Monthly Research Review – June 2022

# # # #

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 June 2022.

The post is divided into 10 parts based on the type of research:

# # # #


So, what happened during June 2022?

In world news:

June 9th – researchers reported that Zophoba Morio “superworms” were perfectly happy to eat plastic. The worms could partially digest foamed polystyrene (Styrofoam) and gain weight, suggesting they were able to attain some nutrition from the material (Source).

 

June 13th – A senior software engineer at Google named Blake Lemoine was suspended after sharing transcripts of a conversation with an artificial intelligence known as  LaMDA (Language Model for Dialogue Applications) that Lemoine claimed to be “sentient”.

 

June 14Canada and Denmark ended their competing claims for Hans Island. The island lies in the middle of the Kennedy Channel between Greenland and Ellesmere Island. By dividing the island roughly in half, the two countries peacefully ended the 40+ years “Whisky War“.

 

June 24th  – The US Supreme Court overruled Roe in Dobbs v. Jackson Women’s Health Organization on the grounds that the substantive right to abortion was not “deeply rooted in this Nation’s history or tradition“, nor considered a right when the Due Process Clause was ratified in 1868, and was unknown in U.S. law until Roe (Source).

 

June 29th – Scientists (at the International Earth Rotation and Reference Systems Service – an organization in charge of global timekeeping) recorded the shortest day on Earth since the invention of the atomic clock. Our planet’s rotation measured in at 1.59 milliseconds short of the normal 24-hour day (Source).

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

In June 2022, there were 864 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (6,209 for all of 2022 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 7 pieces of Parkinson’s news

1. Alpha synuclein meets the P-bodies:

Researchers revealed an unexpected aspect of the functioning of the Parkinson’s-associated protein α-synuclein: it directly modulates processing bodies. Processing bodies (or P-bodies) are membraneless cellular structures that function in mRNA turnover & storage. The investigators found that as alpha synuclein reaches toxic levels in cells, mRNA decay kinetics begin to be disrupted. They also reported that genetic modulation of P-body components alters the toxicity of alpha synuclein (Click here to read more about this).

 

2. Parkin becomes more inflammatory:

Parkinson’s has been shown to be associated with inflammatory responses by the immune system. NLRP3 is a protein involved in inflammation and researchers have just demonstrated that the Parkinson’s-associated protein Parkin binds to NLRP3 and keeps it at bay. Loss or reduction of Parkin primes & activates an inflammatory structure called the NLRP3 inflammasome in dopamine neurons. The scientists also found that the accumulation of another protein (called PARIS) due to Parkin loss  also drives the activation of the NLRP3 inflammasome (Click here to read more about this).

 

3.  “NeuroString” :

Scientists have invented a tissue-like, string-shaped sensor that allows for long-term monitoring in the brain of various neurotransmitters. They have called this invention “NeuroString”. Neurotransmitters are chemicals that play crucial roles in the communication that occurs between cells in the brain. Potential applications for NeuroString are many, including real time monitoring of neurotransmitters like serotonin in depression & dopamine in Parkinson’s (Click here to read more about this and click here to read the press summary).

 

4.  The cerebellum and dykinesias

Here’s one for the “Cerebellum has nothing to do with Parkinson’s” crowd: The cerebellum is a structure at the back of your head, located just inside your skull above your next. It is a large pair of lobes, but for a long time it has been considered as having no role in Parkinson’s. Now researchers have demonstrated that short trains of stimulation of cerebellar Purkinje neurons was “sufficient to suppress Levodopa-induced dyskinesia or even prevent their development” (in mice – click here to read more about this).

 

5. The modification of acidification:

Lysosomes are a key component of the cellular waste disposal system. Researchers have reported that the Parkinson’s-associated protein TMEM175 is a highly proton-selective channel in the membrane of lysosomes that modulate the acidity of the inner environment of these tiny bags of enzymes. Deficiency in TMEM175 resulted in lysosomal over-acidification, which impaired the disposal/recycling of old proteins & the accumulation of alpha synuclein aggregation models of Parkinson’s (Click here to read more about this and click here to read an SoPD post on this topic).

6.  Time to plan for a sartan?

In a new study, researchers reported that angiotensin type-1 (AT1) receptor & angiotensin-converting enzyme 2 (ACE2) serum autoantibodies were higher in 117 individuals with Parkinson’s (vs 106 controls). Crucially, AT1 autoantibodies increased neurodegeneration in cell culture conditions, and also increased levels of neuroinflammation markers. This situation was prevented by treatment with the AT1 antagonist candesartan. Of particular interest, AT1 autoantibodies were also found in the cerebrospinal fluid of people with Parkinson’s. Further support for repurposing angiotensin type-1 receptor blockers for Parkinson’s? (Click here to read more about this).

