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Neurological Disease
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
In Duchenne muscular dystrophy, most patients use wheelchairs by their teens and die in their twenties. Becker muscular dystrophy is much less severe, and most patients die with their disease rather than because of it.
Basic genetics and patterns of inheritance
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Finally, methods for manipulating the expression or splicing of mutant genes are being investigated. Drugs that induce read-through of a stop codon during translation of a mutant gene can result in increased expression of full-length protein. This approach has been tried experimentally with cystic fibrosis and Duchenne muscular dystrophy. In other studies, antisense oligonucleotides have been used to induce skipping during mRNA splicing of exons that contain mutations; this approach will produce a smaller protein, but one that might retain some residual function. This method of therapy has been investigated for Duchenne muscular dystrophy. It is anticipated that more such opportunities will become available in the future for targeted therapy of the disease manifestations of genetic disorders.
Muscular Dystrophy Diseases
Published in Maher Kurdi, Neuromuscular Pathology Made Easy, 2021
In summary, muscular dystrophy is characterized clinically and histologically with myopathic features, dystrophic pattern, and muscle fibrosis. Pathologists should do the usual and common panel of dystrophy proteins. The panel rarely shows protein deficiency; however, molecular analysis is important for the final diagnosis.
Optimizing assays of zebrafish larvae swimming performance for drug discovery
Published in Expert Opinion on Drug Discovery, 2023
Jeffrey J. Widrick, Matthias R. Lambert, Louis M. Kunkel, Alan H. Beggs
The touch-evoked escape response is normally a qualitative method that relies upon human vision and discretion to judge whether larval swimming velocity and/or displacement is impaired. Some investigators have modified the touch-evoked escape response in order to make the approach more quantitative in nature. For example, by placing a transparent plastic sheet printed with concentric rings under the dish holding the larvae, initiating the escape response with the larvae centered in the inner most ring, and recording the response on video, the time required by the larvae to swim to the outermost ring could be determined [69]. This approach was used to evaluate a novel drug treatment for muscular dystrophy. Another method for quantifying escape response swimming is to record the movement using high-speed videography to then calculate maximum acceleration of larvae after the touch stimulus [48]. This approach was able to differentiate a nemaline myopathy model from wild type larvae.
Shaping the future from the small scale: dry powder inhalation of CRISPR-Cas9 lipid nanoparticles for the treatment of lung diseases
Published in Expert Opinion on Drug Delivery, 2023
Simone P. Carneiro, Antonietta Greco, Enrica Chiesa, Ida Genta, Olivia M. Merkel
Cheng and colleagues [105] designed Selective Organ Targeting (SORT) LNPs for CRISPR-Cas9 mRNA and sgRNA delivery aiming to reach the lungs, spleen, and liver and selectively modify therapeutically relevant cells such as T cells, B cells, and hepatocytes. Kenjo and colleagues [54] studied a new therapeutic approach for the treatment of Duchenne muscular dystrophy. They developed pH-dependent ionizable lipids with three hydrophobic tails employed to formulate LNPs for the transient delivery of Cas9 mRNA and sgRNA to the skeletal muscle tissues in vivo. This therapeutic approach allowed the repeated injection of LNPs to cover all skeletal muscle. Moreover, investigating the limb perfusion injection method (interesting for the targeting of multiple skeletal muscle groups), LNPs were administered in smaller volumes, compared to conventional hydrodynamic injection, due to the enhanced release of CRISPR-Cas9 from LNPs. Considering the treatment of patients, the injection of small volumes is a huge advantage to avoid compartment syndrome. In comparison to approved antisense oligonucleotide drugs, the effect of LNP-delivered CRISPR-Cas studied by Kenjo was maintained over months. Interestingly, the treated cells did not show mutagenesis overcoming the off-target limitation; however, different candidate DNA cleavage sites were identified.
Soluble guanylate cyclase stimulators and their potential use: a patent review
Published in Expert Opinion on Therapeutic Patents, 2021
Peter Sandner, Alexandros Vakalopoulos, Michael G. Hahn, Johannes-Peter Stasch, Markus Follmann
CF is driven by mutations of a chloride channel (CFTR) in the lung epithelium leading to a reduction of the airway surface liquid layer and of the mucociliary clearance which causes sticky mucus, airway infections, decline of lung function and overall still a significant reduction of life expectancy. Given the genetic cause of the disease, gene therapy and gene editing might provide future treatments, however these treatments are not available for patients yet and therefore, pharmacological therapies are needed. In the patent application WO2011095534 [64] it was shown that sGC agonists increase trafficking and function of a mutated chloride channel carrying the major mutation in CF (F508delCFTR). These effects seemed to be more pronounced when combined with F508del CFTR correctors and potentiators which are already used in CF (WO2015011086) [72], overall suggesting that sGC agonists are effective treatment options for CF. Duchenne Muscular Dystrophy (DMD)