Lecanemab in patients with early Alzheimer’s disease: detailed results on biomarker, cognitive, and clinical effects from the randomized and open-label extension of the phase 2 proof-of-concept study

Alzheimer s Research & Therapy, Journal Year: 2022, Volume and Issue: 14(1)

Published: Dec. 21, 2022

Abstract Background Lecanemab, a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils), has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in early AD. The objective this analysis is to report results from study 201 blinded period (core), the open-label extension (OLE), gap (between core OLE) supporting effectiveness lecanemab. Methods lecanemab was double-blind, randomized, placebo-controlled 856 patients randomized one five dose regimens or placebo. An OLE initiated allow receive 10mg/kg biweekly for up 24 months, with an intervening off-treatment (gap period) ranging 9 59 months (mean months). Results At 12 18 treatment core, 10 mg/kg dose-dependent reductions measured PET corresponding changes plasma biomarkers cognitive decline. rates progression during were similar placebo subjects, differences maintained after discontinued dosing over average period. During gap, Aβ42/40 ratio p-tau181 levels began return towards pre-randomization more quickly than PET. baseline, vs at across 3 assessments. In OLE, produced SUVr, improvements ratio, p-tau181. Conclusions Lecanemab resulted significant plaques Data indicate rapid pronounced correlates benefit potential disease-modifying effects, as well use monitor effects. Trial registration ClinicalTrials.gov NCT01767311 .

Language: Английский

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Multifunctional nanoparticle-mediated combining therapy for human diseases

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Jan. 1, 2024

Abstract Combining existing drug therapy is essential in developing new therapeutic agents disease prevention and treatment. In preclinical investigations, combined effect of certain known drugs has been well established treating extensive human diseases. Attributed to synergistic effects by targeting various pathways advantages, such as reduced administration dose, decreased toxicity, alleviated resistance, combinatorial treatment now being pursued delivering combat major clinical illnesses, cancer, atherosclerosis, pulmonary hypertension, myocarditis, rheumatoid arthritis, inflammatory bowel disease, metabolic disorders neurodegenerative Combinatorial involves combining or co-delivering two more for a specific disease. Nanoparticle (NP)-mediated delivery systems, i.e., liposomal NPs, polymeric NPs nanocrystals, are great interest wide range due targeted delivery, extended release, higher stability avoid rapid clearance at infected areas. This review summarizes targets diseases, clinically approved combinations the development multifunctional emphasizes strategies based on severe Ultimately, we discuss challenging NP-codelivery translation provide potential approaches address limitations. offers comprehensive overview recent cutting-edge NP-mediated combination

Language: Английский

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Human microglia show unique transcriptional changes in Alzheimer’s disease

Nature Aging, Journal Year: 2023, Volume and Issue: 3(7), P. 894 - 907

Published: May 29, 2023

Abstract Microglia, the innate immune cells of brain, influence Alzheimer’s disease (AD) progression and are potential therapeutic targets. However, microglia exhibit diverse functions, regulation which is not fully understood, complicating therapeutics development. To better define transcriptomic phenotypes gene regulatory networks associated with AD, we enriched for nuclei from 12 AD 10 control human dorsolateral prefrontal cortices (7 males 15 females, all aged >60 years) before single-nucleus RNA sequencing. Here describe both established previously unrecognized microglial molecular phenotypes, inferred driving observed change, apply trajectory analysis to reveal putative relationships between phenotypes. We identify more prevalent in cases compared controls. Further, heterogeneity subclusters expressing homeostatic markers. Our study demonstrates that deep profiling brain can provide insight into transcriptional changes AD.

Language: Английский

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Oxidative stress in Alzheimer’s disease: current knowledge of signaling pathways and therapeutics

Molecular Biology Reports, Journal Year: 2024, Volume and Issue: 51(1)

Published: Jan. 2, 2024

Language: Английский

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The FDA-approved anti-amyloid-β monoclonal antibodies for the treatment of Alzheimer’s disease: a systematic review and meta-analysis of randomized controlled trials

European journal of medical research, Journal Year: 2023, Volume and Issue: 28(1)