7.  Need to rate your butyrate:

New research found that decreased levels of bacterially produced butyrate are related to epigenetic changes in leucocytes & neurons from Parkinson’s patients, as well as the severity of their depressive symptoms (Click here to read more about this).

Articles of general interest

  • Quality of Life for Patients With Parkinson’s” – an easy to read review of some recent research on this topic (Click here to read more about this).
  • A useful piece on Parkinson’s drug trial results to watch out for in 2022 (Click here to read more about this).
  • Dr Kevin Kwok spoke for the Davis Phinney Foundation about “Why Does it Take So Long to Develop a Cure for Parkinson’s?
  • A roadmap for the future of Parkinson’s pharmacogenomics in Asia; “A united effort is needed to speed up the clinical implementation of pharmacogenomics in PD, especially in low resource settings such as Asia” (Click here to read more about this).
  • Prof Thomas Foltynie spoke to the No Silver Bullet group about whether “Does the repurposing of diabetes drugs offer hope for Parkinson’s patients?”

 

Basic biology news

  • A 48-hour retinoic acid-pulse promotes rapid conversion of human pluripotent stem cells into neural stem cells with midbrain-like identity; Potential alternative route for cell therapy in & disease modelling of Parkinson’s (Click here to read more about this).
  • Single-cell transcriptomics has revealed specific glial activation states in Alzheimer’s & Parkinson’s, now researchers applied proteomic analysis in mice to identify glial CSF proteins “that largely match the transcriptomic changes” (Click here to read more about this).
  • CLSTN2 & PTPRO are identified as specific surface markers of midbrain dopamine progenitors – predictive of mDA neuron differentiation & able to facilitate high enrichment (up to 80%) following progenitor sorting & transplantation into models of Parkinson’s (Click here to read more about this).
  • A Nurr1 ligand C-DIM12 attenuates brain inflammation (via suppression of iNOS induction) & improves functional recovery after intracerebral hemorrhage in mice – has anyone explored this in models of Parkinson’s? (Click here to read more about this).

  • Fragmented mitochondria & “p62- and synuclein-positive Lewy body-like aggregates” observed in neuron-specific FBXO7-deficient (FBXO7flox/flox: Nestin-Cre) mice; Juvenile motor dysfunction & decreased numbers of dopaminergic neurons (Click here to read more about this).
  • What a WHOPPA! Researchers present the Wallings-Hughes Optimized Protocol for PBMC Assessment (or WHOPPA) assay to determine if LRRK2 & GCase activities in monocytes; Useful new tool for Parkinson’s research (Click here to read more about this).
  • New biorxivpreprint manuscript reports that human pericytes degrade alpha-synuclein aggregates in a strain-dependent manner; Plus pericytes derived from Parkinson’s brains “have a less uniform response” (vs control brains – click here to read more about this).
  • New research reports deletion in chromosome 6 spanning Parkinson’s-associated α-synuclein locus (& multimerin1) in the Rab27a/b double knockout mouse suggests potential interplay between Rab27 isoforms & α-synuclein (Click here to read more about this).
  • New study reports the structure of Parkinson’s-associated Parkin activated through this feed-forward mechanism (Click here to read more about this).

  • Researchers report a functional class of channelrhodopsins that are highly selective for K+ over Na+. Light-gated channels, named “Kalium (correct spelling) channelrhodopsins”, enable robust inhibition of mouse cortical neurons with millisecond precision (Click here to read more about this).
  • New research explores the structural basis for dityrosine-mediated inhibition of Parkinson’s-associated α-synuclein fibrillization; Findings point towards an important role of mild oxidation (Click here to read more about this).
  • Researchers report two peptides from the SARS-CoV-2 proteome that self-assemble into amyloid structures & are highly toxic to neuronal cells; They “suggest that cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurological symptoms in COVID-19” (Click here to read more about this).
  • Exogenous human α-Synuclein acts in vitro as a mild platelet anti-aggregant inhibiting α-thrombin-induced platelet activation (Click here to read more about this).
  • New biorxiv manuscript uses 3D FRET-CLEM to reveal structural organization, & location of Parkinson’s-associated α-Synuclein aggregation hotspots inside the cell; Notably: mitochondrial membranes; Cardiolipin again! The mitochondrial lipid triggers rapid oligomerization of A53T α-Syn, & is sequestered within aggregating lipid-protein complexes; The mitochondrial aggregates impair complex I activity & increase ROS generation (Click here to read more about this).

