis that causes short-term memory impairment” – Infected mice display mild memory impairment that resolves with fungal clearance ( to read more about this and click here to read the press release).
  • Interesting analysis of 6 Alpha-Synuclein point mutations associated with Parkinson’s (A30P, E46K, H50Q, G51D, A53E & A53T): “A30P was particularly prone to form metal ion induced oligomers, whereas A53T exhibited only weak tendencies to form oligomers” ( to read more about this).
  • The ability to measure microglial activity in the Parkinson’s brain would greatly aid the study of neuroinflammation. Now researchers present a new PET imaging technique targeting macrophage colony-stimulating factor 1 receptor (CSF1R) ( to read more about this).
  • Researchers report that mesencephalic-astrocyte-derived neurotrophic factor (or MANF) is a systemic regulator of homeostasis in young animals. A therapeutic application for MANF in age-related metabolic conditions like Parkinson’s? ( to read more about this and click here to read the press release).

  • Researchers provide evidence that striatal cholinergic interneurons amplify thalamostriatal excitation of striatal indirect pathway neurons in models of Parkinson’s ( to read more about this).
  • New research finds that Parkinson’s-associated LRRK2 kinase plays a critical role in manganese-induced inflammation & apoptosis in microglia ( to read more about this).
  • Researchers present results suggesting that Parkinson’s-associated alpha synuclein may affect lysosomal clustering in non-neuronal cells, similar to its role in presynaptic vesicles in neurons ( to read more about this).
  • A simple change converts Quinazoline compounds from inhibitors to activators of β-Glucocerebrosidase (GCase), partially stabilising GCase & improving its activity. Therapeutic potential for GBA-associated Parkinson’s? ( to read more about this).
  • Researchers & collaborators screened the fruit extracts of 15 different olive varieties to identify compounds that can inhibit Parkinson’s-associated alpha synuclein aggregation & oligomer toxicity. Oleuropein stands out in the results ( to read more about this).
  • Researchers find that cholesterol 24S-hydroxylase (CYP46A1) increases dopamine neurogenesis (both in vitro & in vivo – but has no effect on occulomotor or red nucleus neurogenesis). Implications for stem cell-based cell transplantation for Parkinson’s? ( to read more about this).
  • Somatostatin is a modulator of GABAergic inhibitory transmission. New research suggests somatostatin levels are reduced in GABAergic neurons derived from induced pluripotent stem cells from patients with Parkinson’s-associated PARKIN variants. Could a deficiency of somatostatin in GABAergic neurons of the frontal cortex “lead to the motor and/or non-motor symptoms of Parkinson’s via the regulation of the excitatory-inhibitory imbalance of the neural network” ( to read more about this).
  • Researchers find that the herbicide linuron amplifies astrocyte pro-inflammatory activities (by activating signaling via sigma receptor 1, inositol-requiring enzyme-1α (IRE1α), & X-box binding protein 1 (XBP1)). Implications for Parkinson’s? ( to read more about this).
  • The inflammasome is activated in aged hematopoietic stem cells (HSC). New results suggest that mitochondrial stress-initiated aberrant activation of the NLRP3 inflammasome is a reversible driver of the functional decline of HSC aging ( to read more about this).
  • Ukgansan is a traditional medicines from East Asia, composed of 7 medicinal herbs. Now Korean researchers report Ukgansan complements L-Dopa by ameliorating dopamine cell loss & L-Dopa-induced dyskinesias in model of Parkinson’s ( to read more about this).
  • Researchers find that trodusquemine causes more Alzheimer’s-associated Aβ42 aggregate formation, but less Aβ42-induced toxicity. It does this by displacing oligomers from cell membranes. Implications for Parkinson’s? ( to read more about this).

