Disease-modifying Potential Research Articles

Palmitoylethanolamide supplementation for human health: A state-of-the-art systematic review of Randomized Controlled Trials in patient populations.

Interest in preventative dietary interventions for human health has increasingly focused on the endocannabinoid (eCB)-like compound palmitoylethanolamide (PEA), a bioactive lipid mediator with anti-inflammatory, analgesic, and neuroprotective properties. This Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020-compliant systematic review aimed at collecting and comprehensively discussing all available data from Randomized Controlled Trials (RCTs) evaluating the efficacy and tolerability of PEA supplementation across human illnesses in patient populations. Overall, 48 eligible outputs from 47 RCTs were extracted, covering neuropsychiatric (n=15), neurological (n=17), somatic (n=13), and visceral (n=11) disturbances, as well as PEA effects on blood/plasma or other tissue biomarkers (n=10). The strongest evidence emerged from RCTs exploring PEA impact on pain management and measures of general wellbeing, especially in its ultramicronized/micronized or cold-water dispersible formulations, showing good tolerability compared to controls. Also, alongside symptom improvement, PEA demonstrated to modulate biomarkers early altered in the initial phases of an illness or contributing to its progression, suggesting a disease-modifying potential. This systematic review provided a comprehensive overview of the therapeutic potential of PEA across RCTs, highlighting its versatility either as monotherapy or add-on treatment for various clinical conditions.

OP01 Systemic antibody responses predict the onset of Inflammatory Bowel Disease up to 10 years before diagnosis

Abstract Background Identification of immune signatures in pre-clinical IBD provides a unique window of therapeutic intervention with disease-modifying potential. This study aimed to define the antigen specificities, breadth, longitudinal stability, and predictive ability of pre-clinical serum antibody repertoires using a novel, high-throughput phage-display immunoprecipitation sequencing assay (PhIP-Seq). Methods Longitudinal serum samples from active component US military personnel collected at diagnosis and at ~10, ~4, and ~2 years pre-Crohn’s disease (CD, n=200), pre-ulcerative colitis (UC, n=200) and in age- and sex-matched healthy controls (HC, n=100) were analysed (Fig. 1A-B). Serum antibody repertoires were defined against 357,000 microbial-, viral-, food-, and immune-associated peptide antigens (Fig. 1C). Conditional logistic regression analyses were performed to identify differentially abundant antibodies per timepoint. Temporal stability of antibodies was assessed using point-biserial correlations. Longitudinal sample analyses were performed using generalized linear mixed-effects models. Finally, machine learning models, including tree-based ensemble methods, were used for prediction of disease. Results Across 2,000 samples, 123,980 unique antibodies were identified (Fig. 1D). Antibody repertoire diversity was significantly lower in pre-CD (P<0.05) and pre-UC (P<0.001) sera compared to HC sera (Fig. 1E). Up to ~4 years pre-diagnosis, pre-CD samples exhibited more fluctuations in antibody repertoires compared to pre-UC and HC samples (both P<0.001, Fig. 2A). Distinct antibody responses were evident up to 10 years pre-CD and pre-UC versus HCs (Fig. 2B-C). Pre-CD individuals demonstrated escalating trajectories of antibody responses against herpesviruses including Epstein-Barr virus (EBV), cytomegalovirus, and varicella zoster virus, and against a wide range of bacterial flagellins (Fig. 2D-E). Pre-UC individuals exhibited rising antibody responses against herpesviruses and autoantigens including MAP-kinase-activating death domain protein and reduced reactivity against encapsulated pathogens (e.g., Streptococcus pneumoniae- and Haemophilus influenzae) (Fig. 2F-G). Machine learning models identified antibody signatures highly predictive of CD (AUC=0.90) and UC (AUC=0.84) up to 10 years pre-diagnosis (Fig. 2H-K). Additionally, antibody repertoires differentiated complicated from non-complicated CD up to ~10 years pre-diagnosis with high accuracy (AUC=0.85). Conclusion Antibody profiling delineates a previously unappreciated landscape of serological responses against microbial and non-microbial antigens up to 10 years before disease onset in patients with CD and UC, allowing for novel insights on IBD pathogenesis and disease prediction.

