Browsing by Author "Almeida, Luís Pereira de"
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- Brain-targeted drug delivery - nanovesicles directed to specific brain cells by brain-targeting ligandsPublication . Moreira, Ricardo; Nóbrega, Clévio; Almeida, Luís Pereira de; Mendonça, LilianaNeurodegenerative diseases are characterized by extensive loss of function or death of brain cells, hampering the life quality of patients. Brain-targeted drug delivery is challenging, with a low success rate this far. Therefore, the application of targeting ligands in drug vehicles, such as lipid-based and polymeric nanoparticles, holds the promise to overcome the blood-brain barrier (BBB) and direct therapies to the brain, in addition to protect their cargo from degradation and metabolization. In this review, we discuss the barriers to brain delivery and the different types of brain-targeting ligands currently in use in brain-targeted nanoparticles, such as peptides, proteins, aptamers, small molecules, and antibodies. Moreover, we present a detailed review of the different targeting ligands used to direct nanoparticles to specific brain cells, like neurons (C4-3 aptamer, neurotensin, Tet-1, RVG, and IKRG peptides), astrocytes (Aquaporin-4, D4, and Bradykinin B2 antibodies), oligodendrocytes (NG-2 antibody and the biotinylated DNA aptamer conjugated to a streptavidin core Myaptavin-3064), microglia (CD11b antibody), neural stem cells (QTRFLLH, VPTQSSG, and NFL-TBS.40–63 peptides), and to endothelial cells of the BBB (transferrin and insulin proteins, and choline). Reports demonstrated enhanced brain-targeted delivery with improved transport to the specific cell type targeted with the conjugation of these ligands to nanoparticles. Hence, this strategy allows the implementation of high-precision medicine, with reduced side effects or unwanted therapy clearance from the body. Nevertheless, the accumulation of some of these nanoparticles in peripheral organs has been reported indicating that there are still factors to be improved to achieve higher levels of brain targeting. This review is a collection of studies exploring targeting ligands for the delivery of nanoparticles to the brain and we highlight the advantages and limitations of this type of approach in precision therapies.
- Motor dysfunctions and neuropathology in mouse models of spinocerebellar ataxia type 2: A comprehensive reviewPublication . Alves-Cruzeiro, João M. da Conceição; Mendonça, Liliana; Almeida, Luís Pereira de; Nóbrega, ClévioSpinocerebellar ataxia type 2 (SCA2) is an autosomal dominant ataxia caused by an expansion of CAG repeats in the exon 1 of the gene ATXN2, conferring a gain of toxic function that triggers the appearance of the disease phenotype. SCA2 is characterized by several symptoms including progressive gait ataxia and dysarthria, slow saccadic eye movements, sleep disturbances, cognitive impairments, and psychological dysfunctions such as insomnia and depression, among others. The available treatments rely on palliative care, which mitigate some of the major symptoms but ultimately fail to block the disease progression. This persistent lack of effective therapies led to the development of several models in yeast, C. elegans, D. melanogaster, and mice to serve as platforms for testing new therapeutic strategies and to accelerate the research on the complex disease mechanisms. In this work, we review 4 transgenic and 1 knock-in mouse that exhibit a SCA2-related phenotype and discuss their usefulness in addressing different scientific problems. The knock-in mice are extremely faithful to the human disease, with late onset of symptoms and physiological levels of mutant ataxin-2, while the other transgenic possess robust and well-characterized motor impairments and neuropathological features. Furthermore, a new BAC model of SCA2 shows promise to study the recently explored role of non-coding RNAs as a major pathogenic mechanism in this devastating disorder. Focusing on specific aspects of the behavior and neuropathology, as well as technical aspects, we provide a highly practical description and comparison of all the models with the purpose of creating a useful resource for SCA2 researchers worldwide.
- Polyglutamine disorders prefacePublication . Nóbrega, Clévio; Almeida, Luís Pereira de; Nóbrega, Clévio; Almeida, Luís Pereira dePolyglutamine (polyQ) diseases are a group of rare neurodegenerative disorders that share a common genetic cause: they arise as a result of abnormal expansions of CAG trinucleotide sequences occurring at particular genome loci. In contrast with other repeat-related disorders, the repeat-bearing tracts associated with polyQ diseases are present at the codifying region of genes, being translated as expanded polyQ tracts in their respective protein products. Although these genes and proteins are otherwise unrelated and share no significant homology outside the CAG/polyQ tract, proteins carrying an abnormally expanded polyQ tract tend to aggregate, forming insoluble protein aggregates that constitute a key neuropathological feature of polyQ disorders. The group currently includes nine disorders: Huntington’s disease (HD), dentatorubral-pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and six different types of spinocerebellar ataxia: SCA 1, 2, 3, 6, 7, and 17. PolyQ diseases are highly incapacitating and, to this date, no therapy able to modify disease progression is available for any of them.