  • New research presents Praja1 RING-finger E3 ubiquitin ligase (PJA1) as a common sensing factor for aggregate-prone proteins to counteract their aggregation propensity; Potential therapeutic target for neurodegenerative conditions, like Parkinson’s? (Click here to read more about this).
  • Accumulating evidence indicates that liquid-liquid phase separation takes part in different synaptic compartments. A new review discusses recent data suggesting Parkinson’s-associated α-synuclein as a component of the synaptic vesicles liquid phase (Click here to read more about this).
  • New biorxiv manuscript finds the gut bacteria Enterobacteriaceae induces Parkinson’s-associated α-syn aggregation; Respiration of nitrate by Escherichia coli K-12 yields nitrite which creates an oxidizing redox potential (Click here to read more about this).
  • Researchers report quantitative detection of Parkinson’s-associated α-Synuclein & Tau oligomers & other aggregates by digital single particle counting – propose diagnostic, patient stratification & monitoring applications (Click here to read more about this).
  • New study finds mitochondrial electron transport chain defects (complexes I, II, III, & IV) enhance or suppress Parkinson’s phenotypes in flies with PARKIN variants; COX5A & suppressor mutation in cyclope (Click here to read more about this).

  • New study investigates how the non-enzymatic glycosylation (glycation) affects the function of Parkinson’s-associated α-Synuclein, hampering its binding to synaptic-like vesicles & its effect on their fusion; “How glycation stimulates the development of neurodegenerative disorders cannot be achieved looking only at its effect on the aggregation, but it is also necessary to completely understand how it affects the physiological protein function” (Click here to read more about this).
  • A link between ER-lysosome lipid transfer & innate immune activation? New research reports depleting Parkinson’s-associated VPS13C causes an increase in lysosomes with an altered lipid profile & activation of cGAS-STING pathway (Click here to read more about this).
  • New research presents mechanistic insights into accelerated Parkinson’s-associated α-synuclein aggregation mediated by human microbiome-associated functional amyloids; A focus on the E. coli functional amyloid CsgA (Click here to read more about this).
  • Researchers report that PFKP, the gatekeeper of glycolysis, is a substrate of Parkinson’s-associated Fbxo7; Fbxo7 promotes Cdk6 activity to inhibit PFKP & glycolysis in T cells (Click here to read more about this).
  • Researchers report that exogenous α-synuclein impaired neuronal cholesterol levels; The cholesterol binding domain of Parkinson’s-associated α-synuclein was sufficient to exert the same presynaptic phenotype as the full-length protein (Click here to read more about this).

  • New research presents multi-platform quantitation of Parkinson’s-associated alpha-synuclein human brain proteoforms, that suggests disease-specific biochemical profiles of synucleinopathies (Click here to read more about this).
  • Researchers identify mutations in endocannabinoid synthase 2-AG synthase diacylglycerol lipase β (DAGLB) associated with with early onset autosomal recessive Parkinsonism; DAGLB conditional knockout mice have nigral dopaminergic neuron dysfunction (Click here to read more about this).
  • A pathophysiological role for the D620N mutation in vacuolar protein sorting protein 35 (VPS35) gene in Parkinson’s remains unclear; C. elegans carrying D620N-VPS35 mutations exhibit motor dysfunction & a impaired DAT-mediated dopamine recycling pathway (Click here to read more about this).
  • New biorxiv manuscript finds that the E326K GBA variant is associated with Parkinson’s-associated alpha-synuclein aggregation & lipid droplet accumulation in human cell lines (Click here to read more about this).
  • Mass Spec-based analysis of serum proposes that revealed site-specific N-glycosylation changes in serum could be potential biomarkers for Parkinson’s; Increased abundance of glycans containing core fucose, sialic acid, & bisecting N-acetyl glucosamine were detected (Click here to read more about this).
  • New research reports discovery & preliminary development of an entirely novel structural class of potent & selective G2019S-LRRK2 kinase inhibitors: Biaryl-1H-pyrazoles (Click here to read more about this).

