How should future clinical trials be designed in the search for disease-modifying therapies for Parkinson’s disease? DOI
Abhishek Lenka, Joseph Jankovic

Expert Review of Neurotherapeutics, Journal Year: 2023, Volume and Issue: 23(2), P. 107 - 122

Published: Feb. 1, 2023

Although there has been substantial progress in research and innovations symptomatic treatments, similar success not achieved disease-modifying therapy (DMT) for Parkinson's disease (PD). Considering the enormous motor, psychosocial financial burden associated with PD, safe effective DMT is of paramount importance.One reasons lack PD poor or inappropriate design clinical trials. In first part article, authors focus on plausible why previous trials have failed latter part, they provide their perspectives future trials.There are several potential failed, including broad etiopathogenic heterogeneity definition documentation target engagement, appropriate biomarkers outcome measures, short duration follow-up. To address these deficiencies, may consider- (i) a more customized approach to select most suitable participants therapeutic approaches, (ii) explore combination therapies that would multiple pathogenetic mechanisms, (iii) moving beyond targeting only motor symptoms also assessing non-motor features well-designed longitudinal studies.

Language: Английский

Functionalized Nanomaterials Capable of Crossing the Blood–Brain Barrier DOI Creative Commons
Shuai Zha, Haitao Liu, Hengde Li

et al.

ACS Nano, Journal Year: 2024, Volume and Issue: 18(3), P. 1820 - 1845

Published: Jan. 9, 2024

The blood–brain barrier (BBB) is a specialized semipermeable structure that highly regulates exchanges between the central nervous system parenchyma and blood vessels. Thus, BBB also prevents passage of various forms therapeutic agents, nanocarriers, their cargos. Recently, many multidisciplinary studies focus on developing cargo-loaded nanoparticles (NPs) to overcome these challenges, which are emerging as safe effective vehicles in neurotheranostics. In this Review, first we introduce anatomical physiological functions BBB. Second, present endogenous exogenous transport mechanisms by NPs cross We report nanomaterials, carriers, cargos, with detailed uptake permeability characteristics. Third, describe effect regulating size, shape, charge, surface ligands affect permeability, can be exploited enhance promote classify typical functionalized nanomaterials developed for crossing. Fourth, provide comprehensive review recent progress functional polymeric applications multimodal bioimaging, therapeutics, drug delivery. Finally, conclude discussing existing directions, future perspectives employing

Language: Английский

Citations

80
Non-Invasive Drug Delivery across the Blood–Brain Barrier: A Prospective Analysis DOI Creative Commons
Sarfaraz K. Niazi

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(11), P. 2599 - 2599

Published: Nov. 7, 2023

Non-invasive drug delivery across the blood–brain barrier (BBB) represents a significant advancement in treating neurological diseases. The BBB is tightly packed layer of endothelial cells that shields brain from harmful substances blood, allowing necessary nutrients to pass through. It highly selective barrier, which poses challenge delivering therapeutic agents into brain. Several non-invasive procedures and devices have been developed or are currently being investigated enhance BBB. This paper presents review prospective analysis art science address pharmacology, technology, systems, regulatory approval, ethical concerns, future possibilities.

Language: Английский

Citations

43
Focused ultrasound gene delivery for the treatment of neurological disorders DOI Open Access
Rikke Hahn Kofoed, Isabelle Aubert

Trends in Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(3), P. 263 - 277

Published: Jan. 11, 2024

Language: Английский

Citations

20
The blood–brain barriers: novel nanocarriers for central nervous system diseases DOI Creative Commons
Jiajun Liu, Ting Wang, Jianwei Dong

et al.

Journal of Nanobiotechnology, Journal Year: 2025, Volume and Issue: 23(1)

Published: Feb. 26, 2025

Abstract The central nervous system (CNS) diseases are major contributors to death and disability worldwide. However, the blood–brain barrier (BBB) often prevents drugs intended for CNS from effectively crossing into brain parenchyma deliver their therapeutic effects. is a semi-permeable with high selectivity. BBB primarily manages transport of substances between blood CNS. To enhance drug delivery disease treatment, various brain-based strategies overcoming have been developed. Among them, nanoparticles (NPs) emphasized due multiple excellent properties. This review starts an overview BBB’s anatomical structure physiological roles, then explores mechanisms, both endogenous exogenous, that facilitate NP passage across BBB. text also delves how nanoparticles' shape, charge, size, surface ligands affect ability cross offers different nanoparticle classifications. concludes examination current challenges in utilizing nanomaterials discusses corresponding directions solutions. aims propose innovative diagnostic approaches design more effective Graphical abstract

Language: Английский

Citations

5
Putaminal Recombinant Glucocerebrosidase Delivery with Magnetic Resonance–Guided Focused Ultrasound in Parkinson's Disease: A Phase I Study DOI Creative Commons
Ying Meng, Christopher B. Pople, Yuexi Huang

et al.

