Stop Disease Progression Research Articles

The Redox Stress Test: A novel technique reveals oxidative stress in Parkinson’s disease

A novel Redox Stress Test has been developed to identify symptoms of diseases associated with oxidative stress by observing symptom changes induced by short-term activation of the transcription factor Nrf2, to restore redox homeostasis. The Nrf2 pathway is triggered by a herbal preparation, Broccoli Seed Tea, developed to deliver a therapeutic dose of highly bioavailable sulforaphane, a potent activator of Nrf2. We discuss the rationale behind the tea and describe the methods used to optimise the bioavailability of sulforaphane to match the pharmacodynamics of Nrf2 activation. When consumed by people with Parkinson’s disease, the Redox Stress Test induced powerful and concurrent attenuation of a diverse group of Parkinson’s non-motor symptoms, including fatigue, constipation and urinary urgency. Motor symptoms were strictly unaffected. This observation indicates that oxidative stress may be a common factor contributing to non-motor symptoms involving sites in the CNS and peripheral organs. We tentatively interpret the results in terms of a hypothetical model for Parkinson’s Syndrome which we describe as a multisystem redox disorder with reservoirs of the disease in peripheral organs as well as in the brain. Eliminating the disease in peripheral organs is therefore a prerequisite to stopping disease progression in the brain. According to this model, the redox disorder in the brain provokes progressive neurological damage, which is not recognised as such in the early years. More specific neurological symptoms only come to light many years later, when damage to dopaminergic neurons creates a dopamine deficiency which eventually exceeds the threshold required for normal motor control, generating a new coherent group of neurological symptoms which define movement disorder. Given the apparent ease with which oxidative stress can be quenched in several locations simultaneously, we briefly discuss possible implications for public health, medical research, patients and patient advocacy groups. We note that the Redox Stress Test may have the potential to explore symptoms of other diseases where oxidative stress is believed to play a major role, although this remains subject to validation by further research.

Molecular Pathogenesis and Treatment Strategies of Chronic Myeloid Leukemia (CML)

Chronic Myeloid Leukemia (CML) is a myeloproliferative disease diagnosed in bone marrow, arising from a chromosomal translocation between chromosomes 9 and 22, resulting in the formation of fusion oncogene BCR–ABL. The product of this fusion oncogene is a new oncoprotein bcr–abl which possesses abnormal tyrosine kinase activity. In response to this, abnormal signaling pathway activation occurs, leading to cell transformation. BCR–ABL oncogene could be targeted by tyrosine kinase inhibitors (TKIs) to delay or inhibit the disease progression. Imatinib is the first drug designed against CML but resistance to this has led to the development of the second- and third generations of inhibitors that are active against many types of BCR–ABL gene mutations. However, somehow, due to disease progression, TKIs do not remain as effective. There are three well-characterized phases of CML: The chronic phase (CP), the accelerated phase, and the terminal stage which is the blast crisis (BC) stage. In the CP of CML, mature granulocytes and myeloid precursors become aggregated majorly in the bone marrow and peripheral blood. The accelerated phase is marked by increased disease severity and an increase in progenitor/precursor cell number. In the BC stage, undifferentiated blast cells grow in number. Many patients with CML are diagnosed during the CP of the disease, so the survival rate of CML is high. However, 20% of CML patients proceed to advanced stages that result in drug resistance, intolerance, and mortality. So, for proper CML treatment, drugs are needed to target multiple BCR– ABL mutations, delay or stop disease progression, and overcome resistance caused by BCR–ABL independent mechanisms, especially during advanced phases of CML. Moreover, drugs could be developed to eradicate the stem cells of CML. These targets could be achieved by understanding mechanisms of disease progression, disease relapse, and drug resistance by utilizing high throughput molecular genetics, cell biology and immunology techniques.

Altering Calcium Sensitivity in Heart Failure: A Crossroads of Disease Etiology and Therapeutic Innovation.