Disease mechanism

  • The circadian clock protein Rev-erbα may play a role in attenuating neuroinflammation in Parkinson’s pathology; Preclinical mouse model s rescued by the Rev-erbα agonist SR9009 (Click here to read more about this).
  • New research finds cognitive deficits & altered cholinergic innervation in young adult male mice carrying the Parkinson’s associated Lrrk2-G2019S genetic mutation; Donepezil rescued the behavioral deficits in these mice (Click here to read more about this).
  • New research identifies the rate-limiting lipase enzyme, LIPE, as a new Parkinson’s-relevant therapeutic target; Reducing LIPE reduced α-synuclein inclusions in human cells & alleviated neurodegeneration in C Elegans (Click here to read more about this).
  • New research reports that Metformin ameliorates phenotypes in Parkinson’s-associated DJ-1-deficient human cells; DJ-1β mutant flies are more vulnerable to hyperglycemic conditions – could loss of DJ-1 function exert a more detrimental effect in diabetes? (Click here to read more about this).

  • Spatial transcriptomic & proteomic analysis of fresh-frozen human brain tissue identifies early neurodegenerative pathways in progressive Multiple Sclerosis; “Provides a new framework for drug development strategies” (Click here to read more about this).
  • A revised biorxiv manuscript finds sex-specific life extension & rescue in tauopathy mice (via CSF1R inhibition causing selective microglial depletion – click here to read more about this).
  • A new study reports that targeting parafascicular thalamic circuits (in mice) improves both motor & non-motor deficits in PD model; Different pathways & stimulation approaches identified (Click here to read more about this).
  • Yet again: Ptbp1 deletion does NOT lead to glia-to-neuron conversion in the retina; scRNA-seq shows that glial identity is maintained after Ptbp1 deletion (Click here to read more about this).
  • New biorxiv manuscript explores specific structural features of selected flavonoids that provide neuroprotection against environmental toxin-induced a drosophila model of Parkinson’s pathogenesis (Click here to read more about this).
  • Faulty autolysosome acidification in Alzheimer’s mouse models induces autophagic build-up of Amyloid-β in neurons, yielding senile plaques (Click here to read more about this).
  • New research identifies the pacemaker function of neuronal Cav1.3 channels in mice, providing support for repurposing isradipine to selectively modulate the activity of vulnerable dopamine neuron subpopulations in Parkinson’s (Click here to read more about this).

Clinical research

  • Are cardiac arrest survivors at increased risk for Parkinson’s? New study of Danish medical registries (1996-2016; N=250 838) indicates ‘NO’ (8 per 1000 persons; HR, 0.96; 95% CI, 0.65-1.42), but higher risk of stroke, epilepsy, depression, & anxiety (Click here to read more about this).
  • New research explores the performance of α-synuclein RT-QuIC in relation to neuropathological staging of Lewy body disease; CSF samples from individuals with clinically diagnosed Parkinson’s, PDD, MSA, PSP… (Click here to read more about this).
  • “Alterations in peripheral LRRK2-dependent Rab phosphorylation are not uniformly linked to either disease status or genotype”; New study reports phosphorylation of Rab10 is increased in G2019S carriers, but only those with Parkinson’s; Also increased in 2 cohorts of iPD (Click here to read more about this).
  • New medrxiv manuscript explores health care utilization of US Medicare beneficiaries living with Parkinson’s (Click here to read more about this).
  • The practicalities of genome sequencing in the Parkinson’s clinic: Researchers report broad interest in comprehensive genetic testing among patients with PD; In 203 PD patients, they found 41 with genetic risk score for PD (Click here to read more about this).
  • Using data from three Parkinson’s cohorts (N=5770), researchers have discovered 4 new genetic loci associated with impulse control disorder (ICD) risk in PD; PRKAG2, MEFV, DAB1 & PRKCE; Enriches for subgroups of PD at very high versus very low risk for ICD (Click here to read more about this).