  • Researchers have a manuscript on BioRxiv that suggests the chaperone protein Hsc70 can rescue a vesicle recycling defect caused at synapses by high levels of Parkinson’s-associated alpha synuclein ( to read more about this).
  • Researchers demonstrate “timed” (doxycycline-inducible gene switch) treatment of glial cell line-derived neurotrophic factor (GDNF) gene therapy can promote motor neuron survival & axon outgrowth in rodents. “Persistent GDNF expression impaired axon regeneration by inducing axon entrapment. These findings demonstrate that timed expression can resolve the deleterious effect of uncontrolled growth factor delivery and shows that inducible growth factor gene therapy can be employed”. Implications for Parkinson’s? ( to read more about this).
  • Parkinson’s-associated LRRK2 genetic variants affect dimers differently: R1441C & I2020T mutations both enhance the rate of dimer formation; whereas the G2019S kinase domain mutant is similar to WT, & G2385R risk factor variant de-stabilizes dimers ( to read more about this).
  • Researchers present further pieces of the puzzle associated with PINK1/PARKIN mitophagy/autophagy (cellular waste disposal/recycling), which may be affected in Parkinson’s ( to read more about this and click here to read the press release).
  • αB-crystallin (CRYAB) is a small heat shock protein which functions as a natural inhibitor of astrocytic autophagy. Reducing levels of CRYAB remarkably promoted clearance of Parkinson’s-associated α-synuclein preformed fibrils ( to read more about this).
  • Researchers have an interesting manuscript on BioRxiv providing a framework for understanding the cellular basis of complex brain conditions & a role for oligodendrocytes in Parkinson’s (!) ( to read more about this).
  • New manuscript on BioRxiv demonstrates that protein misfolding cyclic amplification (PMCA) can reproduce some characteristics of Parkinson’s-associated alpha-synuclein aggregation & seeded-propagation ( to read more about this).
  • Researchers have an interesting manuscript on BioRxiv describing how absence of one Engrailed1 allele can enhance Parkinson’s-associated alpha synuclein pathology. A useful new double-hit model ( to read more about this).
  • Natural red grape extract, Resveratrol, provides neuroprotective effects in cell culture model of Parkinson’s via modulation of mitochondrial dynamics & ERK1/2 regulated autophagy ( to read more about this).

  • CGP37157 is an inhibitor of the mitochondrial Na+/Ca2+ exchanger & it appears to protect striatal neurons from Parkinson’s-associated alpha-synuclein plus rotenone-induced toxicity ( to read more about this).
  • Interesting new prodromal mouse model to study the disease pathogenesis & develop novel therapeutics for Parkinson’s. Also revealed the mechanism by which heterozygous GBA deficiency contributes to PD (via abnormal lipid metabolism & altered alpha-syn – to read more about this).
  • α-synuclein from brain homogenates from Multiple Systems Atrophy (MSA) patients retains its ability to propagate between 2 distinct mouse lines, provides compelling evidence that MSA is a prion-like disease ( to read more about this).
  • Interesting proof-of-principle report that targeting nucleotide metabolic pathways to limit adenosine production & neuroinflammation in Parkinson’s might be a promising therapeutic strategy ( to read more about this).
  • Ufbp1 has been previously identified as one of the new genetic risk loci in Parkinson’s. New research suggests it has an indispensable role in maintaining intestinal homeostasis & controlling gut inflammation ( to read more about this).
  • Researchers find that plasticity in the red nucleus region of the brain helps to compensate for dysfunctional movement control, which may partly explain why primates develop stable Parkinson’s ( to read more about this).

 

Disease mechanism

  • Using targeted gene correction & antisense oligonucleotide technology, researchers report that Parkinson’s-associated LRRK2 G2019S variant alters calcium uptake & buffering upon endo. reticulum Ca2+ influx block (
  • Researchers find increasing OR decreasing levels of Cdk5α impairs autophagy, which in turn causes the degeneration of sensitive neuronal populations (such as dopamine cells) through hyperactivation of an innate immune response (Click here to read more about this and click here to read the press release).
  • Parkinson’s & Alzheimer’s share many clinical & pathological features, but genetic association between them remains unclear. New study suggests PD genetic risk factors do not predict AD risk, but the α-synuclein genetic variants in PD reduce the AD risk ( to read more about this).
  • Researchers provide further evidence that human mutant Glucocerebrosidase contributes to accumulation & aggregation of Parkinson’s-associated α-synuclein ( to read more about this).

