# # # # 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 2023. The post is divided into 10 parts based on the type of research: Top 5 pieces of Parkinson’s news Articles of general interest Basic biology Disease mechanism Clinical research New clinical trials Clinical trial news Conferences/lectures Other news Review articles/videos # # # #

---

So, what happened during June 2023?

In world news:

June 5th – One of the largest programs in NASA’s James Webb Space Telescope‘s first year of operation is the JWST Advanced Deep Extragalactic Survey (JADES), which is devote to uncovering and characterizing faint, distant galaxies. The project has announced the discovery of hundreds of galaxies that existed when the universe was less than 600 million years old (Click here to read more about this).

 

June 12th – Former staffer of Boris Johnson, Charlotte Owen was made Baroness Owen of Alderley Edge, of Alderley Edge in the County of Cheshire. Her appointment, at age 30, made her the youngest member of the House of Lords and the youngest person ever to receive a life peerage (the unelected role is not salaried, but members can opt to receive a £332 per day attendance allowance, plus travel expenses and subsidised restaurant facilities):

 

June 14th – Scientists have created synthetic human embryos using stem cells, in a advance that sidesteps the need for eggs or sperm – more “look-what-I-can-do” rather than “groundbreaking”. Certainly outpacing laws… maybe Charlotte can help (Click here to read more about this).

 

June 19th – The United Nations General Assembly unanimously adopts the High Seas Treaty, the first treaty aimed towards marine conservation in international waters:

 

June 23rd – The ignominious Russian invasion of Ukraine became farcical when the Wagner Group (led by Yevgeny Prigozhin) began an armed conflict with the Russian military, seizing the city of Rostov-on-Don and portions of the Voronezh Oblast before withdrawing the next day, after a peace agreement brokered by Belarusian President Alexander Lukashenko.

 

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

In June 2023, there were 1,012 research articles added to the Pubmed website with the tag word “Parkinson’s” attached (5,524 for all of 2023 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 4 pieces of Parkinson’s news

1. UDCA in Parkinson’s (UP) study results:

The results of the double-blind, randomized, placebo-controlled clinical trial of ursodeoxycholic acid (UDCA) in Parkinson’s was published. The study involved 30 people taking UDCA (or a placebo) for 48-weeks. The study demonstrated that the agent is was safe and tolerable, but a larger trial will be needed to further evaluate the disease-modifying potential (Full disclosure: this study was supported by Cure Parkinson’s of which the author of the blog is the director of research – click here to read more about the study results, click here to read a press summary, and click here to read a SoPD post on the topic).

 

2. Being dead is different to being alive:

A recent medrxiv manuscript reported on the analyses of 220 brain tissue samples (from 130 people with Parkinson’s undergoing DBS), and concluded that the “Molecular signatures identified in postmortem human brain samples are inaccurate representations of disease processes occurring in the living brain” (Click here to read more about this).

 

3. Positive results for the BlueRock Phase 1 study:

Pharmaceutical company Bayer & BlueRock Therapeutics announced positive top-line results in the Phase I clinical trial of their investigational cell transplantation therapy, Bemdaneprocel (BRT-DA01), in Parkinson’s. The treatment was safe & well-tolerated in all 12 participants. Detailed trial data (primary & secondary endpoints) will be presented at the 2023 Movement Disorder meeting in Copenhagen (August 27 – 31st). Motor symptoms will be assessed at two years post-transplant. Planning is now underway for a Phase II study that is expected to begin enrolling patients in the first half of 2024 (Click here to read more about this).

 

4. Before everything else: Coffee

Researchers assessed data from more than 35,000 US participants with Parkinson’s from the Michael J Fox Foundation Fox Insight Study & found coffee drinkers had fewer problems swallowing, but aspirin intake correlated with more tremor (Click here to read more about this).

 

Articles of general interest

• The 2023 update of the Parkinson’s disease drug therapies in the clinical trial pipeline is now available OPEN ACCESS at the Journal of Parkinson’s – from Kevin McFarthing (he of the Hope list), Sue Buff, Gary Rafaloff, Brian Fiske (of the Michael J Fox Foundation) and the research team at Cure Parkinson’s (Click here to read more about this).

• To restrict or not to restrict? Practical considerations for optimizing dietary protein interactions on levodopa absorption in Parkinson’s (Click here to read more about this).