  • A history of cancer has a protective effect on Parkinson’s?!? New research suggests “that premorbid cancer acts as a surrogate for motor reserve in patients with PD & provide imaging evidence that history of cancer has a protective effect on PD” (Click here to read more about this).
  • New imaging data provides “specific quantitative brain signatures highly predictive of transcranial magnetic resonance-guided focused ultrasound-subthalamotomy responsiveness in Parkinson’s”; N=35 (Click here to read more about this).
  • New research presents proteome profiling of cerebrospinal fluid that reveals biomarker candidates for Parkinson’s; >1.7K proteins from >200 individuals; OMD, CD44, VGF, PRL, & MAN2B1 significantly correlated with clinical scores (Click here to read more about this).
  • In a new report, researchers present the first multiscale model of how a Parkinson’s brain responds to deep brain stimulation; “Proof-of-concept study for multiscale co-simulations to individually tailor DBS” (Click here to read more about this and click here to read the press summary).
  • Using MRI markers of structural alterations for 130 patients, researchers try to simulate the progression of brain structural alterations in Parkinson’s (Click here to read more about this).
  • A 2 year gut microbiota study involving 165 recently diagnosed Parkinson’s patients reports decreased of short-chain fatty acid-producing genera (Fusicatenibacter, Faecalibacterium, & Blautia), & an increase of mucin-degrading genus Akkermansia predicted accelerated progression (Click here to read more about this).

  • New publication presents fully computerized & automated phonemes-based detection of Parkinson’s; Lots of potential applications for telehealth (Click here to read more about this).
  • Introducing NERD-ND: Adult-onset Nucleotide Excision Repair Disorders in NeuroDegeneration; A multicenter study investigated the frequency & clinical features of patients with biallelic variants in NER genes (Click here to read more about this).
  • New research demonstrates the feasibility of in-vivo tracking of Parkinson’s progressive via network degeneration using a multimodal imaging approach; Points towards a hypometabolic midbrain cluster driving widespread striatocortical dysfunction (Click here to read more about this).
  • Researchers propose a modeling framework to introduce a new method of analyzing & interpreting the progression of Multiple system atrophy (MSA – click here to read more about this).
  • Association of structural measurements of brain reserve with motor progression in Parkinson’s; Patients with greater brain resources had greater compensatory capacity (Click here to read more about this).
  • “Our findings indicate that males and females express the disease differently at both the clinical and endophenotypic levels, since the early phase and independently from the clinical subtypes” (Click here to read more about this).

  • Dopaminergic machinery on peripheral immune cells displays an association with human Parkinson’s, with exciting implications in facilitating diagnosis & investigation of human PD pathophysiology” (Click here to read more about this).
  • New research has found that four previously defined clinical Parkinson’s subtypes have different genetic determinants which may help to inform future studies looking at underlying disease mechanisms & pathogenesis; Data from the Tracking Parkinson’s cohort (Click here to read more about this).
  • New research finds altered baseline alpha oscillations & task-dependent modulation of alpha & theta oscillations may be neural markers of poor sequential working memory in Parkinson’s (Click here to read more about this).
  • Researchers report on the presence of phosphorylated alpha-synuclein in Iba1-positive macrophages in the skin of patients with Parkinson’s; Could dermal macrophages, which are innate immune cells, be a novel biomarker for idiopathic PD? (Click here to read more about this).
  • A 10-year community-based study of LRRK2-G2385R carriers’ conversion to Parkinson’s in an Asian population reports an increased conversion (8% vs 2.6% in noncarriers – click here to read more about this).
  • Systematic review/meta-analysis finds “beta-antagonist use to be associated with a modestly increased risk of Parkinson’s, whereas beta-agonist use was associated with a modestly decreased risk of PD”; Protopathic bias & indirect associations needs addressing (Click here to read more about this).

  • New research investigates the influence of Type 2 diabetes on aspects of disease progression in Parkinson’s; Results= T2DM is associated with faster disease motor & non-motor progression; “The importance of this is that insulin resistance is potentially a modifiable metabolic state…Thus, targeting insulin resistance may represent a novel target for alleviating parkinsonian symptoms, ameliorating neurodegeneration, & slowing progression to disability & dementia” (Click here to read more about this).
  • How curious: A longitudinal study finds low religiosity in adulthood may be a strong risk factor for developing Parkinson’s; N=9,796; Those who considered religion “not at all important” had 10 fold risk of developing PD (OR, 9.99; 95% CI 3.28–30.36 – click here to read more about this).
  • New research investigated the relationship between microstructural integrity & bimanual coordination using diffusion-weighted MRI in 23 patients with Parkinson’s; Model revealed distinct microstructural alterations associated with poor bimanual coordination (Click here to read more about this).
  • Pathological α-synuclein forms derived from neuronal extracellular vesicles could be detected under native conditions & were significantly increased in all individuals with Parkinson’s & clearly distinguished disease from the non-disease state” (Click here to read more about this).
  • New research finds that deep brain stimulation of the subthalamic nucleus does not increase the risk of sialorrhea in patients with advanced Parkinson’s (Click here to read more about this).