Seizing the opportunity to therapeutically address neuronal hyperexcitability in Alzheimer's disease.

Seizures in people with Alzheimer's disease are increasingly recognized to worsen disease burden and accelerate functional decline. Harnessing established antiseizure medicine discovery strategies in rodents with Alzheimer's disease associated risk genes represents a novel way to uncover disease modifying treatments that may benefit these Alzheimer's disease patients. This commentary discusses the recent evaluation by Dejakaisaya and colleagues to assess the antiseizure and disease-modifying potential of the repurposed cephalosporin antibiotic, ceftriaxone, in the Tg2576 mouse model. The use of established epilepsy models in Alzheimer's disease research carries the potential to advance novel disease-modifying treatments.

The effect of HLA genotype on disease onset and severity in CTLA-4 insufficiency.

Human Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) insufficiency caused by heterozygous germline mutations in CTLA4 is a complex immune dysregulation and immunodeficiency syndrome presenting with reduced penetrance and variable disease expressivity, suggesting the presence of disease modifiers that trigger the disease onset and severity. Various genetic and non-genetic potential triggers have been analyzed in CTLA-4 insufficiency cohorts, however, none of them have revealed a clear association to the disease. Multiple HLA haplotypes have been positively or negatively associated with various autoimmune diseases and inborn errors of immunity (IEI) due to the relevance of MHC in the strength of the T cell responses. In this exploratory study, we investigated the association of disease onset, severity and clinical manifestations of CTLA-4 insufficiency with specific HLA class I (A, B and C) and class II (DRB1 and DQB1) alleles in forty-three individuals harboring heterozygous mutations in CTLA4. Twenty-six out of the 43 recruited individuals presented moderate or severe clinical symptoms whereas 17 were completely healthy. HLA frequency analysis, odds ratio analysis and genetic linkage analysis were used. The principal statistical analyses showed no positive association between the HLA genotypes analyzed with the disease onset or the disease severity. We found potential risk associations of HLA-DQB1*05:01 and HLA-DRB1*01:02 with respiratory tract involvement and HLA-C*05:01 with affection of the neurological system in the CTLA-4-insufficient patients. Additionally, wefound a potential protective association of HLA-DRB1*01:01 with gastrointestinal symptoms. Even though, our findings suggest that HLA-A, -B, -C, DRB1, and DQB1 do not contribute to the onset or severity of disease in CTLA-4 insufficiency, certain HLA-alleles may influence the manifestation of specific symptoms. We advocate for further investigation of specific class I and class II HLA alleles as potential disease modifiers in larger clinical cohorts of CTLA-4 insufficiency.

Therapeutic Efficacy of the Inositol D-Pinitol as a Multi-Faceted Disease Modifier in the 5×FAD Humanized Mouse Model of Alzheimer's Amyloidosis.

Alzheimer's disease (AD), a leading cause of dementia, lacks effective long-term treatments. Current therapies offer temporary relief or fail to halt its progression and are often inaccessible due to cost. AD involves multiple pathological processes, including amyloid beta (Aβ) deposition, insulin resistance, tau protein hyperphosphorylation, and systemic inflammation accelerated by gut microbiota dysbiosis originating from a leaky gut. Given this context, exploring alternative therapeutic interventions capable of addressing the multifaceted components of AD etiology is essential. This study suggests D-Pinitol (DPIN) as a potential treatment modifier for AD. DPIN, derived from carob pods, demonstrates insulin-sensitizing, tau hyperphosphorylation inhibition, and antioxidant properties. To test this hypothesis, we studied whether chronic oral administration of DPIN (200 mg/kg/day) could reverse the AD-like disease progression in the 5×FAD mice. Results showed that treatment of 5×FAD mice with DPIN improved cognition, reduced hippocampal Aβ and hyperphosphorylated tau levels, increased insulin-degrading enzyme (IDE) expression, enhanced pro-cognitive hormone circulation (such as ghrelin and leptin), and normalized the PI3K/Akt insulin pathway. This enhancement may be mediated through the modulation of cyclin-dependent kinase 5 (CDK5). DPIN also protected the gut barrier and microbiota, reducing the pro-inflammatory impact of the leaky gut observed in 5×FAD mice. DPIN reduced bacterial lipopolysaccharide (LPS) and LPS-associated inflammation, as well as restored intestinal proteins such as Claudin-3. This effect was associated with a modulation of gut microbiota towards a more balanced bacterial composition. These findings underscore DPIN's promise in mitigating cognitive decline in the early AD stages, positioning it as a potential disease modifier.