Heart failure (HF) presents a significant clinical challenge, with current treatments mainly easing symptoms without stopping disease progression. The targeting of calcium (Ca2+) regulation is emerging as a key area for innovative HF treatments that could significantly alter disease outcomes and enhance cardiac function. In this review, we aim to explore the implications of altered Ca2+ sensitivity, a key determinant of cardiac muscle force, in HF, including its roles during systole and diastole and its association with different HF types-HF with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). We further highlight the role of the two rate constants kon (Ca2+ binding to Troponin C) and koff (its dissociation) to fully comprehend how changes in Ca2+ sensitivity impact heart function. Additionally, we examine how increased Ca2+ sensitivity, while boosting systolic function, also presents diastolic risks, potentially leading to arrhythmias and sudden cardiac death. This suggests that strategies aimed at moderating myofilament Ca2+ sensitivity could revolutionize anti-arrhythmic approaches, reshaping the HF treatment landscape. In conclusion, we emphasize the need for precision in therapeutic approaches targeting Ca2+ sensitivity and call for comprehensive research into the complex interactions between Ca2+ regulation, myofilament sensitivity, and their clinical manifestations in HF.

ASynPEP-DB: a database ofbiogenic peptides forinhibiting α-synuclein aggregation.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder, yet effective treatments able to stop or delay disease progression remain elusive. The aggregation of a presynaptic protein, α-synuclein (aSyn), is the primary neurological hallmark of PD and, thus, a promising target for therapeutic intervention. However, the lack of consensus on the molecular properties required to specifically bind the toxic species formed during aSyn aggregation has hindered the development of therapeutic molecules. Recently, we defined and experimentally validated a peptide architecture that demonstrated high affinity and selectivity in binding to aSyn toxic oligomers and fibrils, effectively preventing aSyn pathogenic aggregation. Human peptides with such properties may have neuroprotective activities and hold a huge therapeutic interest. Driven by this idea, here, we developed a discriminative algorithm for the screening of human endogenous neuropeptides, antimicrobial peptides and diet-derived bioactive peptides with the potential to inhibit aSyn aggregation. We identified over 100 unique biogenic peptide candidates and ensembled a comprehensive database (aSynPEP-DB) that collects their physicochemical features, source datasets and additional therapeutic-relevant information, including their sites of expression and associated pathways. Besides, we provide access to the discriminative algorithm to extend its application to the screening of artificial peptides or new peptide datasets. aSynPEP-DB is a unique repository of peptides with the potential to modulate aSyn aggregation, serving as a platform for the identification of previously unexplored therapeutic agents. Database URL: https://asynpepdb.ppmclab.com/.

Exploring The Link Between Vitamin D and Type 2 Diabetes Prevention: A Comprehensive Meta-Analysis of Observational Studies

Albeit the reasonableness of vitamin D supplementation in lessening unmistakable diabetes stays muddled, vitamin D has arisen as a huge indicator of progress in type 2 diabetes. We played out a thorough meta-examination that included hybrid investigations and controlled preliminaries randomly chosen to account for this uncertainty. Our findings add to the ongoing discussion surrounding this issue and provide useful information regarding the possibility that vitamin D plays a role in the treatment of type 2 diabetes. In this systematic review, we wanted to provide a comprehensive overview of the most recent data on the effects of vitamin D on people with type 2 diabetes. We searched multiple databases in accordance with PRISMA guidelines and found 40 relevant studies published between 2015 and 2022. may make the disease more likely to happen to you. However, other considerations, such as one's lifestyle, diet, and genetic predisposition to type 2 diabetes, are essential. Conversely, our meta-investigation of randomized clinical preliminaries found that vitamin D supplementation didn't fundamentally lessen the gamble of creating type 2 diabetes. According to these findings, supplementing vitamin D levels may not be sufficient to stop disease progression. The individual and the underlying pathophysiology of the disease may determine how Diabetes type 2 can be fought with vitamin D. Basically the survey takes a better reaching evaluation of the nowadays information on the types of diabetes with the connection. More exploration is expected to all the more likely comprehend the components in question and to investigate extra preventive methodologies and mediations for type 2 diabetes.