  • A two-sample Mendelian randomization in-depth statistical investigation finds that the pro-inflammatory activity of the interleukin-6 cytokine could be a determinant of prodromal Parkinson’s (Click here to read more about this).
  • New research explores differences in gait & balance impairments in 322 people with Parkinson’s with & without GBA variants; GBA variant carriers had more impaired gait (pace & variability) & balance vs non-GBA group (Click here to read more about this).
  • It’s a story of 2 brothers. Both have Parkin-associated Parkinson’s, but differ significantly in terms of onset, progression, & clinical symptoms. Interesting gen-, transcript- & metabolomic profiling work on iPSC-derived neurons; Analysis of hiPSC-derived dopamine neurons found a significant reduced regulation of the expression of 3 neurodevelopmentally relevant cell adhesion molecules, CNTN6, CNTN4 & CHL1, in the cells of the more severely affected brother. Plus several HLA genes were differentially regulated (Click here to read more about this).
  • Researchers identify “two novel LRRK2 variants, H230R and A1440P, which segregate with the disease” from large autosomal-dominant Parkinson’s families; Both alter the phosphorylation rates of LRRK2 & its ability to phosphorylate RAB10 (Click here to read more about this).
  • New research provides evidence that dance classes improve self-esteem, quality of life & motor symptoms in people with Parkinson’s (Click here to read more about this).

  • It’s not just dopamine… New PET imaging research finds “GABAergic dysfunction coexists with dopaminergic loss not only in the putamen but also over the extrastriatal region in patients with early Parkinson’s & is related to frontal dysfunction” (Click here to read more about this).
  • New study finds that rare variants of TFG (Trafficking From ER To Golgi Regulator) were not enriched in α-synucleinopathy (MSA, Parkinson’s) or ALS cohorts (Click here to read more about this).
  • Heterozygous PARKIN mutations are common but DO NOT increase the risk of Parkinson’s; “Those with one PRKN pathogenic variant were as likely as non-carriers to have PD” (Click here to read more about this and click here for an OPEN ACCESS manuscript of the report).

New clinical trials

  • New clinical trial registered: Researchers are conducting the CANadian Adaptive DBS TriAl (CANADA) study – adaptive/closed loop vs. continuous/open loop deep brain stimulation for Parkinson’s (Click here to read more about this).
  • New clinical trial registered: Combining aerobic exercise & virtual reality for cognitive-motor rehabilitation in Parkinson’s; A pilot 3 week proof-of-concept study, recruiting 25 individuals with PD (Click here to read more about this).

  • New clinical trial registered: Inhibikase Therapeutics are initiating a Phase 2 study of their c-ABL inhibitor IkT-148009 in 120 individuals with untreated Parkinson’s; Safety & tolerability of 3 doses; 12-week study (Click here to read more about this).
  • New clinical trial registered: Biogen & Denali Therapeutics have initiated the 2nd late-stage study of their LRRK2 inhibitor BIIB122; Phase 3, randomized, double-blind, placebo-controlled efficacy & safety study in 400 individuals with LRRK2-associated Parkinson’s; This is the “Lighthouse study”; 225mg of BIIB122 (or placebo) tablets orally, once daily for up to 180 weeks; Primary endpoint = MDS-UPDRS II & III “Up to week 180”; Inclusion criteria = MDS-UPDRS II & III (in OFF state) combined score ≤40 at screening + LRRK2 variant (Click here to read more about this).

Clinical trial news

  • The pharmacokinetics of intravenously (DIZ101), subcutaneously (DIZ102), & intestinally (LCIG) infused Levodopa in advanced Parkinson’s; DIZ102 (at a pH of 5) may rapidly (≤30 min) produce stable plasma levodopa levels in blood at magnitude to enable use as monotherapy (Click here to read more about this).
  • The results of a randomized single blind clinical trial has been published, providing quantitative assessment of training effects using EksoGT® exoskeleton in individuals with Parkinson’s (Click here to read more about this).

  • Results of the STARTUP trial have been published: A double-blind, randomised trial investigating transcutaneous stimulation of the tibial nerve for urinary problems associated with Parkinson’s; N=242; Encouraging findings, fully powered RCTs are required (Click here to read more about this).

Conferences/lectures

  • The 2022 Edinburgh Parkinson’s Lecture will be held on 28th Sept 2022 and will be given by Dr Julie Jones of Robert Gordon University (Aberdeen). The lecture is entitled “The Importance of Exercise for People with Parkinson’s: Evidence, Empowerment and Enablement” (Click here to read more about this).