Basic biology news

• Researchers present evidence that sortilin acts as an endocytic receptor for pathogenic form of Parkinson’s-associated α-synuclein; They also find sortilin in the core structure of Lewy bodies (Click here to read more about this).
• Resident macrophages in the enteric nervous system refine it early in life by pruning synapses & phagocytosing enteric neurons; Deletion of these macrophages before weaning results in abnormal intestinal transit; Later these cells have a neuro-supportive phenotype (Click here to read more about this).
• PINK1-dependent mitophagy is a likely factor in Parkinson’s and is being investigated for therapeutic targeting. Researchers looks back at a 2010 PLOSBiology paper that shed light on the importance of PINK1 in mitophagy (Click here to read more about this).

• Researchers identify a novel function of Nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological (ASO) reduction of Nlk increased lysosome formation & improved clearance of aggregated TDP-43; Nlk destabilizes TFEB (Click here to read more about this).
• Pop quiz: Pair each of the 90 SNPs previously reported to be associated with Parkinson’s with one of 7.8 million quality-controlled SNPs from a genome-wide panel, & what do you get? Answer: An interesting link between LRRK2 & SYT10 (Click here to read more about this)
• Researchers introduce ‘border-associated macrophages’, which play an essential role in mediating α-synuclein related neuroinflammation; Identified in post-mortem Parkinson’s brains in close proximity to T cells (Click here to read more about this).
• Researchers present a 3D human blood-brain barrier chip study that finds astrocytes derived from female donors harboring Parkinson’s-related LRRK2-G2019S = pro-inflammatory & fail to support the formation of a functional capillary in vitro (Click here to read more about this).
• “The Monogenic Network of the Global Parkinson’s Genetics Program (GP2) aims to create an efficient infrastructure to accelerate the identification of novel genetic causes of PD & to improve our understanding of already identified genetic causes” (Click here to read more about this).

• New research presents transcriptomic profiling of Parkinson’s brains, & reveals disease stage specific gene expression changes – highlighting 2 genes (MAP4K4 & PHYHIP) as candidate genes for future functional studies (Click here to read more about this).
• METTL14 is decreased in PBMCs of people with Parkinson’s; Overexpression of Mettl14 dramatically increased N6-methyladenosine (m6A) modification of α-synuclein mRNA & weakens its stability; Does METTL14 have diagnostic capability for PD? (Click here to read more about this).
• New research finds that loss of Parkinson’s-associated FBXO7 in various cell types (HeLa, HEK293T, iNeurons) did not lead to significant defects in clearing damaged mitochondria or PINK1/Parkin activation (Click here to read more about this).
• Unsaturated fatty acids uniquely alter aggregation rate of Parkinson’s-associated α-synuclein & insulin; Changing the secondary structure & toxicity of amyloid aggregates formed in their presence (Click here to read more about this).
• New research explores mitochondrial dysfunction & mitophagy defects in LRRK2-R1441C-associated Parkinson’s models; Also shows LRRK2 interaction with MIRO1 occurs at mitochondria, in a genotype-independent manner (Click here to read more about this).
• New paper finds Parkinson’s-associated LRRK2-G2019S variant significantly increases the disease phenotype & inflammatory response in a mouse model of experimental colitis (DSS); Bone marrow transplantation of WT cells rescues this (Click here to read more about this).

• Researchers present “optogenetics-assisted α-synuclein (α-syn) aggregation induction system” (OASIS) & identify BAG956 (dual PDPK1 & class I PI 3-K inhibitor) in a drug screen as a dug of interest for Parkinson’s research (Click here to read more about this).
• Researchers present a bimolecular fluorescence complementation assay in living cells to monitor de novo ubiquitination of Parkinson’s-associated protein α-synuclein; Key endosomal effectors (Click here to read more about this).

Disease mechanism

• New research provides a holistic view of retromer function in regulating lysosomal homeostasis & emphases its role in neuroprotection – implications for Parkinson’s? (Click here to read more about this).
• Researchers report pharmacologic inhibition of NLRP3 (using Olatec‘s’ OLT1177) reduced levels of α-synuclein & protected dopaminergic neurons in a model of Parkinson’s – more inflammasome data! (Click here to read more about this).

• Researchers from Boehringer present 306C7B3: a CNS-penetrant, aggregate-specific α-synuclein antibody with picomolar affinity devoid of binding to the monomeric, physiologic protein; Significantly increased survival of mouse model of Parkinson’s (Click here to read more about this).
• Colony-stimulating factor 1 receptor (CSF1R) research is weird: 14-day exposure to CSF1R inhibitor PLX5622 reduced inclusion numbers & levels of insoluble α-synuclein in aged male Parkinson’s mice (but not female) & unexpectedly increase in inclusion sizes in both sexes (Click here to read more about this).
• Researchers present a small-molecule benzosulfonamide, USP30inh, that is highly potent & selective for neuronal USP30 – a very interesting target for Parkinson’s (Click here to read more about this).
• New research finds that the penta-saccharide head of the GM1 ganglioside (GM1 oligosaccharide) significantly increased neuronal survival & preserved neurite networks of dopaminergic neurons affected by Parkinson’s-associated α-synuclein oligomers (Click here to read more about this).