Abstract 16155: Achieving Coronary Artery Disease Regression: A Triumph of Lifestyle Modification and Optimal Medical Therapy

Background: Coronary artery disease (CAD) is the leading cause of death worldwide. Early recognition of risk factors and targeting them using lifestyle modifications and pharmacological measures is vital for secondary prevention. This case demonstrates the effectiveness of comprehensive management in achieving marked regression of CAD. Case presentation: A 45-year-old female with a history of type II diabetes mellitus, hypertension, and hyperlipidemia with markedly elevated lipoprotein (A) of 233 nmol/L presented with chronic coronary syndrome (CCS). She had a strong family history of CAD and denied smoking, alcohol use, and recreational drug use. Transthoracic echocardiography revealed preserved left ventricular systolic function with an ejection fraction of 50%, regional wall motion abnormalities in the form of inferior wall hypokinesia, and mild mitral regurgitation. She underwent coronary angiography (CA) which revealed significant three-vessel CAD. Figure 1 Decision making: She underwent successful percutaneous coronary intervention (PCI) to the RCA and PDA with two overlapping drug-eluted stents and plain balloon angioplasty to the PL branch. The patient adhered to strict lifestyle modification and was prescribed optimal anti-ischemic and anti-diabetic medications. She lost 22 lbs over two years, her LDL went down from 178 to 14 mg/dl and A1c from 12.2 to 6.8. During follow up, she started to complain of dyspnea on exertion for two weeks. Despite the marked laboratory improvement and despite she was found to be anemic at that time which can explain her symptoms, decision was to proceed to CA given her high pretest probability. A repeat CA showed marked regression in her CAD. Figure 2 Conclusion: Regression of coronary artery disease is a reality giving hope for not just stopping disease progression but achieving reduction in plaque size with optimal medical therapy, where pharmacological measures and lifestyle modifications work synergistically.

Incretin Mimetics Restore the ER-Mitochondrial Axis and Switch Cell Fate Towards Survival in LUHMES Dopaminergic-Like Neurons: Implications for Novel Therapeutic Strategies in Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder that afflicts more than 10 million people worldwide. Available therapeutic interventions do not stop disease progression. The etiopathogenesis of PD includes unbalanced calcium dynamics and chronic dysfunction of the axis of the endoplasmic reticulum (ER) and mitochondria that all can gradually favor protein aggregation and dopaminergic degeneration. In Lund Human Mesencephalic (LUHMES) dopaminergic-like neurons, we tested novel incretin mimetics under conditions of persistent, calcium-dependent ER stress. We assessed the pharmacological effects of Liraglutide-a glucagon-like peptide-1 (GLP-1) analog-and the dual incretin GLP-1/GIP agonist DA3-CH in the unfolded protein response (UPR), cell bioenergetics, mitochondrial biogenesis, macroautophagy, and intracellular signaling for cell fate in terminally differentiated LUHMES cells. Cells were co-stressed with the sarcoplasmic reticulum calcium ATPase (SERCA) inhibitor, thapsigargin. We report that Liraglutide and DA3-CH analogs rescue the arrested oxidative phosphorylation and glycolysis. They mitigate the suppressed mitochondrial biogenesis and hyper-polarization of the mitochondrial membrane, all to re-establish normalcy of mitochondrial function under conditions of chronic ER stress. These effects correlate with a resolution of the UPR and the deficiency of components for autophagosome formation to ultimately halt the excessive synaptic and neuronal death. Notably, the dual incretin displayed a superior anti-apoptotic effect, when compared to Liraglutide. The results confirm the protective effects of incretin signaling in ER and mitochondrial stress for neuronal degeneration management and further explain the incretin-derived effects observed in PD patients.

Characterizing the role of human behavior in the effectiveness of contact-tracing applications.

