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Therapeutic approaches to treat human spliceosomal diseases.

ABSTRACT: Mutated RNA splicing machinery drives many human diseases and is a promising therapeutic target for engineering and small molecule therapy. In the case of mutations in individual genes that cause them to be incorrectly spliced, engineered splicing factors can be introduced to correct splicing of these aberrant transcripts and reduce the effects of the disease phenotype. Mutations that occur in certain splicing factor genes themselves have been implicated in many cancers, particularly myelodysplastic syndromes. Small molecules that target splicing factors have been developed as therapies to preferentially induce apoptosis in these cancer cells. Specifically, drugs targeting the splicing factor SF3B1 have led to recent clinical trials. Here, we review the role of alternative splicing in disease, approaches to rescue incorrect splicing using engineered splicing factors, and small molecule splicing inhibitors developed to treat hematological cancers.

SUBMITTER: DeNicola AB

PROVIDER: S-EPMC6694006 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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Therapeutic approaches to treat human spliceosomal diseases.

DeNicola Anthony B AB Tang Yi Y

Current opinion in biotechnology 20190215

Mutated RNA splicing machinery drives many human diseases and is a promising therapeutic target for engineering and small molecule therapy. In the case of mutations in individual genes that cause them to be incorrectly spliced, engineered splicing factors can be introduced to correct splicing of these aberrant transcripts and reduce the effects of the disease phenotype. Mutations that occur in certain splicing factor genes themselves have been implicated in many cancers, particularly myelodyspla ...[more]

PMID: 30772756

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Project description:Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death. Venoms are fruitful natural sources of new molecules, which have been relentlessly enhanced by evolution through natural selection. Several studies indicate that venom components can exhibit selectivity and affinity for a wide variety of targets in mammalian systems. For instance, an expressive number of natural peptides identified in venoms from animals, such as snakes, scorpions, bees, and spiders, were shown to lessen inflammation, regulate glutamate release, modify neurotransmitter levels, block ion channel activation, decrease the number of protein aggregates, and increase the levels of neuroprotective factors. Thus, these venom components hold potential as therapeutic tools to slow or even halt neurodegeneration. However, there are many technological issues to overcome, as venom peptides are hard to obtain and characterize and the amount obtained from natural sources is insufficient to perform all the necessary experiments and tests. Fortunately, technological improvements regarding heterologous protein expression, as well as peptide chemical synthesis will help to provide enough quantities and allow chemical and pharmacological enhancements of these natural occurring compounds. Thus, the main focus of this review is to highlight the most promising studies evaluating animal toxins as therapeutic tools to treat a wide variety of neurodegenerative conditions, including Alzheimer's disease, Parkinson's disease, brain ischemia, glaucoma, amyotrophic lateral sclerosis, and multiple sclerosis.

Dataset Information

Therapeutic approaches to treat human spliceosomal diseases.

Publications

Therapeutic approaches to treat human spliceosomal diseases.

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