  • Researchers report that the cellular prion protein (PrPC) neither binds to Parkinson’s-associated alpha synuclein oligomers nor mediates their detrimental actions in models of PD ( to read more about this).
  • Researchers find that Radicicol – a heat shock protein-90 (Hsp90) inhibitor/anti oxidant – rescues yeast cells from Parkinson’s-associated aggregated α-synuclein toxicity, but not Alzheimer’s-associated β-amyloid toxicity ( to read more about this).
  • Researchers report that different strains of Parkinson’s-associated human alpha synuclein protein spread within ‘normal’ human neuronal networks in a prion-like manner. Accumulating phospho-α-Syn induces early neuronal dysfunctions ( to read more about this).
  • Researchers & colleagues have a manuscript on BioRxiv suggesting a strong interaction between Parkinson’s-associated LRRK2 & alpha synuclein transmission across mouse & human models. Could LRRK2 inhibitors stop the spread of pathology? ( to read this manuscript).
  • The International Parkinson Disease Genomics Consortium have published new research providing compelling genetic evidence that the endocytic membrane trafficking pathway plays a major role in the risk of Parkinson’s. Mendelian randomization identified 11 endocytic membrane‐trafficking pathway genes (Click here to read more about this).

  • Researchers examine the consequences of O-GlcNAcylation on the aggregation & toxicity of Parkinson’s-associated protein α-synuclein. They find O-GlcNAcylation can inhibit the aggregation of an aggressive mutant of α-synuclein ( to read more about this).
  • Researchers target Parkinson’s-associated alpha synuclein with shRNA in rodents, reducing α-synuclein levels by >70% at 12 months. Long-term α-synuclein knockdown in the adult brain does not cause neurodegeneration ( to read more about this).
  • Retromer is an endosome-Golgi retrieval complex whose Vps35 subunit is strongly associated with Parkinson’s. Now researchers suggests a possible connection between the retromer & Rab32 in the trafficking and biological functions of LRRK2 ( to read more about this).
  • Could high lithium levels in tobacco contribute to reduced risk of Parkinson’s in smokers? Researchers have recently been exploring this idea ( to read more about this).
  • Researchers provide a protocol describing production & intravenously administration of novel AAV variant vectors to adult mice for noninvasive gene transfer to the brain. Implications for GBA-associated Parkinson’s ( to read more about this).
  • Extracellularly added alpha synuclein causes lysosomal impairments, leading to further alpha syn accumulation. Trehalose – an autophagy inducer – prevents lysosomal alterations & reduces alpha syn accumulation ( to read more about this).

  • A new manuscript on BioRxiv suggests that the spread of pathological Parkinson’s-associated protein α-synuclein from urogenital nerves initiates multiple system atrophy-like symptoms. Further preclinical evidence of prion-like activity in MSA ( to read more about this).
  • Researchers find that LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity (rescued by LRRK2 inhibitor). A Parkinson’s pathogenic mechanism converging around PINK1/Parkin-dependent mitophagy? ( to read more about this).
  • New research suggests Repressor Element-1 Silencing Transcription factor/neuron-restrictive silencer factor (REST/NRSF) is localised to the nucleus of aged dopamine neurons. But in Parkinson’s REST is mostly present in Lewy bodies & absent from the nucleus ( to read more about this).
  • Yet more evidence that astrocytes – the supportive cells in the brain – may contribute to the neurodegeneration in Parkinson’s. Chemical enhancement of chaperone-mediated autophagy protected astrocytes & dopamine neurons via the clearance of α-synuclein ( to read more about this and click here to read the press release).

 

Clinical research

  • Organochlorine pesticides are associated with increased risk of Parkinson’s. Now researchers find – after analysing 705 brains – that these pesticides are associated with the presence of Lewy pathology in the brain, EVEN AFTER exclusion of PD cases ( to read more about this).
  • Researchers report reproducible detection of iron depositions in the substantia nigra of two Parkinson’s cohorts using neuromelanin‐sensitive MRI ( to read more about this).
  • Investigators published the protocol of a 3-arm study to test implementation of computer-based cognitive training that aims to produce improvements/maintenance of motor & motor fatigue symptoms in people with Parkinson’s ( to read more about this).
  • Researchers have a manuscript on BioRxiv in which they compare Alzheimer’s (AD), Lewy body disease (LBD) & dementia with Lewy bodies. They find faster cognitive decline in dementia due to AD with clinically undiagnosed LBD ( to read more about this).
  • Daytime sleepiness may be an independent symptom unrelated to sleep quality in Parkinson’s ( to read more about this).