Although numerous countries relied on contact-tracing (CT) applications as an epidemic control measure against the COVID-19 pandemic, the debate around their effectiveness is still open. Most studies indicate that very high levels of adoption are required to stop disease progression, placing the main interest of policymakers in promoting app adherence. However, other factors of human behavior, like delays in adherence or heterogeneous compliance, are often disregarded. To characterize the impact of human behavior on the effectiveness of CT apps we propose a multilayer network model reflecting the co-evolution of an epidemic outbreak and the app adoption dynamics over a synthetic population generated from survey data. The model was initialized to produce epidemic outbreaks resembling the first wave of the COVID-19 pandemic and was used to explore the impact of different changes in behavioral features in peak incidence and maximal prevalence. The results corroborate the relevance of the number of users for the effectiveness of CT apps but also highlight the need for early adoption and, at least, moderate levels of compliance, which are factors often not considered by most policymakers. The insight obtained was used to identify a bottleneck in the implementation of several apps, such as the Spanish CT app, where we hypothesize that a simplification of the reporting system could result in increased effectiveness through a rise in the levels of compliance.

Prevention of Alzheimer pathology by blocking neuregulin signaling on microglia.

Plaque formation, microglial activation, and synaptic loss are pathological hallmarks of Alzheimer's disease, however, removing plaques have had little clinical benefit. Here, we show that neuregulin-1, a glial growth factor, induces inflammatory cytokines and promotes phagocytic activity in vitro and augments microglial activation and plaque formation in 5XFAD Alzheimer's mice. Brain-specific targeting of neuregulin-1 by intraventricular delivery of a novel neuregulin-1 fusion protein antagonist GlyB4 significantly alters microglial morphology and function to a non-pathogenic morphology in early-stage 5XFAD mice and prevents plaques from forming. Once plaques have already formed, GlyB4 reduces new plaque formation and prevents synaptic loss. Selective, targeted disruption of neuregulin-1 signaling on brain microglia with GlyB4 could be a novel 'upstream' approach to slow or stop disease progression in Alzheimer's disease.Significance StatementMicroglia-associated neuroinflammation is a major hallmark of Alzheimer's disease. Here, we show that neuregulin1 (NRG1), an important neuron-glial signaling factor in development, induces microglial activation and promotes pathological changes in the 5XFAD mouse model of Alzheimer's disease. Inhibition of NRG1 using a targeted NRG1 antagonist called GlyB4 blocks NRG1 receptor activation in microglia, reduces Amyloid β plaque formation, and prevents synaptic loss. While NRG1 clearly has important functions at other sites in the nervous system, excessive NRG1 signaling in microglia leads to pathological neuroinflammation and neurodegeneration. Selective disruption of NRG1 signaling in microglia using GlyB4 could be a novel approach to block disease progression in patients with Alzheimer's disease.

Assessment of Safety and Biodistribution of AAVrh.10hCLN2 Following Intracisternal Administration in Nonhuman Primates for the Treatment of CLN2 Batten Disease.

CLN2 disease is a fatal, childhood autosomal recessive disorder caused by mutations in ceroid lipofuscinosis type 2 (CLN2) gene, encoding tripeptidyl peptidase 1 (TPP-1). Loss of TPP-1 activity leads to accumulation of storage material in lysosomes and resultant neuronal cell death with neurodegeneration. Genotype/phenotype comparisons suggest that the phenotype should be ameliorated with increase of TPP-1 levels to 5-10% of normal with wide central nervous system (CNS) distribution. Our previous clinical study showed that intraparenchymal (IPC) administration of AAVrh.10hCLN2, an adeno-associated vector serotype rh.10 encoding human CLN2, slowed, but did not stop disease progression, suggesting that this may be insufficient to distribute the therapy throughout the CNS (Sondhi 2020). In this study, we assessed whether the less invasive intracisternal delivery route would be safe and provide a wider distribution of TPP-1. A study was conducted in nonhuman primates (NHPs) with intracisternal delivery to cerebrospinal fluid (CSF) of AAVrh.10hCLN2 (5 × 1013 genome copies) or phosphate buffered saline (PBS). No abnormal behavior was noted. CNS magnetic resonance imaging and clinical chemistry data were all unremarkable. Histopathology of major organs had no abnormal finding attributable to the intervention or the vector, except that in one out of two animals treated with AAVrh.10hCLN2, dorsal root ganglia showed mild-to-moderate mononuclear cell infiltrates and neuronal degeneration. In contrast to our previous NHP study (Sondhi 2012) with IPC administration where TPP-1 activity was >2 × above controls in 30% of treated brains, in the two intracisternal treated NHPs, the TPP-1 activity was >2 × above controls in 50% and 41% of treated brains, and 52% and 84% of brain had >1,000 vector genomes/μg DNA, compared to 0% in the two PBS NHP. CSF TPP1 levels in treated animals were 43-62% of normal human levels. Collectively, these data indicate that AAVrh.10hCLN2 delivered by intracisternal route is safe and widely distributes TPP-1 in brain and CSF at levels that are potentially therapeutic. Clinical Trial Registration: NCT02893826, NCT04669535, NCT04273269, NCT03580083, NCT04408625, NCT04127578, and NCT04792944.

