However, delivery of these genetic therapeutics to the brain still remains challenging owing to several factors: 1) fast clearance of genetic therapeutics in the blood circulation 2) inadequate cellular internalization 3) limited specificity and off-target effect 4) inability to cross the blood-brain barrier (BBB). Additionally, the clustered regularly interspaced short palindromic repeat-associated protein (CRISPR/Cas)-mediated genome editing also yielded promising results to modulate genes, which has the potential to revolutionize the treatment of CNS diseases. A number of promising formats that are able to activate or deactivate those targets have been identified, including plasmid DNA, small interference RNA (siRNA), antisense oligonucleotides (AONs), miRNA, and mRNA. The genotyping of many, if not most, CNS diseases has revealed numerous novel therapeutic targets. Gene therapy is also linked to immunotherapy and/or cellular therapy as exemplified by the chimeric antigen receptor T cells (CART) therapy, which uses the genetically engineered T cells and becomes the most advanced approach. Compared to classic small molecule-based therapeutic approaches, gene therapy offers unprecedented leverage in drug development, including the prospect of regulating genes encoding proteins that are deemed undruggable by conventional small molecules, high target specificity, reversible effect, and the potential to be re-programmed without alternating pharmacokinetics features. With the explosive development of genome engineering technologies, gene therapy has heralded a new era for improving the treatments of brain diseases. In recent years, immunotherapies, such as modulation of cytokines, vaccinations using monoclonal antibodies and specific antigens, may provide an alternative therapeutic approach, though they are still at the infant stage. For glioblastoma (GBM) and other CNS cancers, temozolomide (TMZ) is still the only first-line drug that is approved by U.S. Nevertheless, they are not curative but symptomatic treatments to delay disease progression. For instance, aducanumab, donepezil, rivastigmine, galantamine, and memantine are used to treat AD, L-Dopa is applied to manage PD, and tetrabenazine is utilized to address HD. To date, small molecule drugs remain to be the first line of treatments in clinics. ![]() Despite the bitter truth, the development of CNS disease therapeutics has made little progress for decades. It is estimated that the prevalence of CNS diseases continues to increase, with more than 103 million people to be affected in 2030. In 2016, CNS diseases resulted in 9.0 million deaths, contributing 16.5% of total deaths from all causes over the world. Globally, the population affected by CNS diseases has substantially increased from 1990 to 2015. In this review, an overview of gene therapies for CNS diseases is provided and describes recent advances in the development of nanomedicines, including their unique characteristics, chemical modifications, bioconjugations, and the specific applications that those nanomedicines are harnessed to deliver gene therapies.Ĭentral nervous system (CNS) diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), stroke, Huntington's disease (HD), brain tumors, and multiple sclerosis, are the leading cause of disability and the second leading cause of mortality worldwide. Various non-viral nanomedicines have been recently explored to circumvent this limitation. Despite the significant progress that has undoubtedly been achieved in terms of the design and modification of genetic modulators with desired potency and minimized unwanted immune responses, the efficient and safe in vivo delivery of gene therapies still poses major translational challenges. In recent years, various gene therapies have come into the spotlight as versatile therapeutics providing the potential to prevent and treat these diseases. Central Nervous System (CNS) diseases, such as Alzheimer's diseases (AD), Parkinson's Diseases (PD), brain tumors, Huntington's disease (HD), and stroke, still remain difficult to treat by the conventional molecular drugs.
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