  • James Parkinson & his father both suffered from gout. Now researchers report that analysis of 1.7 million Medicare beneficiaries suggests that gout was associated with a higher risk of incident Parkinson’s in 65–75 years age group ( to read more about this).
  • Researchers propose that increased leucine‐rich repeat kinase 2 (LRRK2) levels in immune cells (neutrophils) from people with Parkinson’s may have potential for use in patient stratification ( to read more about this).
  • Scientists report reduced ‘delay discounting’ of erotic rewards in Parkinson’s+hypersexual, both at the behavioural & brain system levels. Plus an abnormal reinforcing effect of L-dopa when PD+HS individuals are confronted with erotic stimuli ( to read more about this).
  • Analysis of IL-10 rs1800871 & rs1800872 genetic variations in 371 people with Parkinson’s finds less severe gastrointestinal dysfunctions in carriers of both IL-10 rs1800871 & rs1800872 than noncarriers ( to read more about this).
  • Researchers provide further evidence of an association between Parkinson’s & osteoporosis ( to read more about this).
  • New study suggest that cerebral gray matter volume in the early stages of Parkinson’s may be a predisposing factor for cognitive decline of people with COMT Val/Val genotypes ( to read more about this).
  • A review of studies addressing Parkinson’s-associated lewy body pathology in the spinal cord finds interesting patterns ( to read more about this).

  • Researchers have published meta analysis (and world map) of alpha synuclein genetic multiplications in familial Parkinson’s. Rare, but globally-distributed ( to read more about this).
  • Researchers provide the outline of a randomised controlled clinical trial to assess the effects of robot-assisted gait training in patients with Parkinson’s ( to read more about this).
  • Interesting case study of deep brain stimulation treatment in Parkinson’s – stimulating two targets (globus pallidus to treat motor symptoms & the nucleus basalis of Meynert to treat cognitive issues) at different frequencies with a single electrode lead ( to read more about this).
  • ‘Interactive Walkway‘ outcome measures show significant differences between people with Parkinson’s freezers, non-freezers & healthy controls ( to read more about this).
  • Researchers have published a research report considering the clinical feasibility of “NIMBLE patches” – a wearable, conformable sensor patch – to monitor motor features in Parkinson’s ( to read more about this).
  • Meta-analysis of 8 prospective studies (500 000+ adults followed for 12 years, with more than 2100 cases of Parkinson’s) provides evidence that moderate to vigorous physical activity is associated with a significantly reduced risk of developing PD ( to read more about this).
  • Researchers report that Nanopore MinION can detect genetic variations (missense mutations & an exonic deletion) in Parkinson’s-associated GBA – a “difficult gene”. Is MinION still the only portable real-time device for DNA/RNA sequencing? ( to read more about this).

  • Researchers asked “can clinical subtyping of Parkinson’s at diagnosis estimate disease progression & neuropathology?” Their answer: to find out!
  • Integrating blood metabolomics data combined with PET brain imaging data considerably enhances the diagnostic discrimination power in Parkinson’s ( to read more about this).
  • A BioRxiv manuscript outlines an independent validation of the revised 2017 Movement disorder society clinical diagnostic criteria for Progressive supranuclear palsy (PSP) – similar to Parkinson’s ( to read more about this).
  • Dopamine restores cognitive motivation in Parkinson’s (Click here to read more about this).
  • An interesting manuscript on BioRxiv describing differences in beta waveform shape in people with Parkinson’s off meds (detected with scalp EEG). Detection of PD pathophysiology using non-invasive recordings? ( to read more about this).
  • A Danish population-based case-control Study finds cancer patients have a lower risk of developing Parkinson’s even after controlling 4 cancer-related lifestyles factors & correcting for survival bias ( to read more about this).
  • According to 2014 Medicare beneficiaries data, the prevalance of Parkinson’s in the USA varies from 845/100,000 in Minnesota to 1781/100,000 in New York. Top 6: New York, Illinois, Connecticut, Florida, Pennsylvania, & Rhode Island ( to read more about this).