Magnetically actuated glaucoma drainage device for regulating intraocular pressure after implantation

The key risk factor for glaucoma is increased intraocular pressure (IOP). Glaucoma drainage devices implanted in the eye can reduce IOP and thus stop disease progression. However, most devices currently used in clinical practice are passive and do not allow for postsurgical IOP control, which may result in serious complications such as hypotony (i.e., excessively low IOP). To enable noninvasive IOP control, we demonstrate a novel, miniature glaucoma implant that will enable the repeated adjustment of the hydrodynamic resistance after implantation. This is achieved by integrating a magnetic microvalve containing a micropencil-shaped plug that is moved using an external magnet, thereby opening or closing fluidic channels. The microplug is made from biocompatible poly(styrene-block-isobutylene-block-styrene) (SIBS) containing iron microparticles. The complete implant consists of an SIBS drainage tube and a housing element containing the microvalve and fabricated with hot embossing using femtosecond laser-machined glass molds. Using in vitro and ex vivo microfluidic experiments, we demonstrate that when the microvalve is closed, it can provide sufficient hydrodynamic resistance to overcome hypotony. Valve function is repeatable and stable over time. Due to its small size, our implant is a promising, safe, easy-to-implant, minimally invasive glaucoma surgery device.

Current State and Future Directions in the Therapy of ALS.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder affecting upper and lower motor neurons, with death resulting mainly from respiratory failure three to five years after symptom onset. As the exact underlying causative pathological pathway is unclear and potentially diverse, finding a suitable therapy to slow down or possibly stop disease progression remains challenging. Varying by country Riluzole, Edaravone, and Sodium phenylbutyrate/Taurursodiol are the only drugs currently approved in ALS treatment for their moderate effect on disease progression. Even though curative treatment options, able to prevent or stop disease progression, are still unknown, recent breakthroughs, especially in the field of targeting genetic disease forms, raise hope for improved care and therapy for ALS patients. In this review, we aim to summarize the current state of ALS therapy, including medication as well as supportive therapy, and discuss the ongoing developments and prospects in the field. Furthermore, we highlight the rationale behind the intense research on biomarkers and genetic testing as a feasible way to improve the classification of ALS patients towards personalized medicine.

Knowledge, Attitude, and Practice among Dubai Health Authority Health Care Workers toward the COVID-19 Vaccine

Introduction: Vaccine attitude can change disease progress, facilitate herald immunity among the community, and stop disease progression. According to the available data, there is no current curative treatment against the virus. The only way to stop the spread of infection is to develop the vaccine and accelerate the vaccine, as shown previously with the influenza pandemic. Objective: The study’s main goal was to investigate health care workers’ knowledge, attitude, and practice toward the coronavirus disease 2019 (COVID-19) vaccine in Dubai Health Authdority (DHA), United Arab Emirates (UAE). Methods: In April 2021, an anonymous cross-sectional comparative study measured the willingness and hesitancy to take the COVID-19 vaccine among health care providers in the primary health care sector at DHA. Results: In terms of COVID-19 vaccine knowledge, there was widespread agreement on the significance of the vaccine in preventing the transmission of illness (91.6%) and on the vaccine’s value for the public and community (95.6%). Furthermore, based on health care providers’ opinions, most individuals agreed to promote the COVID-19 vaccination in patients, family, and friends (92.7%), with just 6.9% doubtful. In actuality, 72.1 percent of those who got the vaccination received two doses, while 27.9% received just one dosage. In terms of vaccine type, Pfizer (72.7%), Sinopharm (23.8%), and AstraZeneca (3.6%) were the available vaccines during the study period. Discussion: The majority of participants agreed that the vaccine is essential for health care providers and the community (more than 90%), and they were willing to recommend it to their families (92.7%). They also agreed that the vaccine is necessary to prevent the spread of the disease (91 percent), boosting vaccine confidence. Conclusion: COVID-19 vaccine was widely accepted by Dubai’s health care workers. Several factors were identified as significant determinants of vaccine acceptance. UAE health care authorities can use the study’s findings to develop public health policies and implement campaigns to address concerns about the COVID-19 vaccine and other emerging infectious diseases.