Unbiased Analysis of Knee Cartilage Thickness Change Over Three Years Post-Treatment with Sprifermin vs. Placebo – A Post-Hoc Analysis from the Phase II FORWARD Study

ObjectivePost-treatment cartilage morphometry in the FORWARD study was performed without blinding to MRI acquisition order, involving potential reader bias. Here we obtained unbiased estimates of cartilage change post-treatment, reading year (Y)2 and Y5 MRIs with blinding to time point. We studied whether post-treatment cartilage thickness change differed between sprifermin- and placebo-treated knees. MethodsFORWARD was a 5-year randomized control trial in 549 knee osteoarthritis patients. Here, Y2/Y5 images were analyzed with blinding to relative temporal order and treatment group. Cartilage change during Y2→Y5 was obtained in 337 participants: n=57 treated with placebo intra-articular injections every 6 months (q6M); n=69 with 30μg sprifermin every 12 months (q12M), n=67 with 30μg q6M, n=73 with 100μg q12M, and n=71 with 100μg q6M between baseline (BL) and 18M. Total femorotibial joint (TFTJ) cartilage thickness was the primary analytic focus. ResultsTFTJ cartilage thickness change during Y2→Y5 was -26μm (SD64; 95%CI -32,-19) across the cohort; no statistically significant difference (p=0.80) was observed between treatment or placebo arms (one-way ANOVA). All groups lost cartilage, but the treatment-related difference in cartilage thickness in Sprifermin arms relative to placebo at Y2 was maintained until Y5. Annualized cartilage change in placebo participants was -8.2μm (SD21; 95%CI -14,-2.5) during Y2→Y5 vs. -5.4μm (SD27; 95%CI -13,1.8) during BL→Y2; no significant difference was identified (t-test). ConclusionFORWARD is the first study evaluating post-treatment benefits of a potential disease modifying osteoarthritis drug. Cartilage thickness gained with 100μg sprifermin at Y2 is maintained to Y5 and thus appears viable and sustainable.This is a post-hoc analysis of the FORWARD trial: ClinicalTrials.gov Identifier: NCT01919164

Exercise as a Therapeutic Intervention in Multiple Sclerosis

The role of exercise as a therapeutic intervention in multiple sclerosis (MS) has shifted over time. Early views surrounding exercise in MS advocated for caution against participation. With increasing evidence, perspectives shifted to promote exercise as a therapeutic approach for symptom management. Recent efforts have focused on understanding the potential disease-modifying effects of exercise in MS, although this work is still in its infancy. While efforts continue to optimize exercise prescriptions and unravel underlying mechanisms of exercise effects, current knowledge and implementation gaps limit the accessibility of exercise as therapy for all people living with MS. This topical review is based on an invited presentation on ‘Exercise as a Therapeutic Intervention in MS’ delivered at the ACTRIMS Forum 2024. The review summarizes current evidence for the role of exercise as a therapeutic intervention in MS from symptomatic to disease-modifying potential. We highlight directions for future research efforts to advance our understanding of potential exercise benefits and translate findings into real-world contexts for people living with MS.