  • The Grand Challenger in Parkinson’s conference will be held on September 28th & 29th. The topic for this year’s meeting is Modifying Progression — From Molecules to Trials, and it will highlight recent advances that may fuel development of therapies to slow or stop disease progression (Click here to read more about this).

Other news

  • The next step in the clinical evaluation of LRRK2 inhibition for Parkinson’s – Biogen & Denali Therapeutics have initiated dosing in the Phase 2b LUMA study to evaluate efficacy & safety of BIIB122 (DNL151 vs placebo) in 640 participants with early-stage PD (Click here to read more about this).
  • Bayer has announced that BlueRock Therapeutics has established a new site for cell therapy innovation on Bayer’s campus in Berlin & intends to initiate a global non-interventional study for Parkinson’s patients in the second half of 2022 (Click here to read more about this).

 

  • Biogen & Alectos Therapeutics announce a license & collaboration agreement for AL01811 (a first-in-class oral GBA2 inhibitor) for the potential treatment of Parkinson’s; Both will collaborate on preclinical, Biogen assumes all clinical dev.; Regarding AL01811: “Small-molecule GBA2 inhibitors have been shown to reduce lysosomal pH & increase levels of the lysosomal proton pump vATPase, which is involved in maintaining the acidic pH required for lysosomal function” (Click here to read more about this).
  • The team at Denali Therapeutics presented preclinical & Phase 1 research on their LRRK2 inhibitor DNL201 which was being developed for Parkinson’s; The company has recently initiated the LUMA study with their lead inhibitor, DNL151 (Click here to read more about this and click here to read a summary of this research).

  • Yumanity Therapeutics bows out: Johnson & Johnson pays $26M to take on company’s lead stearoyl-CoA desaturase (SCD) inhibitor YTX-7739 program (being developed for Parkinson’s) & other unpartnered discovery-stage candidates (Click here to read more about this).
  • FDA unveils 5-year action plan for neurodegenerative drugs (Click here to read more about this).
  • Biogen has pulled the plug on the observational ICARE Alzhiemer’s clinical trial – meant to collect real-world data on Aduhelm’s use – because only 29 participants (6000 required) have enrolled after 7 months due to limited Medicare coverage (Click here to read more about this).

  • Interesting pieces of information from ABL Bio regarding their drug development program for Parkinson’s; ABL301 (CNS penetrant bispecific a-syn antibody) is set to start Phase 1 clinical trials at the end of the year (Click here to read more about this).
  • Seelos Therapeutics announces new data demonstrating statistically significant downregulation of mRNA & ~40% reduction of Parkinson’s-associated alpha synuclein (in vitro) using their gene therapy agent SLS-004, which utilizes CRISPR-dCas9 (Click here to read more about this).
  • Rune Labs secures US FDA clearance for Parkinson’s monitoring through StrivePD Ecosystem on the Apple watch; By combining powerful wearable technology & self-reported information, StrivePD enables a data-driven approach to management & trials (Click here to read more about this).

  • Addex terminates Phase 2b/3 study of Dipraglurant in dyskinesia-associated with Parkinson’s – due to the slow recruitment of patients & staffing shortages/turnover within study sites related to COVID19 (Click here to read more about this).
  • AlzeCure Pharma announces positive data from their clinical Phase I multiple ascending dose study testing their allosteric modulator of Trk-signaling, ACD856, being developed for Alzheimer’s, sleep apnea, traumatic brain injury & Parkinson’s (Click here to read more about this).
  • Interesting update from Inhibikase Therapeutics regarding the development of their cABL inhibitor IkT-148009; It’s moving to a Phase 2 randomized, double-blind, 12-week dosing trial assessing safety & tolerability in untreated Parkinson’s (Click here to read more about this).

  • Deja vu? Biogen & ionis pharma presented 12-month data from the Phase 3 VALOR study of Tofersen open-label extension indicating that earlier initiation (vs delayed initiation) = slower decrease in ALS clinical function, respirat. funct., muscle strength, & QoL (Click here to read more about this).
  • Biotech firm Alzprotect has been awarded a research grant from the Michael J Fox Foundation to evaluate their primary clinical candidate Ezeprogind – a brain penetrant small molecule targeting Progranulin – in models of GBA-associated Parkinson’s (Click here to read more about this).