Successful treatment for retinopathy of prematurity in a very preterm baby: a case report

Background: Retinopathy of prematurity (ROP) is a leading cause of childhood blindness worldwide, including in Indonesia. ROP screening and intervention are essential to establish the diagnosis, stop disease progression, and prevent retinal detachment that causes blindness. ROP treatments such as vitrectomy and laser are beneficial. This case aims to report the anatomical and functional outcomes after surgery for ROP. Case description: A very preterm baby with 29 weeks of gestational age and birthweight of 1300 grams was referred to the pediatric ophthalmology clinic at Cipto Mangunkusumo Hospital for ROP screening. Retinal camera (RetCam®) examination revealed stage 3 ROP in the right eye (RE) and stage 4A ROP in the left eye (LE). The LE underwent a vitrectomy, while the RE underwent laser photocoagulation under general anesthesia. Upon examination under sedation (EUS) after surgery, the retina was examined using RetCam® and was found attached to the LE and regressed on the RE. The baby is able to fixate on and follow objects. However, the refraction examination showed myopia in both eyes. Glasses were prescribed due to the myopia outcome in this case. Conclusion: Vitrectomy for stage 4A ROP and laser photocoagulation for stage 3 ROP are effective in anatomical and functional outcomes in a very preterm baby.

Results from 96 Weeks Open-Label Extension of a Phase 2 Trial of Losmapimod in Subjects with FSHD: ReDUX4 (S48.008)

<h3>Objective:</h3> Evaluate the 96-week results from the open-label extension of a Phase 2 trial of losmapimod in subjects with FSHD. <h3>Background:</h3> Facioscapulohumeral muscular dystrophy (FSHD) is a relentless, variably progressive disease leading to accumulation of disability. Fulcrum is developing losmapimod, a small molecule p38 α/β MAPK inhibitor, to treat FSHD. <h3>Design/Methods:</h3> ReDUX4 is a 48-week, placebo-controlled study assessing 80 subjects, 18–65 years old with genetically confirmed FSHD1, Ricci score 2–4, randomized 1:1 to receive 15 mg losmapimod or placebo (PO BID), followed by an Open-Label Extension (OLE) with all participants receiving losmapimod. <h3>Results:</h3> Seventy-six of 77 (99%) participants entered the OLE after 48 weeks, and 74 (97%) were enrolled at Week 96. For participants continuing to receive losmapimod (LOS/LOS), durability of treatment response was observed at 96 weeks, by assessing upper extremity function with Reachable Workspace (RWS). Placebo participants who converted to losmapimod (PBO/LOS) at Week 48 demonstrated trends of slowing or stopping disease progression based on RWS. Annualized total (Q1–5) relative surface area (RSA) in the dominant arm with weights demonstrated stability in the LOS/LOS group during the 2^nd year of dosing compared to the first (0.18%/yr vs −0.77%/yr, respectively) and improvement in PBO/LOS (4.07% vs −9.96%). Mean change in RSA from Week 48 to Week 96 was 0.0 for LOS/LOS and 0.02 for PBO/LOS with similar findings in the non-dominant arm in both groups and without weight. No related serious adverse events or discontinuations due to adverse events were reported in 96 weeks of dosing. Most commonly reported adverse events were fall (22.4%), headache (14.5%), arthralgia (7.9%), and back pain (7.9%). <h3>Conclusions:</h3> Losmapimod slowed disease progression and demonstrated maintenance of effect for through a 96-week period, with no new safety findings. <b>Disclosure:</b> Dr. Wang has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for AskBio. Dr. Wang has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Fulcrum Therapeutics. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Mitsubishi Tanabe. Dr. Wang has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Argenx. Dr. Wang has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avidity. Dr. Wang has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Scholar Rock. The institution of Dr. Wang has received research support from National Institute of Health. Dr. Wang has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with US Government. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Fulcrum. Dr. Han has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Sanofi. The institution of Dr. Han has received research support from Fulcrum. Dr. Shoskes has received personal compensation for serving as an employee of Fulcrum Therapeutics. An immediate family member of Dr. Shoskes has received personal compensation for serving as an employee of Exact Science. Dr. Jiang has received personal compensation for serving as an employee of Fulcrum Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for DYNE Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arrowhead Pharma. Dr. Tawil has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Fulcrum Therapeutics. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acceleron Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for MT Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Pharma. Dr. Tawil has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for miRecule. The institution of Dr. Tawil has received research support from Friends of FSH Research. The institution of Dr. Tawil has received research support from FSH Society. The institution of Dr. Tawil has received research support from NIH. The institution of Dr. Tawil has received research support from Fulcrum. Dr. Tawil has received intellectual property interests from a discovery or technology relating to health care. Dr. Tawil has received publishing royalties from a publication relating to health care.

