Introduction The system of clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated proteins (cas) is a new technology that allows easier manipulation of the genome. Its potential to edit genes opened a new door in treatment development for incurable neurological monogenic diseases (NMGDs). The aim of this systematic review was to summarise the findings on the current development of CRISPR-cas for therapeutic purposes in the most frequent NMGDs and provide critical assessment. Methods and data acquisition We searched the MEDLINE and EMBASE databases, looking for original studies on the use of CRISPR-cas to edit pathogenic variants in models of the most frequent NMGDs, until end of 2017. We included all the studies that met the following criteria: 1. Peer-reviewed study report with explicitly described experimental designs; 2. In vitro, ex vivo, or in vivo study using human or other animal biological systems (including cells, tissues, organs, organisms); 3. focusing on CRISPR as the gene-editing method of choice; and 5. featured at least one NMGD. Results We obtained 404 papers from MEDLINE and 513 from EMBASE. After removing the duplicates, we screened 490 papers by title and abstract and assessed them for eligibility. After reading 50 full-text papers, we finally selected 42 for the review. Discussion Here we give a systematic summary on the preclinical development of CRISPR-cas for therapeutic purposes in NMGDs. Furthermore, we address the clinical interpretability of the findings, giving a comprehensive overview of the current state of the art. Duchenne’s muscular dystrophy (DMD) paves the way forward, with 26 out of 42 studies reporting different strategies on DMD gene editing in different models of the disease. Most of the strategies aimed for permanent exon skipping by deletion with CRISPR-cas. Successful silencing of the mHTT gene with CRISPR-cas led to successful reversal of the neurotoxic effects in the striatum of mouse models of Huntington’s disease. Many other strategies have been explored, including epigenetic regulation of gene expression, in cellular and animal models of: myotonic dystrophy, Fraxile X syndrome, ataxias, and other less frequent dystrophies. Still, before even considering the clinical application of CRISPR-cas, three major bottlenecks need to be addressed: efficacy, safety, and delivery of the systems. This requires a collaborative approach in the research community, while having ethical considerations in mind.

Background/Aim: Pulmonary function tests are used for screening respiratory insufficiency in patients with myotonic dystrophy (DM). We analysed the agreement between two different approaches in assessment of abnormal findings of forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP), in DM patients. Methods: We used Cohen’s κ- and Bangdiwala’s B- statistic to compare the agreement between different cut-off values recommended by experts (ENMC) and the cut-off values based on the reference range (RR). We further analysed their sensitivity (Sn) and specificity (Sp) in detecting symptoms associated with respiratory insufficiency. Results: The observed agreement was: 1) for FVC: κ= –0.002, B = 0.406; 2) for FEV1: κ= 0.944, B = 0.946; 3) for MIP: κ= 0.625, B = 0.674; and 4) for MEP: κ= 0.241, B = 0.373. Overall, RR cut-off values showed higher sensitivity, whereas the ENMC values showed higher specificity in detecting symptoms of respiratory involvement. Conclusions: The two approaches showed perfect agreement in assessment of FEV1, substantial agreement for MIP, and weak agreement for FVC and MEP. RR is an established method of assessment for spirometry and should be favoured because it takes variability within the population into account. Further development and validation of regression equations for RR calculations of predicted maximal respiratory pressures, with corresponding lower limits of normal, is required. The B statistic is more robust in assessing agreement between two diagnostic methods, resolving the issue of the κ paradox.