GLP‐1 receptor agonists for Parkinson's disease: An updated meta-analysis

IntroductionTreatments for Parkinson's disease (PD) focus on symptom reduction through dopaminergic therapies, without clear evidence of disease-modifying effects. Glucagon-like peptide-1 (GLP-1) receptor agonists may reduce neuroinflammation by decreasing microglia activation in PD. Clinical trials suggest these agents have disease-modifying potential in PD. ObjectiveEvaluate the efficacy of GLP-1 receptor agonists in PD. MethodsPubMed, Embase and Cochrane Library were searched to identify randomized controlled trials (RCTs) of GLP-1 agonists for PD, up to July 2024. The risk of bias was assessed using the RoB-2 tool, and statistical analysis was performed with RevMan 5.4.1 software. ResultsGLP-1 receptor agonists showed a beneficial effect on MDS-UPDRS part III motor scores compared to placebo. Off-medication state, there was a −1.22 point improvement (95%CI -2.46, 0.22; P = 0.05). On-medication state, scores improved by −2.52 points (95%CI -4.02, −1.01; P = 0.001). The global MDS-UPDRS score showed a −3.43-point difference (95%CI -6.48, −0.48; P = 0.02). Cognitive performance, assessed via the Mattis DRS-2, improved by 1.32 points (95%CI 0.16, 2.52; P = 0.03). There were no significant differences in the NMSS (−0,19; 95%IC -3,44, 3,05; P = 0.91), in MADRS (−1,04; 95%IC -2,57, 0,48; P = 0.18), or PDQ-39 (−0,91; 95%IC -2,22, 0,39; P = 0.17). ConclusionGLP-1 receptor agonists improved motor and cognitive performance in PD, suggesting potential symptomatic benefits. However, further studies are needed to evaluate their long-term effects and their role in disease modification, especially considering ethnic and disease severity variations.

Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review.

This review explores recent advancements in gene therapy as a potential treatment for neurodegenerative diseases, focusing on intervention mechanisms, administration routes, and associated limitations. Following the PRISMA procedure guidelines, we systematically analyzed studies published since 2020 using the PICO framework to derive reliable conclusions. The efficacy of various gene therapies was evaluated for Parkinson's disease (n = 12), spinal muscular atrophy (n = 8), Huntington's disease (n = 3), Alzheimer's disease (n = 3), and amyotrophic lateral sclerosis (n = 6). For each condition, we assessed the therapeutic approach, curative or disease-modifying potential, delivery methods, advantages, drawbacks, and side effects. Results indicate that gene therapies targeting specific genes are particularly effective in monogenic disorders, with promising clinical outcomes expected in the near future. In contrast, in polygenic diseases, therapies primarily aim to promote cell survival. A major challenge remains: the translation of animal model success to human clinical application. Additionally, while intracerebral delivery methods enhance therapeutic efficacy, they are highly invasive. Despite these hurdles, gene therapy represents a promising frontier in the treatment of neurodegenerative diseases, underscoring the need for continued research to refine and personalize treatments for each condition.

A novel peptide-based tau aggregation inhibitor as a potential therapeutic for Alzheimer's disease and other tauopathies.