• When SERCA goes berserker: SERCA inhibition improves lifespan & healthspan in a rotenone model of Parkinson’s in C. elegans; Inhibition of SERCA also improved mitochondria function & associative learning (Click here to read more about this).
• Researchers report specific types & severity of intestinal inflammation, mediated by monocyte/macrophage signaling in mice, that could have implications for Parkinson’s (Click here to read more about this).
• The saga continues: Ptbp1 deletion does not induce astrocyte-to-neuron conversion (Click here to read more about this).
• Necrosulfonamide (a specific mixed lineage kinase domain-like protein inhibitor) exerts neuroprotective effect by inhibiting necroptosis, neuroinflammation, & α-synuclein oligomerization in a subacute neurotoxin (MPTP) mouse model of Parkinson’s (Click here to read more about this).

Clinical research

• Two new studies tackle genetic testing for Parkinson’s: The first (a multicenter, exploratory pilot study of US research centres) explores the feasibility & impact of offering genetic testing & counseling as part of the Parkinson’s Foundation PD GENEration study (Click here to read more about this).
• The 2nd study focuses on international efforts & “highlights not only the diversity of barriers in different regions, but also the shared & highly actionable needs for improved education & access to genetic counseling & testing for Parkinson’s worldwide” (Click here to read more about this).

• New research presents the largest Parkinson’s genetic burden test to date; identifying GBA1 & LRRK2 as 2 genes harboring rare variants associated with PD & nominating several other previously unidentified gene (Click here to read more about this).
• A 3-year natural history of orthostatic blood pressure dysregulation in early Parkinson’s – “various forms of positional blood pressure dysregulation existed in the early PD patients” (Click here to read more about this).
• New paper reports that functional & loss-of-function ARSA variants may be associated with Parkinson’s (no association survived multiple comparisons correction), but large case–control/familial cohorts replication required (Click here to read more about this).
• New study of nasal & oral swabs analysis finds that hsa-miR-1260a expression levels correlated with diseases severity, as well as olfactory function, in the Parkinson’s (n=28) & REM sleep behavior disorder (iRBD; n=8) cohorts (Click here to read more about this).
• Scream it from the hills: “RehaBEElitation“. This sounds interesting: A serious game to evaluate motor signs in Parkinson’s (Click here to read more about this).
• A protocol for conducting a systematic review to provide an overview of the AI methods being used for the assessment, monitoring, & management of Parkinson’s symptoms (Click here to read more about this).

• Robust & language-independent acoustic features in Parkinson’s; Researchers identified a set of features minimally dependent on gender, language, & recording modalities (Click here to read more about this).
• Using resting-state functional MRI, researchers find functional connectivity alterations in the locus coeruleus-related resting-state networks between idiopathic REM sleep behavior disorder (n=53), Parkinson’s + RBD+ (58), PD without RBD (69) & controls (69 – click here to read more about this).
• The ALPS-index for diffusion tensor image analysis along the perivascular space (basically neuroimaging marker of glymphatic function); Correlates with Parkinson’s severity, motor symptoms, & autonomic function, + predictive of faster deterioration; N=289 (Click here to read more about this).
• New work sought to validate previously proposed subsets of the “University of Pennsylvania Smell Identification Test” (UPSIT) odors for predicting conversion to Parkinson’s in an independent, prodromal cohort (Click here to read more about this).
• “Parkinson’s-related morbidity may be underestimated because of underrepresentation, & inverse probability of participation weighting can be used to give greater weight to underrepresented groups & produce more generalizable estimates” (Click here to read more about this).
• Investigation of long-term (5 & 11 years) neuropsychological outcomes of deep brain stimulation in early-stage Parkinson’s finds no significant differences between groups (early DBS vs optimal drug therapy alone – click here to read more about this).