Quantifying mutant huntingtin protein in human cerebrospinal fluid to support the development of huntingtin-lowering therapies

Huntington’s disease (HD) is caused by a cytosine adenine guanine-repeat expansion in the huntingtin gene. This results in the production of toxic mutant huntingtin protein (mHTT), which has an elongated polyglutamine (polyQ) stretch near the protein’s N-terminal end. The pharmacological lowering of mHTT expression in the brain targets the underlying driver of HD and is one of the principal therapeutic strategies being pursued to slow or stop disease progression. This report describes the characterisation and validation of an assay designed to quantify mHTT in the cerebrospinal fluid of individuals with HD, for use in registrational clinical trials. The assay was optimised, and its performance was characterised with recombinant huntingtin protein (HTT) varying in overall and polyQ-repeat length. The assay was successfully validated by two independent laboratories in regulated bioanalytical environments and showed a steep signal increase as the polyQ stretch of recombinant HTTs pivoted from wild-type to mutant protein forms. Linear mixed effects modelling confirmed highly parallel concentration–response curves for HTTs, with only a minor impact of individual slopes of the concentration–response for different HTTs (typically < 5% of the overall slope). This implies an equivalent quantitative signal behaviour for HTTs with differing polyQ-repeat lengths. The reported method may be a reliable biomarker tool with relevance across the spectrum of HD mutations, which can facilitate the clinical development of HTT-lowering therapies in HD.

Conventional, Complementary and Alternative Medicines: Mechanistic Insights into Therapeutic Landscape of Chronic Obstructive Pulmonary Disease.

COPD (chronic obstructive pulmonary disease) is a major public health concern associated with significant morbidity and mortality worldwide. Current therapeutic guidelines for this disease recommend starting with an inhaled bronchodilator, stepping up to combination therapy as necessary, and/or adding inhaled corticosteroids as symptoms and airflow obstruction progress. However, no drug therapy exists to stop disease progression. The mechanistic definition underlying COPD pathogenesis remains poorly understood, it is generally accepted that oxidative stress and the altered immune response of low-grade airway inflammation are major factors contributing to COPD development. There are several potential therapeutic targets that are currently under investigation, including immune regulatory pathways in inflammation and lung-associated steroid resistance induced by oxidative stress signaling cascades. Patients with COPD have increased levels of inflammatory mediators, including lipid and peptide mediators, as well as a network of cytokines and chemokines that maintain inflammatory immune response and recruit circulating cells into the lungs. Many of these pro-inflammatory mediators are regulated by nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinases (MAPKs), such as p38 MAPK. Increased oxidative stress is a key driving mechanism in perpetuating inflammation and lung injury. Furthermore, many proteases that degrade elastin fibres are secreted by airway resident infiltrating immune cells in COPD patients. In this perspective, we discuss novel aspects of signaling pathway activation in the context of inflammation and oxidative stress, and the broad view of potential effective pharmacotherapies that target the underlying mechanistic disease process in COPD.

