RESUMEN

Recent successive approval of anti-amyloid-ß (Aß) monoclonal antibodies as disease-modifying therapies against Alzheimer's disease (AD) has raised great confidence in the development of anti-AD therapies; however, the current therapies still face the dilemma of significant adverse reactions and limited effects. In this review, we summarized the therapeutic characteristics of the approved anti-Aß immunotherapies and dialectically analyzed the gains and losses from clinical trials. The review further proposed the reasonable selection of animal models in preclinical studies from the perspective of different animal models of Aß deposition and deals in-depth with the recent advances of exploring preclinical nanomedical application in Aß targeted therapy, aiming to provide a reliable systematic summary for the development of novel anti-Aß therapies. Collectively, this review comprehensively dissects the pioneering work of Aß-targeted therapies and proposed perspective insight into AD-modified therapies.

Asunto(s)

Enfermedad de Alzheimer , Animales , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides , Inmunoterapia , Modelos Animales , Nanomedicina , Humanos

RESUMEN

It is without doubt that the gene therapy field is currently in the spotlight for the development of new therapeutics targeting unmet medical needs. Thus, considering the gene therapy scenario, neurological diseases in general and neurodegenerative disorders in particular are emerging as the most appealing choices for new therapeutic arrivals intended to slow down, stop, or even revert the natural progressive course that characterizes most of these devastating neurodegenerative processes. Since an extensive coverage of all available literature is not feasible in practical terms, here emphasis was made in providing some advice to beginners in the field with a narrow focus on elucidating the best delivery route available for fulfilling any given AAV-based therapeutic approach. Furthermore, it is worth nothing that the number of ongoing clinical trials is increasing at a breath-taking speed. Accordingly, a landscape view of preclinical and clinical initiatives is also provided here in an attempt to best illustrate what is ongoing in this quickly expanding field.

RESUMEN

Current therapeutic strategies for Alzheimer's disease (AD) face the dilemma of no effective drugs that can delay the onset or slow the disease progression. Despite tremendous effort being involved, several anti-AD drugs come into clinical trials but with a moderate-to-poor success rate due to the complex AD pathogenesis and the blood-brain barrier (BBB). Insight into the complex AD pathogenesis is enabling new inspiration that have the potential to help improve our understanding and design of anti-AD nanomedicine. Herein, the complex AD pathogenesis and interaction between different therapeutic targets are summarized and highlighted, and key challenges facing translation of anti-AD nanomedicine from benchtop to bedside are discussed. Following combing through the complex pathogenesis and a contextual overview of clinical status of anti-AD compounds, we discuss the recent advances of exploring versatile nanomaterials in AD treatment from the pathogenesis. The focus here is especially on how to design pathogenesis-inspired nanomaterials for delivering therapeutics cross BBB and modulating the AD pathology by themselves as active ingredients. Collectively, this review highlights the pathogenesis-oriented nanomedicine design and provides with an easily accessible guide to the key opportunities and challenges currently facing the anti-AD nanomedicine.

Asunto(s)

Enfermedad de Alzheimer , Nanoestructuras , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/patología , Transporte Biológico , Barrera Hematoencefálica/patología , Humanos , Nanomedicina , Nanoestructuras/uso terapéutico

RESUMEN

Alzheimer's disease (AD) is a chronic disabling disease that affects the central nervous system. The main consequences of AD include the decline of cognitive functions and language disorders. One of the causes leading to AD is the decrease of neurotransmitter acetylcholine (ACh) levels in the brain, in part due to a higher activity of acetylcholinesterase (AChE), the enzyme responsible for its degradation. Many acetylcholinesterase inhibitors (AChEIs), both natural and synthetic, have been developed and used through the years to counteract the progression of the disease. The first of such drugs approved for a therapeutic use was tacrine, that binds through a reversible bond to the enzyme. However, tacrine has since been withdrawn because of its adverse effects. Currently, donepezil and galantamine are very promising AChEIs with clinical benefits. Moreover, rivastigmine is considered a pseudo-irreversible compound with anti-AChE action, providing similar effects at the clinical level. The purpose of this review is to provide an overview of what has been published over the last decade on the effectiveness of AChEIs in AD, analysing the most relevant issues under the clinical and methodological profiles and the consequent possible welfare effects for the whole world. Furthermore, novel drugs and possible therapeutic approaches are also discussed.

RESUMEN

Real-world healthcare data hold the potential to identify therapeutic solutions for progressive diseases by efficiently pinpointing safe and efficacious repurposing drug candidates. This approach circumvents key early clinical development challenges, particularly relevant for neurological diseases, concordant with the vision of the 21st Century Cures Act. However, to-date, these data have been utilized mainly for confirmatory purposes rather than as drug discovery engines. Here, we demonstrate the usefulness of real-world data in identifying drug repurposing candidates for disease-modifying effects, specifically candidate marketed drugs that exhibit beneficial effects on Parkinson's disease (PD) progression. We performed an observational study in cohorts of ascertained PD patients extracted from two large medical databases, Explorys SuperMart (N = 88,867) and IBM MarketScan Research Databases (N = 106,395); and applied two conceptually different, well-established causal inference methods to estimate the effect of hundreds of drugs on delaying dementia onset as a proxy for slowing PD progression. Using this approach, we identified two drugs that manifested significant beneficial effects on PD progression in both datasets: rasagiline, narrowly indicated for PD motor symptoms; and zolpidem, a psycholeptic. Each confers its effects through distinct mechanisms, which we explored via a comparison of estimated effects within the drug classification ontology. We conclude that analysis of observational healthcare data, emulating otherwise costly, large, and lengthy clinical trials, can highlight promising repurposing candidates, to be validated in prospective registration trials, beneficial against common, late-onset progressive diseases for which disease-modifying therapeutic solutions are scarce.