  • New research emphasises the diverse phenotypes associated with PARKIN mutations in Parkinson’s & the related diagnostic challenges they present (Click here to read more about this).
  • Jean Martin Charcot first proposed vibration therapy for Parkinson’s; modern meta-analysis of the data suggests not so impressive results ( to read more about this).
  • New research suggests increased levels of DJ-1 & α-synuclein protein in neural-derived exosomes collected from blood plasma could be used as potential biomarkers for Parkinson’s ( to read more about this).
  • A new manuscript on BioRxiv suggests that MRI based measures of Parkinson’s-specific network atrophy pattern is a stronger predictor of prognosis than any of the other tested biomarkers (the study involves 362 newly diagnosed PPMI individuals – to read more about this).
  • More data-driven subtyping of Parkinson’s using the PPMI (Parkinson’s Progression Markers Initiative) dataset. Three subtypes identified; Subtype I (Mild baseline, moderate motor progression) = 43.1% of the participants ( to read more about this).
  • And even more data-driven subtyping of Parkinson’s using the PPMI! This new report suggests that it may be possible to quantify neurodegenerative patterns of progression in the prodromal phase of Parkinson’s with longitudinal diffusion MRI ( to read more about this).
  • More PPMI results – REM sleep behavior disorder (RBD) is strongly associated with development of Parkinson’s, but clinical features do not apparently predict DAT binding in RBD ( to read more about this).

 

New clinical trials

  • A gut microbiome transplantation clinical trial for Parkinson’s was initiated in Belgium (Click here to read more about this).
  • The “NAPS” (Niacin for Parkinson’s) clinical trial has been registered. It aims to investigate whether 18 months of vitamin B3 (niacin or niacinamide) supplementation can reduce inflammation &/or improve Parkinson’s motor/non-motor symptoms ( to read more about this).
  • The NAD-PARK clinical trial has been registered. This is a double-blinded randomised pilot trial of Nicotamide Riboside in 30 drug naïve people with Parkinson’s. 4 weeks; 500 mg x 2/day (or placebo); Primary outcome: FDG-PET (Click here to read more about this).
  • A new Sargramostim clinical study for Parkinson’s has started, evlauating the safety of a 6 month regimen of ‘Leukine’ administered for 5 days (week) + 2-day holiday (weekend). Clinical signs & biomarkers to be assessed ( to read more about this).
  • An open-label, Phase I cell transplantation clinical study of autologous neural cells derived from IPS cells has been registered to investigate the safety & efficacy in Parkinson’s. 10 participants will be transplanted in this Chinese study (Click here to read more about this).

 

Clinical trial news

  • Phase I clinical trial results from Kainos Medicine look good: KM-819 is a small molecule inhibitor for FAF1. A randomised, double-blind, placebo-controlled dose-escalation study in healthy volunteers finds it was safe/tolerable with no drug-related SAEs ( to read more about this).
  • Gene therapy biotech firm Voyager Therapeutics has announced an update to its VY-AADC clinical program for Parkinson’s. The number of subjects in RESTORE-1 Phase II trial now 100, & plans for a staggered-parallel Phase 3 trial (RESTORE-2) of similar size ( to read more about this and click here to learn more about gene therapy).

  • Yoyager Therapeutics & Neurocrine Biosciences announced the formation of a strategic development & commercialization collaboration for Parkinson’s & Friedreich’s Ataxia ( to read more about this).
  • We are still awaiting the results/news of the Phase I & Phase IIa clinical trials, but Enterin are initiating Phase IIb ‘KARMET’ clinical trials of their orally administered ENT-01 treatment for Parkinson’s – things are happening fast in 2019 ( to read more about this).

  • Zonisamide is a medication used to treat epilepsy & Parkinson’s. Now researchers find that Zonisamide administration improves mitochondrial fatty acid β-oxidation, which is suppressed in PD (Click here to read more about this).
  • Parkinson’s-focused LRRK2 inhibitor company Denali Therapeutics joins forces with leading viral vector-based gene delivery technologies company Sirion biotech to ‘increase the availability of protein therapeutics in the brain’ ( to read more about this).

  • Collaborative Medicinal Development has announced results of their Phase I/II open-label study of CuATSM in motor neurone disease/ALS. Over 24 weeks treatment patients with sporadic ALS had dramatic slowing of disease progression. CuATSM is currently being tested in a Phase II clinical trial in Parkinson’s ( to read more about this and click here to read the press release).
  • Acorda Therapeutics announce the publication of the Phase III clinical trial results of INBRIJA/CVT-301 (inhalable L-dopa – to read more about this and click here to read the press release).