Gene Editing Corrects In Vitro a G > A GLB1 Transition from a GM1 Gangliosidosis Patient.

Ganglioside-monosialic acid (GM1) gangliosidosis, a rare autosomal recessive disorder, is frequently caused by deleterious single nucleotide variants (SNVs) in GLB1 gene. These variants result in reduced β-galactosidase (β-gal) activity, leading to neurodegeneration associated with premature death. Currently, no effective therapy for GM1 gangliosidosis is available. Three ongoing clinical trials aim to deliver a functional copy of the GLB1 gene to stop disease progression. In this study, we show that 41% of GLB1 pathogenic SNVs can be replaced by adenine base editors (ABEs). Our results demonstrate that ABE efficiently corrects the pathogenic allele in patient-derived fibroblasts, restoring therapeutic levels of β-gal activity. Off-target DNA analysis did not detect off-target editing activity in treated patient's cells, except a bystander edit without consequences on β-gal activity based on 3D structure bioinformatics predictions. Altogether, our results suggest that gene editing might be an alternative strategy to cure GM1 gangliosidosis.

Therapeutic potential of low dose ionizing radiation against cancer, dementia, and diabetes: evidences from epidemiological, clinical, and preclinical studies.

The growing use of ionizing radiation (IR)-based diagnostic and treatment methods has been linked to increasing chronic diseases among patients and healthcare professionals. However, multiple factors such as IR dose, dose-rate, and duration of exposure influence the IR-induced chronic effects. The predicted links between low-dose ionizing radiation (LDIR) and health risks are controversial due to the non-availability of direct human studies. The studies pertaining to LDIR effects have importance in public health as exposure to background LDIR is routine. It has been anticipated that data from epidemiological and clinical reports and results of preclinical studies can resolve this controversy and help to clarify the notion of LDIR-associated health risks. Accumulating scientific literature shows reduced cancer risk, cancer-related deaths, curtailed neuro-impairments, improved neural functions, and reduced diabetes-related complications after LDIR exposure. In addition, it was found to alter evolutionarily conserved stress response pathways. However, the picture of molecular signaling pathways in LDIR responses is unclear. Besides, there is limited/no information on biomarkers of epidemiological LDIR exposure. Therefore, the present review discusses epidemiological, clinical, and preclinical studies on LDIR-induced positive effects in three chronic diseases (cancer, dementia, and diabetes) and their associated molecular mechanisms. The knowledge of LDIR response mechanisms may help to devise LDIR-based therapeutic modalities to stop disease progression. Modulation of these pathways may be helpful in developing radiation resistance among humans. However, more clinical evidence with additional biochemical, cellular, and molecular data and exploring the side effects of LDIR are the major areas of future research.

Repurposing multiples sclerosis disease-modifying drugs for Parkinson's disease

Parkinson’s disease (PD) is an age-related neurodegenerative disease mainly affecting the elderly population. Despite recent progresses in pharmacologic therapies and surgical interventions such as deep brain stimulation, current PD therapies are limited to relieving disease symptoms rather than stopping disease progression, highlighting an urgent yet unmet need for disease-modifying interventions. Neuroinflammation has been proposed as a pivotal contributing factor that drives the initiation and progression of PD pathology. Owing to the revolution in disease-modifying drugs (DMDs) that successfully change the course of multiple sclerosis (MS), a central nervous system inflammatory autoimmune disease, it has become tempting to repurpose MS DMDs as new treatment options for PD. This review summarizes the ongoing and completed studies of MS DMDs in PD as a potential opportunity to address this unmet need. Future clinical trials are warranted to further evaluate the efficacy of DMDs in patients with PD.