As aggregation underpins Tau toxicity, aggregation inhibitor peptides may have disease-modifying potential. They are therefore currently being designed and target either the 306VQIVYK311 aggregation-promoting hotspot found in all Tau isoforms or the 275VQIINK280 aggregation-promoting hotspot found in 4R isoforms. However, for any Tau aggregation inhibitor to potentially be clinically relevant for other tauopathies, it should target both hotspots to suppress aggregation of Tau isoforms, be stable, cross the blood-brain barrier, and rescue aggregation-dependent Tau phenotypes in vivo. We developed a retro-inverso, stable D-amino peptide, RI-AG03 [Ac-rrrrrrrrGpkyk(ac)iqvGr-NH2], based on the 306VQIVYK311 hotspots which exhibit these disease-relevant attributes. Unlike other aggregation inhibitors, RI-AG03 effectively suppresses aggregation of multiple Tau species containing both hotspots in vitro and in vivo, is non-toxic, and suppresses aggregation-dependent neurodegenerative and behavioral phenotypes. RI-AG03 therefore meets many clinically relevant requirements for an anti-aggregation Tau therapeutic and should be explored further for its disease-modifying potential for Tauopathies. Our manuscript describes the development of a novel peptide inhibitor of Tau aggregation, a retro-inverso, stable D-amino peptide called RI-AG03 that displays many clinically relevant attributes. We show its efficacy in preventing Tau aggregation in both in vitro and in vivo experimental models while being non-toxic to cells. RI-AG03 also rescues a biosensor cell line that stably expresses Tau repeat domains with the P301S mutation fused to Cer/Clo and rescues aggregation-dependent phenotypes in vivo, suppressing neurodegeneration and extending lifespan. Collectively our data describe several properties and attributes of RI-AG03 that make it a promising disease-modifying candidate to explore for reducing pathogenic Tau aggregation in Tauopathies such as Alzheimer's disease. Given the real interest in reducing Tau aggregation and the potential clinical benefit of using such agents in clinical practice, RI-AG03 should be investigated further for the treatment of Tauopathies after validation in mammalian models. Tau aggregation inhibitors are the obvious first choice as Tau-based therapies as much of Tau-mediated toxicity is aggregation dependent. Indeed, there are many research efforts focusing on this therapeutic strategy with aggregation inhibitors being designed against one of the two aggregation-promoting hotspots of the Tau protein. To our knowledge, RI-AG03 is the only peptide aggregation inhibitor that inhibits aggregation of Tau by targeting both aggregation-promoting hotspot motifs simultaneously. As such, we believe that our study will have a significant impact on drug discovery efforts in this arena.

Inflammatory proteins associated with Alzheimer’s disease reduced by a GLP1 receptor agonist: a post hoc analysis of the EXSCEL randomized placebo controlled trial

BackgroundGlucagon-like peptide-1 receptor agonists are a viable option for the prevention of Alzheimer’s disease (AD) but the mechanisms of this potential disease modifying action are unclear. We investigated the effects of once-weekly exenatide (EQW) on AD associated proteomic clusters.MethodsThe Exenatide Study of Cardiovascular Event Lowering study compared the cardiovascular effects of EQW 2 mg with placebo in 13,752 people with type 2 diabetes mellitus. 4,979 proteins were measured (Somascan V0.4) on baseline and 1-year plasma samples of 3,973 participants. C-reactive protein (CRP), ficolin-2 (FCN2), plasminogen activator inhibitor 1 (PAI-1), soluble vascular cell adhesion protein 1 (sVCAM1) and 4 protein clusters were tested in multivariable mixed models.ResultsEQW affected FCN2 (Cohen’s d -0.019), PAI-1 (Cohen’s d -0.033), sVCAM-1 (Cohen’s d 0.035) and a cytokine-cytokine cluster (Cohen’s d 0.037) significantly compared with placebo. These effects were sustained in individuals over the age of 65 but not in those under 65.ConclusionsEQW treatment was associated with significant change in inflammatory proteins associated with AD.Trial RegistrationEXSCEL is registered on ClinicalTrials.gov: NCT01144338 on 10th of June 2010.

Polymorphism in the Drug Transporter Gene ABCB1 as a Potential Disease Modifier in Cortisol-Producing Adrenal Adenomas.