  • A randomised clinical study (with a 3-month follow-up) of dual-task aquatic exercise program was able to improve functional mobility, balance & gait of individuals with Parkinson’s ( to read more about this).
  • Pooled‐analysis of data from 2 Phase 3 clinical trials (& their open‐label extensions) of long‐term efficacy of opicapone in fluctuating Parkinson’s suggests that opicapone consistently reduced OFF‐time & increased ON‐time without increasing dyskinesias ( to read more about this).
  • Theravance Biopharma have just dosed the first participant in their Phase III clinical trial of Ampreloxetine (TD-9855) for the treatment of symptomatic neurogenic orthostatic hypotension in Parkinson’s, MSA & pure autonomic failure (PAF) ( to read more about).

  • Long-term, open-label, phase 3 study of MAO-B inhibitor Rasagiline in Japanese patients with early Parkinson’s indicates that the treatment was well tolerated with sustained motor symptom improvement, supporting its use in Japan ( to read more about this).
  • Sanofi Genzyme will be presenting safety, tolerability & pharmacokinetics from their clinical trial of oral Venglustat in GBA-associated Parkinson’s at the annual WORLD Symposia meeting in February (to read more about this).

  • Prana Therapeutics has announced that the US FDA has granted Orphan Drug designation for its lead molecule, PBT434, for the treatment of Multiple System Atrophy (MSA) – PBT434 is already being testing in Phase I trial for Parkinson’s ( to read more about this).
  • The Levodopa in EArly Parkinson’s (or LEAP) study group report that Ldopa+carbidopa had no disease-modifying effect over 80 weeks; 445 patients randomly assigned: 222=early-start Ldopa group & 223=delayed-start group; no difference in dyskinesia rates etc ( to read more about this).

 

Other news

  • Alembic Pharma has received approval from the FDA for extended-release Pramipexole tablets, used for the treatment of Parkinson’s ( to read more about this).
  • Pharmaceutical company Biogen and biotech firm C4 Therapeutics have announced a strategic collaboration to investigate the use of C4T’s protein degradation platform to discover & develop new treatments for Alzheimer’s & Parkinson’s ( to read more about this).
  • The Michael J Fox Foundation has provided a grant to tech firm IBM “to try to better understand Parkinson’s & the route it can take in patients, with the goal of paving the way for more effective treatments” – applying Artificial Intelligence analysis to the PPMI database ( to read more about this).

  • Michigan State University researchers have been awarded a large federal grant to develop a CaV1.3-targetting gene therapy for Parkinson’s. Prelim results suggest their technique completely prevents the development of dyskinesias in models of PD. Loss of dopamine in Parkinson’s results in overaction of CaV1.3 channels, which in turn causes high levels of calcium in cells, leading to retraction of the spines. Some drugs (eg. Isradipine) can block CaV1.3, but high dose required (risk of side effects). Interesting project ( to read more about this).
  • Amarantus Biosciences has received a notice of allowance from the European Patent Office covering the use of Mesencephalic astrocyte-derived neurotrophic factor (or MANF) as a treatment for various neurodegenerative disorders, including Parkinson’s ( to read more about this).
  • Wren Therapeutics has raised £18 Million series A financing to accelerate pipeline for protein misfolding conditions, like Parkinson’s ( and to read more about this).

  • The FDA has determined that it cannot approve the New Drug Application from Sunovion for their Apomorphine Sublingual Film (APL-130277) for Parkinson’s in its present form. The company is working with regulators to remedy the situation ( to read more about this).
  • The founding editor of eLife and Nobel prize winner, Randy Schekman, announced that he will be leaving the journal on the 31st January. He intends to focus more of his time on the Sergey Brin family-sponsored “Aligning Science Across Parkinson’s” (or ASAP) – an initiative to advance research into Parkinson’s (Click here to read more about this).