Review articles/videos

  • This review explores targeted treatment strategies for GBA-associated Parkinson’s (Click here to read more about this).
  • New review explores various human brain-based models utilised in Parkinson’s research & highlight some of the key discoveries that they have helped to facilitate (Click here to read more about this).
  • I always knew pasta was involved somehow… Prof Ronald Melki provides a short review on the molecular & mechanistic processes of the observed pathological diversity associated to Parkinson’s-associated alpha-synuclein aggregation (Click here to read more about this).
  • A new review critically explores the literature on the microbiome–gut–brain axis in Parkinson’s & attempts to present perspectives that may be useful for clinical practice (Click here to read more about this).

  • A useful overview of the research focused on NURR1 in the context of Parkinson’s (Click here to read more about this).
  • Infections & changes in commensal bacteria & the pathogenesis of Parkinson’s; “There is evidence to support prior infection with Helicobacter pylori, hepatitis C virus, Malassezia, & Strep pneumonia in association with PD” (Click here to read more about this).
  • New review explores recent evidence of age-related immune abnormalities in Parkinson’s, with a focus on T-cell senescence (Click here to read more about this).
  • With the “UP study” results imminent, this is very timely: Tauroursodeoxycholic acid – a new review asks if it is a potential therapeutic tool in neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
  • A useful resource: A review of blood & cerebrospinal fluid biomarkers of inflammation in Parkinson’s; Includes 6 key questions (Click here to read more about this).

  • A new “review of the immunobiology of Parkinson’s disease, focusing on the role α-synuclein in the gut-brain axis hypothesis, the innate and adaptive immune responses involved in the disease, & current treatments” (Click here to read more about this).
  • Always useful to review the potential role of Toll-like receptors & neuroinflammation in Parkinson’s (Click here to read more about this).
  • Timely & useful: A new review on mitochondrial targeting drugs for neurodegenerative conditions (like Parkinson’s) – Special focus on design, mechanism & application (Click here to read more about this).
  • New review explores lysosomal functions & dysfunctions, focusing on the molecular & cellular mechanisms underlying Gaucher disease & its association with Parkinson’s (Click here to read more about this).

  • A systematic review provides empirical evidence for biometal dysregulation in Parkinson’s; “Available evidence supports an etiological role for iron & copper dysregulation in PD” (Click here to read more about this).
  • Wow, I didn’t realise just how much work is being done around PROteolysis TArgeting Chimeras (PROTACs) technology. This very useful review provides a nice overview, including a section on potentially treating neurodegenerative conditions, like Parkinson’s (Click here to read more about this).
  • New review explores neuroinflammation & immune changes in prodromal Parkinson’s & other synucleinopathies; “Despite some inconsistencies across studies data so far suggest the following” (Click here to read more about this).
  • New review explores pathological, structural, & functional changes of the cerebellum in Parkinson’s & discusses the role of the cerebellum in PD-related tremor, with the aim of providing an overview of the cerebellum-related mechanism of tremor in PD (Click here to read more about this).

  • New review explores the obstacles & the ways forward for disease modification in Parkinsonisms (Click here to read more about this).
  • Interesting overview of a future closed-loop autonomous wearable ‘sense-and-act’ system for Parkinson’s; “Methods to monitor the levels of levodopa present in the body in real time has been overlooked” (Click here to read more about this).
  • “Whatever the original trigger of neuroinflammation in Parkinson’s, what appears quite clear is that the aberrant activation of glial cells & other components of the immune system creates a vicious circle in which neurodegeneration & neuroinflammation nourish each other” (Click here to read more about this).

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

And there it is, just some of the highlights from June 2022 – 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 July!!!

All of the material on this website is licensed under a
Creative Commons Attribution 4.0 International License
You can do whatever you like with it!


EDITOR’S NOTE: The author of this post is an employee of Cure Parkinson’s, so he might be a little bit biased in his views on research and clinical trials supported by the trust. That said, the trust has not requested the production of this post, and the author is sharing it simply because it may be of interest to the Parkinson’s community.

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.


2 thoughts on “Monthly Research Review – June 2022

  1. Damn it – just when I thought I was getting a handle on Parkinson’s research – Simon has to go an humble me again. Reminds me of the time I played pick up basketball against a couple of division three college players. Sigh!

    Like

  2. Simon Brilliant!!! Best Parkinson’s Resource on the Internet! R

    Sent from my BlackBerry — the most secure mobile device — via the Bell Network

    Like

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s

This site uses Akismet to reduce spam. Learn how your comment data is processed.