Human molecular genetics
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Human molecular genetics · Aug 2018
ReviewDevelopment and application of CRISPR/Cas9 technologies in genomic editing.
Genomic editing to correct disease-causing mutations is a promising approach for the treatment of human diseases. As a simple and programmable nuclease-based genomic editing tool, the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has substantially improved the ability to make precise changes in the human genome. ⋯ Here, we review the application of the CRISPR system over the last 2 years; including its development and application in base editing, transcription modulation and epigenetic editing, genomic-scale screening, and cell and embryo therapy. Finally, the prospects and challenges related to application of CRISPR/Cas9 technologies are discussed.
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Genomic and other related big data (Big Genomic Data, BGD for short) are ushering a new era of precision medicine. This overview discusses whether principles of evidence-based medicine hold true for BGD and how they should be operationalized in the current era. Major evidence-based medicine principles include the systematic identification, description and analysis of the validity and utility of BGD, the combination of individual clinical expertise with individual patient needs and preferences, and the focus on obtaining experimental evidence, whenever possible. ⋯ Randomized controlled trials will continue to be the strongest arbitrator for the clinical utility of genomic technologies, including BGD. Research on BGD needs to focus not only on finding robust predictive associations (clinical validity) but also more importantly on evaluating the balance of health benefits and potential harms (clinical utility), as well as implementation challenges. Appropriate features of such useful research on BGD are discussed.
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Human molecular genetics · Oct 2017
ReviewSpinal muscular atrophy: antisense oligonucleotide therapy opens the door to an integrated therapeutic landscape.
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. ⋯ Since the seminal discovery of the SMA-causing gene in 1995, research has focused on the development of various SMN replacement strategies culminating, in December 2016, in the approval of the first precise molecularly targeted therapy for SMA (nusinersen), and a pivotal proof of principle that therapeutic antisense oligonucleotide (ASO) treatment can effectively target the central nervous system (CNS) to treat neurological and neuromuscular disease. Nusinersen is a steric block ASO that binds the SMN2 messenger RNA and promotes exon 7 inclusion and thus increases full length SMN expression. Here, we consider the implications of this therapeutic landmark for SMA therapeutics and discuss how future developments will need to address the challenges of delivering ASO therapies to the CNS, with appropriate efficiency and activity, and how SMN-based therapy should be used in combination with complementary strategies to provide an integrated approach to treat CNS and peripheral pathologies in SMA.
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Although affecting only 4-5% of those with cystic fibrosis (CF), the G551D-CFTR mutation is the target of the recently approved 'orphan drug', ivacaftor. The promise of such genomically guided therapies heralds a new era in the management of CF. A phase 3 trial demonstrated significant improvements in forced expiratory volume in 1 s (FEV(1)) from baseline, average weight gain, concentration in sweat chloride and reductions in pulmonary exacerbations [Ramsey, B. ⋯ Pharmaceutical and biotech companies have leveraged the incentivized benefits of the Orphan Drug Act to develop more of these drugs for orphan disorders affecting populations of <200 000 patients. With marked clinical efficacy via DNA sequence guidance, these drugs have also set a precedent in terms of the substantial annual costs and if this trend continues, such expenditures may become unsustainable. This paper explores the genomic pathophysiology of CF and how therapies such as ivacaftor provide benefit to those with the disease but at a considerably elevated price point.
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Leukodystrophies (LDs) refer to a group on inherited diseases in which molecular abnormalities of glial cells are responsible for exclusive or predominant defects in myelin formation and/or maintenance within the central and, sometimes, the peripheral nervous system. For three of them [X-linked adrenoleukodystrophy (X-ALD), metachromatic (MLD) and globoid cell LDs], a gene therapy strategy aiming at transferring the disease gene into autologous hematopoietic stem cells (HSCs) using lentiviral vectors has been developed and has already entered into the clinics for X-ALD and MLD. ⋯ Brain gene therapy relying upon intracerebral injections of adeno-associated vectors is also envisaged for MLD. The development of new gene therapy viral vectors allowing targeting of the disease gene into oligodendrocytes or astrocytes should soon benefit other forms of LDs.