 

Review articles/videos

  • An excellent list of the top 10 Parkinson’s research articles from 2018 by Parkinson’s News Today (Click here to read the list).
  • A very good Francis Crick Lecture delivered by Dr Miratul Muqit: Parkinson’s disease: decoding the mysteries of neurodegeneration:

 

 

  • And here is the Q&A session from that event:

 

  • An interesting project – The Parkinson’s Story Exchange – “The Parkinson’s Story Exchange is a way to increase empathy between researchers and patients” ( to read more about this).
  • From MUFA to PUFA – everything you need to know about the role of lipids in Parkinson’s ( to read more about this).
  • Everything you need to know about Dementia with Lewy bodies. An excellent review/guide (as well as a useful outlook – to read more about this).
  • And if that is not enough: A very useful discussion on the pharmacological management of Dementia with Lewy Bodies ( to read more about this).
  • A good review exploring the roles of post-translational modifications in the alpha synuclein-associated pathogenesis of Parkinson’s ( to read more about this).
  • A great write up discussing the use of ‘virtual repurposing’ to accumulate evidence suggesting that reducing inflammation with TNF inhibitors might play a role in preventing Parkinson’s ( to read more about this).
  • A nice review of the last 200 years of Parkinson’s advances ( to read more about this).

  • Very useful open access review of recent advances & perspectives of metabolomics-based investigations in Parkinson’s ( to read more about this).
  • Everything you need to know about TAU PET brain imaging in neurodegenerative tauopathies – the presence of TAU deposits in the brain has been associated with Parkinson’s ( to read more about this).
  • A very impressive list of clinical trials focused on disease modification for Parkinson’s mentioned in the Cure Parkinson’s Trust 2018 research review (and the author of that post is a ridiculously good looking chap). Looking forward to a lot more news in 2019 (Click here to read more about this).
  • Interesting discussion on new technologies in 2019 (Click here to read more about this).
  • A very useful update on current knowledge of the role of Parkinson’s-associated protein PARKIN in direct & indirect transcription factor-mediated control of gene expression – it does a lot more than just mitophagy! ( to read more about this).
  • Interesting interview with Prof Jun Takahashi about preparing for the first human clinical trial of induced pluripotent stem cell-derived cells for Parkinson’s ( to read more about this).

  • A nice update of the latest results about the mechanisms of action of EXTRAcellular synucleins, including Parkinson’s-associated alpha synuclein ( to read more about this).
  • A useful discussion of the intercellular signaling pathways involved in the generation of midbrain dopamine neurons – implications for stem cell-based cell replacement therapy for Parkinson’s ( to read more about this).
  • Interesting review on the current state of iPSC‐based modeling of Parkinson’s with a focus on Leucine‐rich repeat kinase 2 (LRRK2) – one of the most prominent monogenetic risk factors for PD ( to read more about this).
  • An excellent update on the state of play regarding NLRP3 & Parkinson’s. For those interested in the MCC950 work, Inflazome hope to launch a clinical trial in PD sometime next year with one of their next-generation NLRP3 inhibitors ( to read more about this).

 

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

And there it is, just some of the highlights from January 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 February!

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.

Further, the author of this post is an employee of the Cure Parkinson’s Trust. The Trust has not asked for this post to be written, and there has been no effort to highlight the work of the Trust over others (perceptions of any bias should be directed to the author). This post has been written by the author solely for the purpose of sharing what the author considers interesting information.

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.

4 thoughts on “Monthly Research Review – January 2019”

  2. Hi Simon Thanks again for the considerable work that you do to put this site together. I remind my neurologist and GP about your site in order to keep them up to date.

    As research is often a longer term goal though, I look particularly in your posts for actions that I can take now that may slow the PD progression. But I am a little confused.

    In an early post in which you talked about actions you would take if you were diagnosed with PD, you mentioned foods to take and one of them is Olive Oil. But a later post there is research to suggest that oilec acid (as a main component of olives) may increase cell toxicity So -is it good or bad to take olive oil
    ( and coconut oil that you also mentioned) or is the jury still out as there isn’t enough evidence yet, one way or another.

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    1. Hi Paul,
      Thanks for your comment, and yeah it’s a fair question. At present the jury is still out as we wait to see some independent replication of the oleic acid research. And I can only repeat what I wrote on the “Lipodomics of Parkinson’s” post (https://scienceofparkinsons.com/2018/12/18/lipids/) – Oleic acid can be found in many different foods which are generally considered ‘healthy’ beyond olive oil (such as avocadoes), but most of the fatty acids in our brain, are made by our brain. And the fatty acids in our blood generally don’t enter the brain.
      I hope this helps.
      Kind regards,
      Simon

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