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CRISPR Manipulation of Age-Related Macular Degeneration Haplotypes in the Complement System: Potential Future Therapeutic Applications/Avenues
Age-related macular degeneration (AMD) is the leading cause of irreversible vision loss among the elderly in the developed world. Whilst AMD is a multifactorial disease, the involvement of the complement system in its pathology is well documented, with single-nucleotide polymorphisms (SNPs) in different complement genes representing an increased risk factor. With several complement inhibitors explored in clinical trials showing limited success, patients with AMD are still without a reliable treatment option. This indicates that there is still a gap of knowledge in the functional implications and manipulation of the complement system in AMD, hindering the progress towards translational treatments. Since the discovery of the CRISPR/Cas system and its development into a powerful genome engineering tool, the field of molecular biology has been revolutionised. Genetic variants in the complement system have long been associated with an increased risk of AMD, and a variety of haplotypes have been identified to be predisposing/protective, with variation in complement genes believed to be the trigger for dysregulation of the cascade leading to inflammation. AMD-haplotypes (SNPs) alter specific aspects of the activation and regulation of the complement cascade, providing valuable insights into the pathogenic mechanisms of AMD with important diagnostic and therapeutic implications. The effect of targeting these AMD-related SNPs on the regulation of the complement cascade has been poorly explored, and the CRISPR/Cas system provides an ideal tool with which to explore this avenue. Current research concentrates on the association events of specific AMD-related SNPs in complement genes without looking into the effect of targeting these SNPs and therefore influencing the complement system in AMD pathogenesis. This review will explore the current understanding of manipulating the complement system in AMD pathogenesis utilising the genomic manipulation powers of the CRISPR/Cas systems. A number of AMD-related SNPs in different complement factor genes will be explored, with a particular emphasis on factor H (CFH), factor B (CFB), and complement C3 (C3).
Minicircle Delivery to the Neural Retina as a Gene Therapy Approach
Non-viral gene therapy has the potential to overcome several shortcomings in viral vector-based therapeutics. Methods of in vivo plasmid delivery have developed over recent years to increase the efficiency of non-viral gene transfer, yet further improvements still need to be made to improve their translational capacity. Gene therapy advances for inherited retinal disease have been particularly prominent over the recent decade but overcoming physical and physiological barriers present in the eye remains a key obstacle in the field of non-viral ocular drug delivery. Minicircles are circular double-stranded DNA vectors that contain expression cassettes devoid of bacterial DNA, thereby limiting the risks of innate immune responses induced by such elements. To date, they have not been extensively used in pre-clinical studies yet remain a viable vector option for the treatment of inherited retinal disease. Here, we explore the potential of minicircle DNA delivery to the neural retina as a gene therapy approach. We consider the advantages of minicircles as gene therapy vectors as well as review the challenges involved in optimising their delivery to the neural retina.
Guillain-Barré syndrome: A comprehensive review.
Guillain-Barré syndrome (GBS) is a potentially devastating yet treatable disorder. A classically postinfectious, immune-mediated, monophasic polyradiculoneuropathy, it is the leading global cause of acquired neuromuscular paralysis. In most cases, the immunopathological process driving nerve injury is ill-defined. Diagnosis of GBS relies on clinical features, supported by laboratory findings and electrophysiology. Although previously divided into primary demyelinating or axonal variants, this dichotomy is increasingly challenged, and is not endorsed by the recent European Academy of Neurology (EAN)/Peripheral Nerve Society (PNS) guidelines. Intravenous immunoglobulin and plasma exchange remain the primary modalities of treatment, regardless of the electrophysiological subtype. Most patients recover, but approximately one-third require mechanical ventilation, and 5% die. Disease activity and treatment response are currently monitored through interval neurological examination and outcome measures, and the potential role of fluid biomarkers is under ongoing scrutiny. Novel potential therapies for GBS are being explored but none have yet modified clinical practice. This review provides a comprehensive update on the pathological and clinical aspects of GBS for clinicians and scientists.