Current Strategies for the Delivery of Therapeutic Proteins and Enzymes to Treat Brain Disorders

Duskey, Jason Thomas; Belletti, Daniela; Pederzoli, Francesca; Vandelli, Maria Angela; Forni, Flavio; Ruozi, Barbara; Tosi, Giovanni

doi:10.1016/bs.irn.2017.08.006

Cited by 30 publications

(24 citation statements)

References 108 publications

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“…Several strategies to introduce a transgene have been developed, including the use of viral vectors, such as adeno-associated virus (AAV) 122 and lentivirus 123 . Other delivery methods, using nanoparticles, liposomes and exosomes, have also been established 124,125 .…”

Section: The Road To New Therapiesmentioning

confidence: 99%

Lafora disease — from pathogenesis to treatment strategies

et al. 2018

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Lafora disease is a severe, autosomal recessive, progressive myoclonus epilepsy. The disease usually manifests in previously healthy adolescents, and death commonly occurs within 10 years of symptom onset. Lafora disease is caused by loss-of-function mutations in EPM2A or NHLRC1, which encode laforin and malin, respectively. The absence of either protein results in poorly branched, hyperphosphorylated glycogen, which precipitates, aggregates and accumulates into Lafora bodies. Evidence from Lafora disease genetic mouse models indicates that these intracellular inclusions are a principal driver of neurodegeneration and neurological disease. The integration of current knowledge on the function of laforin-malin as an interacting complex suggests that laforin recruits malin to parts of glycogen molecules where overly long glucose chains are forming, so as to counteract further chain extension. In the absence of either laforin or malin function, long glucose chains in specific glycogen molecules extrude water, form double helices and drive precipitation of those molecules, which over time accumulate into Lafora bodies. In this article, we review the genetic, clinical, pathological and molecular aspects of Lafora disease. We also discuss traditional antiseizure treatments for this condition, as well as exciting therapeutic advances based on the downregulation of brain glycogen synthesis and disease gene replacement.

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Section: The Road To New Therapiesmentioning

confidence: 99%

Lafora disease — from pathogenesis to treatment strategies

et al. 2018

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“…In this field, polymeric NPs, particularly those made of polylactide-co-glycolic acid (PLGA), have attracted considerable interest over the last few years as versatile tools for enzymatic delivery [ 10 , 11 , 12 ]. While many promising results have been described, frequently authors declare a certain criticism related to the formulation aspect of enzyme-loaded NP formulations due to both low loading efficiency and the maintenance of the enzymatic activity [ 13 , 14 ].…”

Section: Introductionmentioning

confidence: 99%

Enzyme Stability in Nanoparticle Preparations Part 1: Bovine Serum Albumin Improves Enzyme Function

et al. 2020

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Enzymes have gained attention for their role in numerous disease states, calling for research for their efficient delivery. Loading enzymes into polymeric nanoparticles to improve biodistribution, stability, and targeting in vivo has led the field with promising results, but these enzymes still suffer from a degradation effect during the formulation process that leads to lower kinetics and specific activity leading to a loss of therapeutic potential. Stabilizers, such as bovine serum albumin (BSA), can be beneficial, but the knowledge and understanding of their interaction with enzymes are not fully elucidated. To this end, the interaction of BSA with a model enzyme B-Glu, part of the hydrolase class and linked to Gaucher disease, was analyzed. To quantify the natural interaction of beta-glucosidase (B-Glu,) and BSA in solution, isothermal titration calorimetry (ITC) analysis was performed. Afterwards, polymeric nanoparticles encapsulating these complexes were fully characterized, and the encapsulation efficiency, activity of the encapsulated enzyme, and release kinetics of the enzyme were compared. ITC results showed that a natural binding of 1:1 was seen between B-Glu and BSA. Complex concentrations did not affect nanoparticle characteristics which maintained a size between 250 and 350 nm, but increased loading capacity (from 6% to 30%), enzyme activity, and extended-release kinetics (from less than one day to six days) were observed for particles containing higher B-Glu:BSA ratios. These results highlight the importance of understanding enzyme:stabilizer interactions in various nanoparticle systems to improve not only enzyme activity but also biodistribution and release kinetics for improved therapeutic effects. These results will be critical to fully characterize and compare the effect of stabilizers, such as BSA with other, more relevant therapeutic enzymes for central nervous system (CNS) disease treatments.

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“…Novel surfaces and delivery nanosystems have taken the spotlight as the leading hope to advance new drugs from research into and beyond clinical studies by overcoming factors such as: lack of solubility, poor stability, poor biodistribution, immune response activation, off-target affects, and poor accumulation at the target site. Polymeric and lipid formulations have been taken advantage of to create fine-tuned systems to include targeting [4][5][6], triggerable activation (heat, light, reactive oxygen species (ROS), pH) [7][8][9], and varied uptake mechanisms to deliver pharmaceutics against numerous diseases [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Investigating Novel Syntheses of a Series of Unique Hybrid PLGA-Chitosan Polymers for Potential Therapeutic Delivery Applications

et al. 2020

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Discovering new materials to aid in the therapeutic delivery of drugs is in high demand. PLGA, a FDA approved polymer, is well known in the literature to form films or nanoparticles that can load, protect, and deliver drug molecules; however, its incompatibility with certain drugs (due to hydrophilicity or charge repulsion interactions) limits its use. Combining PLGA or other polymers such as polycaprolactone with other safe and positively-charged molecules, such as chitosan, has been sought after to make hybrid systems that are more flexible in terms of loading ability, but often the reactions for polymer coupling use harsh conditions, films, unpurified products, or create a single unoptimized product. In this work, we aimed to investigate possible innovative improvements regarding two synthetic procedures. Two methods were attempted and analytically compared using nuclear magnetic resonance (NMR), fourier-transform infrared spectroscopy (FT-IR), and dynamic scanning calorimetry (DSC) to furnish pure, homogenous, and tunable PLGA-chitosan hybrid polymers. These were fully characterized by analytical methods. A series of hybrids was produced that could be used to increase the suitability of PLGA with previously non-compatible drug molecules.

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Current Strategies for the Delivery of Therapeutic Proteins and Enzymes to Treat Brain Disorders

Cited by 30 publications

References 108 publications

Lafora disease — from pathogenesis to treatment strategies

Lafora disease — from pathogenesis to treatment strategies

Enzyme Stability in Nanoparticle Preparations Part 1: Bovine Serum Albumin Improves Enzyme Function

Investigating Novel Syntheses of a Series of Unique Hybrid PLGA-Chitosan Polymers for Potential Therapeutic Delivery Applications

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