Movement Disorders, Journal Year: 2022, Volume and Issue: 37(10), P. 2134 - 2139

Published: Sept. 11, 2022

GBA1 mutation is the most common genetic risk factor for Parkinson's disease (PD). Replacement of lysosomal enzyme glucocerebrosidase (GCase) slows neurodegeneration in PD models and may be a promising disease-modifying therapy patients with PD. However, recombinant GCase has limited penetration through blood-brain barrier (BBB). Microbubble-mediated magnetic resonance-guided focused ultrasound (MRgFUS) can reversibly disrupt BBB drug delivery.This open-label phase I study investigated safety feasibility MRgFUS putaminal delivery intravenous at escalating doses (15 to 30 60 IU/kg) every 2 weeks four mutations.BBB permeability was achieved restored all as quantified by dynamic contrast-enhanced resonance imaging after treatment. There were no serious adverse events. Two developed transient dyskinesia Blinded Movement Disorder Society-Unified Disease Rating Scale motor scores off medication decreased 12% 6 months from baseline (from 26 ± 9 22 6). Standardized uptake value ratio on fluorodeoxyglucose positron emission tomography treated putamen reduced 1.66 0.14 1.27 0.08.Results this demonstrate support further investigation approach. © 2022 The Authors. Disorders published Wiley Periodicals LLC behalf International Parkinson Society.

Language: Английский

Citations

40
BBB opening with focused ultrasound in nonhuman primates and Parkinson’s disease patients: Targeted AAV vector delivery and PET imaging DOI Creative Commons
Javier Blesa, José A. Pineda‐Pardo, Ken‐ichi Inoue

et al.

Science Advances, Journal Year: 2023, Volume and Issue: 9(16)

Published: April 19, 2023

Intracerebral vector delivery in nonhuman primates has been a major challenge. We report successful blood-brain barrier opening and focal of adeno-associated virus serotype 9 vectors into brain regions involved Parkinson’s disease using low-intensity focus ultrasound adult macaque monkeys. Openings were well tolerated with generally no associated abnormal magnetic resonance imaging signals. Neuronal green fluorescent protein expression was observed specifically confirmed opening. Similar openings safely demonstrated three patients disease. In these one monkey, followed by 18 F-Choline uptake the putamen midbrain based on positron emission tomography. This indicates cellular binding molecules that otherwise would not enter parenchyma. The less-invasive nature this methodology could facilitate viral for gene therapy might allow early repeated interventions to treat neurodegenerative disorders.

Language: Английский

Citations

40
Brain Waste Removal System and Sleep: Photobiomodulation as an Innovative Strategy for Night Therapy of Brain Diseases DOI Open Access

Oxana Semyachkina-Glushkovskaya,

Ivan V. Fedosov, Thomas Penzel

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 3221 - 3221

Published: Feb. 6, 2023

Emerging evidence suggests that an important function of the sleeping brain is removal wastes and toxins from central nervous system (CNS) due to activation waste (BWRS). The meningeal lymphatic vessels (MLVs) are part BWRS. A decrease in MLV associated with Alzheimer’s Parkinson’s diseases, intracranial hemorrhages, tumors trauma. Since BWRS activated during sleep, a new idea now being actively discussed scientific community: night stimulation might be innovative promising strategy for neurorehabilitation medicine. This review highlights trends photobiomodulation BWRS/MLVs deep sleep as breakthrough technology effective unnecessary compounds order increase neuroprotection CNS well prevent or delay various diseases.

Language: Английский

Citations

23
Translating ultrasound-mediated drug delivery technologies for CNS applications DOI Creative Commons

Ederlyn Perolina,

Svenja Meissner,

Brad Raos

et al.

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 208, P. 115274 - 115274

Published: March 6, 2024

Ultrasound enhances drug delivery into the central nervous system (CNS) by opening barriers between blood and CNS triggering release of drugs from carriers. A key challenge in translating setups vitro to vivo settings is achieving equivalent acoustic energy delivery. Multiple devices have now been demonstrated focus ultrasound brain, with concepts emerging also target spinal cord. Clinical trials date used facilitate blood–brain barrier. While most focused on feasibility safety considerations, therapeutic benefits are beginning emerge. To advance translation these technologies for applications, researchers should standardise exposure protocol fine-tune parameters. Computational modelling be increasingly as a core component develop both delivering accurate reproducible CNS. This field holds promise transformative advancements management pharmacological treatment complex challenging disorders.

Language: Английский

Citations

13
MR-guided focused ultrasound in movement disorders and beyond: Lessons learned and new frontiers DOI
Elena Natera‐Villalba,

María-Agustina Ruiz-Yanzi,

Carmen Gasca‐Salas

et al.

Parkinsonism & Related Disorders, Journal Year: 2024, Volume and Issue: 122, P. 106040 - 106040

Published: Feb. 12, 2024

Language: Английский

Citations

9
Adeno-associated virus vector delivery to the brain: Technology advancements and clinical applications DOI Creative Commons
Dezhuang Ye, Chinwendu Chukwu, Yaoheng Yang

et al.

Advanced Drug Delivery Reviews, Journal Year: 2024, Volume and Issue: 211, P. 115363 - 115363

Published: June 19, 2024

Adeno-associated virus (AAV) vectors have emerged as a promising tool in the development of gene therapies for various neurological diseases, including Alzheimer's disease and Parkinson's disease. However, blood–brain barrier (BBB) poses significant challenge to successfully delivering AAV brain. Strategies that can overcome BBB improve delivery efficiency brain are essential successful brain-targeted therapy. This review provides an overview existing strategies employed brain, direct intraparenchymal injection, intra-cerebral spinal fluid intranasal delivery, intravenous injection BBB-permeable AAVs. Focused ultrasound has technology noninvasive spatially targeted administered by injection. also summarizes each strategy's current preclinical clinical applications treating diseases. Moreover, this includes detailed discussion recent advances emerging focused ultrasound-mediated delivery. Understanding state-of-the-art these approaches is critical future fulfill great promise treatment.

Language: Английский

Citations

9