• New research finds impulse control disorders symptoms (including de novo symptoms) at 12 months follow-up were similar between Parkinson’s patients undergoing DBS & patients treated with pharmacological therapy only (Click here to read more about this).
• New report identifies Parkinson’s subtypes based on resting-state electroencephalography signatures that may provide a more accurate prognosis in patients & help to stratify subgroups in clinical trials (Click here to read more about this).
• A fecal metagenomic study of 420 participants (75 recently diagnosed Parkinson’s, 101 with prodromal PD, 113 controls with constipation & 131 unaffected controls); PD & prodromal PD associated with similar changes in the gut microbiome (reductions in anaerobes – click here to read more about this).
• New study has “implications for understanding how cholinergic system pathology contributes to the clinical features of Lewy body disease, changes in brain metabolism, & disease progression patterns” (Click here to read more about this).
• New results from PPMI data “suggest that the dopamine system in Parkinson’s is implicated not only in acute, early or domain-specific cognitive changes, but also in long-term cognitive impairment, an outcome of great clinical significance to patients” (Click here to read more about this).
• New paper reports significant associations between major depressive disorder, perinatal depression, natural childbirth, LRRK2 genotype, B12 deficiency, & total hysterectomy with increased Parkinson’s severity in women (Click here to read more about this).

New clinical trials

• New clinical trial registered: This study will evaluate the long-term (54 months) safety of MeiraGTx‘s AAV-GAD gene therapy delivered bilaterally to the subthalamic nuclei of 14 participants with Parkinson’s (Click here to read more about this).

• New clinical trial registered: Researchers at Xuanwu Hospital (Beijing) are assessing the safety & efficacy of autologous induced neural stem cell-derived dopaminergic precursor cells in 10 participants with Parkinson’s (Click here to read more about this).
• New clinical trial registered: Phase 1b study of Roche‘s NLRP3-inflammasome inhibitor Selnoflast (RO7486967) in 72 individuals with Parkinson’s is ongoing (Click here to read more about this).

Clinical trial news

• Small open-label & uncontrolled pilot study finds that doxycycline (200 mg/day) is effective in reducing Levodopa-induced dyskinesia & it was safe in 8 people with Parkinson’s over a 12-week treatment period (Click here to read more about this).
• NodThera announced positive clinical data for their two brain-penetrant NLRP3 inflammasome inhibitors NT-0796 and NT-0249 and the start of a pioneering Phase Ib/IIa study in Parkinson’s (Click here to read more about this).

• Results from the Parkinson’s Disease Patient Report of Problems (PD-PROP) study show that clinically useful analysis of large datasets of verbatim reports can help highlight the problems that bother PD patients (Click here to read more about this).
• Results from a phase 2b clinical trial report limited impact from antihypertensive drug/α₂-adrenergic agonist clonidine on impulse control disorder in Parkinson’s (though a greater reduction in the total QUIP-RS score was observed in the treatment group – click here to read more about this).

Conferences/lectures

• The 6th World Parkinson’s Congress will be held in Barcelona (Spain) between the 4th – 7th July. This event only happens once every 3 years, and brings together researchers, clinicians, patients, and the broader Parkinson’s community – a truly unique scientific meeting with something for everyone.

•  The 2023 Grand Challenges in Parkinson’s conference will be held on the 27th & 28th September at the Van Andel Institute in Grand Rapids, Michigan. The theme this year will be “Pathophysiological Mechanisms to Therapeutics” and the list of speakers is excellent.

Other news

• The protocol for the “ANeED study” – ambroxol in new & early dementia with Lewy bodies (DLB) – has been published; A multicentre, phase 2a, double-blinded, randomised & placebo-controlled clinical trial (NCT0458825 – click here to read more about this).
• Biogen & Denali Therapeutics announce discontinuation of their Phase 3 LIGHTHOUSE study of the LRRK2 inhibitor BIIB122 in patients with Parkinson’s with LRRK2 mutations; The Phase 2b LUMA study will continue & now recruit both iPD & LRRK2-PD participants (Click here to read more about this).

• South Korean pharmaceutical companies, Hanall Biopharma & Daewoong Pharmaceutical, have announced a strategic investment in Vincere Biosciences to help advance their experimental Parkinson’s treatment (Click here to read more about this).
• Axial Therapeutics has received a 2nd research grant from Michael J Fox Foundation to further support further preclinical development of AX-5006 (small molecule, gut-restricted amyloid inhibitor) for Parkinson’s (Click here to read more about this).
• Annovis Bio announces that it has reached full enrollment on their Phase III study of buntanetap (aka Posiphen/ANVS401) in Parkinson’s; 520 participants enrolled at 67 sites (43 in the US & 24 in the EU); Top-line data available=end of the year (Click here to read more about this).

Review articles/videos

And there it is, just some of the highlights from June 2023 – 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.

---