Endogenous hypercortisolism presents with variable phenotypes. Etiological factors accounting for the level of hypercortisolism or varying severity of associated comorbidities are lacking. Recently, the adrenal ATP-binding cassette B1 (ABCB1) gene was identified as a modulator of glucocorticoid secretion. To evaluate the effect of ABCB1 polymorphism rs2032582 on steroid metabolome and clinical phenotypes in patients with endogenous hypercortisolism. In this cross-sectional cohort study, 137 patients prospectively enrolled in the German Cushing's registry were included (41 with ACTH-producing pituitary adenoma, 21 with cortisol-producing adrenal adenoma, and 75 with excluded hypercortisolism). In all patients, ABCB1 polymorphism was analyzed using a TaqMan genotyping assay, glucocorticoid metabolite excretion in 24-hour urine samples was analyzed by gas chromatography-mass spectrometry, and the clinical phenotype was assessed systematically. In patients with cortisol-producing adrenal adenomas, but not in patients with ACTH-producing pituitary adenomas, homozygous major allele GG of ABCB1 polymorphism rs2032582 was associated with higher overall cortisol metabolite secretion (median 13515 [IQR 10347; 25669] µg/24h vs. 9645 [6146; 10732] µg/24h in minor homo- and heterozygotes, p=0.036) and elevated major cortisol metabolites αTHF, THF and THE (9339 [6929; 17789] µg/24h vs. 6288 [4184; 7455] µg/24h, p=0.045). Moreover, these patients showed higher mean arterial pressure (116 [111; 131] mmHg in major homozygotes vs. 105 [96; 112] mmHg in minor homo- and heterozygotes, p=0.036). The genotype of drug transporter gene ABCB1 rs2032582 polymorphism is associated with the degree of cortisol metabolite secretion in cortisol-producing adrenal adenomas and could, therefore, represent a modifier of disease severity in this context.

Novel multitarget analgesic candidate SZV-1287 demonstrates potential disease-modifying effects in the monoiodoacetate-induced osteoarthritis mouse model.

Monoiodoacetate (MIA)-induced osteoarthritis (OA) is the most commonly used rodent model for testing anti-OA drug candidates. Herein, we investigated the effects of our patented multitarget drug candidate SZV-1287 (3-(4,5-diphenyl-1,3-oxazol-2-yl) propanal oxime) that is currently under clinical development for neuropathic pain and characterized the mouse model through complex functional, in vivo imaging, and morphological techniques. Knee OA was induced by intraarticular MIA injection (0.5 and 0.8mg). Spontaneous pain was assessed based on weight distribution, referred pain by paw mechanonociception (esthesiometry), edema by caliper, neutrophil myeloperoxidase activity by luminescence, matrix metalloproteinase activity, vascular leakage and bone remodeling by fluorescence imaging, bone morphology by micro-CT, histopathological alterations by semiquantitative scoring, and glia activation by immunohistochemistry. Then, SZV-1287 (20mg/kg/day) or its vehicle was injected intraperitoneally over a 21-day period. MIA induced remarkably decreased thresholds of weight bearing and paw withdrawal, alterations in the tibial and femoral structures (reactive sclerosis, increased trabeculation, and cortical erosions), histopathological damage (disorganized cartilage structure, hypocellularity, decreased matrix staining and tidemark integrity, and increased synovial hyperplasia and osteophyte formation), and changes in the astrocyte and microglia density in the lumbar spinal cord. There were no major differences between the two MIA doses in most outcome measures. SZV-1287 inhibited MIA-induced weight bearing reduction, hyperalgesia, edema, myeloperoxidase activity, histopathological damage, and astrocyte and microglia density. SZV-1287 may have disease-modifying potential through analgesic, anti-inflammatory, and chondroprotective effects. The MIA mouse model is valuable for investigating OA-related mechanisms and testing compounds in mice at an optimal dose of 0.5mg.

Disease-Modifying Symptomatic Treatment (DMST) Potential of Cannabinoids in Patients with Multiple Sclerosis.