Published: Nov. 28, 2023

Abstract Background Alzheimer’s disease (AD) is a worldwide public health problem and difficult to cure. Drugs aimed at slowing the progression of have been developed, with Food Drug Administration (FDA) granting accelerated approval for aducanumab on June 21, 2021 new lecanemab January 22, 2023. We performed this systematic review meta-analysis assess efficacy safety FDA-approved anti-amyloid-β (anti-Aβ) monoclonal antibodies (mabs) treatment AD. Method PubMed, Embase, Cochrane Library were systematically searched identify relevant studies published before May Efficacy outcomes included Aβ, neuroimaging, biomarker outcomes. Safety amyloid-related imaging abnormalities edema or effusions (ARIA-E) ARIA cerebral microhemorrhages, macrohemorrhages, superficial siderosis (ARIA-H). Review Manager 5.4 software was used data. The standard mean differences (SMDs) odds ratio (OR) 95% confidence interval (95% CI) analyzed calculated random effect model fixed model. Result Overall, 4471 patients from 6 randomized controlled trials (RCTs), 2190 in group 2281 placebo meeting inclusion criteria. anti-Aβ mabs showed statistically significant improvements clinical outcomes, including CDR-SB (P = 0.01), ADCS-ADL-MCI 0.00003), ADCOMS < 0.00001), ADAS-Cog 0.00001). Moreover, increased cerebrospinal fluid (CSF) Aβ1-42 0.002) plasma Aβ42/40 ratios 0.0008). They also decreased CSF P-Tau T-Tau p-tau181 perform neuroimaging changes amyloid Positron Emission Tomography Standardized Uptake Value (PET SUVr) However, compared placebo, had higher risk ARIA-E 0.00001) ARIA-H 0001). Conclusion role AD, cost an probability side effects.

Language: Английский

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Alzheimer’s Disease: A Brief History of Immunotherapies Targeting Amyloid β

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3895 - 3895

Published: Feb. 15, 2023

Alzheimer's disease (AD) is the most common form of dementia and may contribute to 60-70% cases. Worldwide, around 50 million people suffer from prediction that number will more than triple by 2050, as population ages. Extracellular protein aggregation plaque deposition well accumulation intracellular neurofibrillary tangles, all leading neurodegeneration, are hallmarks brains with disease. Therapeutic strategies including active passive immunizations have been widely explored in last two decades. Several compounds shown promising results many AD animal models. To date, only symptomatic treatments available because alarming epidemiological data, novel therapeutic prevent, mitigate, or delay onset required. In this mini-review, we focus on our understanding pathobiology discuss current immunomodulating therapies targeting amyloid-β protein.

Language: Английский

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Alzheimer's disease current therapies, novel drug delivery systems and future directions for better disease management

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 367, P. 402 - 424

Published: Feb. 2, 2024

Alzheimer's disease (AD), is a neurodegenerative disorder that escalates with time, exerting significant impact on physical and mental health leading to death. The prevalence of AD progressively rising along its associated economic burden necessitates effective therapeutic approaches in the near future. This review paper aims offer an insightful overview pathogenesis, current FDA-approved drugs, drugs different clinical phases. It also explores innovative formulations drug delivery strategies, focusing nanocarriers long-acting medications (LAMs) enhance treatment efficacy patient adherence. emphasizes preclinical evidence related their potential improve bioavailability, pharmacokinetics, pharmacodynamics parameters, while highlighting ability minimize systemic side effects. By providing comprehensive analysis, this furnishes valuable insights into pathophysiological mechanisms for future development. inform development strategies formulation delivering existing molecules disease, ultimately striving compliance.

Language: Английский

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Efficacy and safety of anti-amyloid-β monoclonal antibodies in current Alzheimer's disease phase III clinical trials: A systematic review and interactive web app-based meta-analysis

Ageing Research Reviews, Journal Year: 2023, Volume and Issue: 90, P. 102012 - 102012

Published: July 7, 2023

Language: Английский

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Aβ-oligomers: A potential therapeutic target for Alzheimer's disease

International Journal of Biological Macromolecules, Journal Year: 2023, Volume and Issue: 239, P. 124231 - 124231

Published: March 28, 2023

Language: Английский

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Focused ultrasound-assisted delivery of immunomodulating agents in brain cancer

Journal of Controlled Release, Journal Year: 2024, Volume and Issue: 367, P. 283 - 299

Published: Jan. 29, 2024

Language: Английский

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