With the recent introduction of a number of highly effective disease-modifying treatments (DMTs) and the resulting almost complete prevention of acute relapses in many patients with multiple sclerosis (MS), the interest of MS clinicians has gradually shifted from relapse prevention to counteraction of disease progression and the treatment of residual symptoms. Targeting the cannabinoid system with nabiximols is an approved and effective strategy for the treatment of spasticity secondary to MS. Recently, the concept of spasticity plus syndrome (SPS) was introduced to account for the evidence that spasticity often appears in MS patients in clusters with other symptoms (such as pain, bladder dysfunction, sleep, and mood disorders), where cannabinoids can also be effective due to their broader action on many immune and neuronal functions. Interestingly, outside these symptomatic benefits, extensive pre-clinical and clinical research indicated how the modulation of the cannabinoid system results in significant anti-inflammatory and neuroprotective effects, all potentially relevant for MS disease control. This evidence makes nabiximols a potential disease modifying symptomatic treatment (DMST), a concept introduced in an attempt to overcome the often artificial distinction between DMTs and symptomatic therapies (STs).

Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN

AbstractMutations in calreticulin (mutCALR) are the second most common drivers of myeloproliferative neoplasms (MPNs) and yet, the current therapeutic landscape lacks a selective agent for mutCALR-expressing MPNs. Here, we show that the monoclonal antibody INCA033989 selectively targets mutCALR-positive cells. INCA033989 antagonized mutCALR-driven signaling and proliferation in engineered cell lines and primary CD34+ cells from patients with MPN. No antibody binding or functional activity was observed in the cells lacking mutCALR. In a mouse model of mutCALR-driven MPN, treatment with an INCA033989 mouse surrogate antibody effectively prevented the development of thrombocytosis and accumulation of megakaryocytes in the bone marrow. INCA033989 reduced the pathogenic self-renewal of mutCALR-positive disease-initiating cells in both primary and secondary transplantations, illustrating its disease-modifying potential. In summary, we describe a novel mutCALR-targeted therapy for MPNs, a monoclonal antibody that selectively inhibits the oncogenic function of MPN cells without interfering with normal hematopoiesis.

Evolutionary rate covariation is pervasive between glycosylation pathways and points to potential disease modifiers.

Mutations in glycosylation pathways, such as N-linked glycosylation, O-linked glycosylation, and GPI anchor synthesis, lead to Congenital Disorders of Glycosylation (CDG). CDG typically present with seizures, hypotonia, and developmental delay but display large clinical variability with symptoms affecting every system in the body. This variability suggests modifier genes might influence the phenotypes. Because of the similar physiology and clinical symptoms, there are likely common genetic modifiers between CDG. Here, we use evolution as a tool to identify common modifiers between CDG and glycosylation genes. Protein glycosylation is evolutionarily conserved from yeast to mammals. Evolutionary rate covariation (ERC) identifies proteins with similar evolutionary rates that indicate shared biological functions and pathways. Using ERC, we identified strong evolutionary rate signatures between proteins in the same and different glycosylation pathways. Genome-wide analysis of proteins showing significant ERC with GPI anchor synthesis proteins revealed strong signatures with ncRNA modification proteins and DNA repair proteins. We also identified strong patterns of ERC based on cellular sub-localization of the GPI anchor synthesis enzymes. Functional testing of the highest scoring candidates validated genetic interactions and identified novel genetic modifiers of CDG genes. ERC analysis of disease genes and biological pathways allows for rapid prioritization of potential genetic modifiers, which can provide a better understanding of disease pathophysiology and novel therapeutic targets.

Identifying disease-modifying potential in myelofibrosis clinical trials

AbstractThe ultimate goal of bringing most new drugs to the clinic in hematologic malignancy is to improve overall survival. However, the use of surrogate end points for overall survival is increasingly considered standard practice, because a well validated surrogate end point can accelerate the outcome assessment and facilitate better clinical trial design. Established examples include monitoring minimal residual disease in chronic myeloid leukemia and acute leukemia, and metabolic response assessment in lymphoma. However, what happens when a clinical trial end point that is not a good surrogate for disease-modifying potential becomes ingrained as an expected outcome, and new agents are expected or required to meet this end point to demonstrate “efficacy”? Janus kinase (JAK) inhibitors for myelofibrosis (MF) have a specific impact on reducing symptom burden and splenomegaly but limited impact on the natural history of the disease. Since the introduction of ruxolitinib more than a decade ago there has been modest incremental success in clinical trials for MF but no major leap forward to alter the natural history of the disease. We argue that the clinical development of novel agents for MF will be accelerated by moving away from using end points that are specifically tailored to measure the beneficial effects of JAK inhibitors. We propose that specific measures of relevant disease burden, such as reduction in mutation burden as determined by molecular end points, should replace established end points. Careful reanalysis of existing data and trials in progress is needed to identify the most useful surrogate end points for future MF trials and better serve patient interest.

The Role of Diet in Parkinson's Disease.

The aim of this review is to examine the intersection of Parkinson's disease (PD) with nutrition, to identify best nutritional practices based on current evidence, and to identify gaps in the evidence and suggest future directions. Epidemiological work has linked various dietary patterns and food groups to changes in PD risk; however, fewer studies have evaluated the role of various diets, dietary components, and supplements in the management of established PD. There is substantial interest in exploring the role of diet-related interventions in both symptomatic management and potential disease modification. In this paper, we evaluate the utility of several dietary patterns, including the Mediterranean (MeDi), Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), Alternative Healthy Eating Index (AHEI), vegan/vegetarian, and ketogenic diet in persons with PD. Additionally, we provide an overview of the evidence relating several individual food groups and nutritional supplements to PD risk, symptoms and progression.

Impaired instructive and protective barrier functions of the endothelial cell glycocalyx pericellular matrix is impacted in COVID-19 disease.

The aim of this study was to review the roles of endothelial cells in normal tissue function and to show how COVID-19 disease impacts on endothelial cell properties that lead to much of its associated symptomatology. This places the endothelial cell as a prominent cell type to target therapeutically in the treatment of this disorder. Advances in glycosaminoglycan analytical techniques and functional glycomics have improved glycosaminoglycan mimetics development, providing agents that can more appropriately target various aspects of the behaviour of the endothelial cell in-situ and have also provided polymers with potential to prevent viral infection. Thus, promising approaches are being developed to combat COVID-19 disease and the plethora of symptoms this disease produces. Glycosaminoglycan mimetics that improve endothelial glycocalyx boundary functions have promising properties in the prevention of viral infection, improve endothelial cell function and have disease-modifying potential. Endothelial cell integrity, forming tight junctions in cerebral cell populations in the blood-brain barrier, prevents the exposure of the central nervous system to circulating toxins and harmful chemicals, which may contribute to the troublesome brain fogging phenomena reported in cognitive processing in long COVID disease.

A novel selective NLRP3 inhibitor shows disease-modifying potential in animal models of Parkinson’s disease

Pathological activation of the Nod-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome signaling underlies many autoimmune and neuroinflammatory conditions. Here we report that, a rationally designed, novel, orally active, selective NLRP3 inflammasome inhibitor, Usnoflast (ZYIL1), showed potent inhibition of ATP, Nigericin and monosodium urate-mediated interleukin (IL)-1β release in THP-1 cells and human PBMC. In isolated microglia cells, the IC50 of ZYIL1 mediated inhibition of IL-1β was 43 nM. ZYIL1 displayed good pharmacokinetic profile in mice, rats and primates after oral administration and the concentrations found in the brain and cerebrospinal fluid (CSF) were markedly higher than the IC50 values. In an in vivo model of neuroinflammation, ZYIL1 demonstrated robust suppression of NLRP3 inflammasome activation and IL-1β upon oral administration. This translated into efficacy in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-Hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) models in mice. In MPTP and/or 6-OHDA models, treatment with ZYIL1 ameliorated motor deficits, degeneration of nigrostriatal dopaminergic neurons and abnormal accumulation of α-synuclein. There were positive changes in the genes related to walking, locomotor activity, neurogenesis, neuroblast proliferation and neuronal differentiation in the PD brain indicating improvement in neural health which translated into improved mobility. These findings clearly indicate that selective NLRP3 inhibitor ZYIL1, ameliorates neuroinflammation and appears to have the potential for disease modification and progression associated with PD.