In vivo liver targeted genome editing as therapeutic approach: progresses and challenges.

The liver is an essential organ of the body that performs several vital functions, including the metabolism of biomolecules, foreign substances, and toxins, and the production of plasma proteins, such as coagulation factors. There are hundreds of genetic disorders affecting liver functions and, for many of them, the only curative option is orthotopic liver transplantation, which nevertheless entails many risks and long-term complications. Some peculiar features of the liver, such as its large blood flow supply and the tolerogenic immune environment, make it an attractive target for in vivo gene therapy approaches. In recent years, several genome-editing tools mainly based on the clustered regularly interspaced short palindromic repeats associated protein 9 (CRISPR-Cas9) system have been successfully exploited in the context of liver-directed preclinical or clinical therapeutic applications. These include gene knock-out, knock-in, activation, interference, or base and prime editing approaches. Despite many achievements, important challenges still need to be addressed to broaden clinical applications, such as the optimization of the delivery methods, the improvement of the editing efficiency, and the risk of on-target or off-target unwanted effects and chromosomal rearrangements. In this review, we highlight the latest progress in the development of in vivo liver-targeted genome editing approaches for the treatment of genetic disorders. We describe the technological advancements that are currently under investigation, the challenges to overcome for clinical applicability, and the future perspectives of this technology.

Myositis and acute kidney injury in bacterial atypical pneumonia: Systematic literature review.

BACKGROUND: Bacterial community-acquired atypical pneumonia is sometimes complicated by a myositis or by a renal parenchymal disease. Available reviews do not mention the concurrent occurrence of both myositis and acute kidney injury. METHODS: In order to characterize the link between bacterial community-acquired atypical pneumonia and both myositis and a renal parenchymal disease, we reviewed the literature (United States National Library of Medicine and Excerpta Medica databases). RESULTS: We identified 42 previously healthy subjects (35 males and 7 females aged from 2 to 76, median 42 years) with a bacterial atypical pneumonia associated both with myositis (muscle pain and creatine kinase ≥5 times the upper limit of normal) and acute kidney injury (increase in creatinine to ≥1.5 times baseline or increase by ≥27 µmol/L above the upper limit of normal). Thirty-six cases were caused by Legionella species (N = 27) and by Mycoplasma pneumoniae (N = 9). Further germs accounted for the remaining 6 cases. The vast majority of cases (N = 36) presented a diffuse myalgia. Only a minority of cases (N = 3) were affected by a calf myositis. The diagnosis of rhabdomyolysis-associated kidney injury was retained in 37 and that of acute interstitial nephritis in the remaining 5 cases. CONCLUSION: Bacterial atypical pneumonia may occasionally induce myositis and secondary kidney damage.

Clindamycin clearance during Cytosorb® hemoadsorption: A case report and pharmacokinetic study.

Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus infections are rare but associated with very high mortality rates. We report the case of a 14-year-old patient with Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus infection and Influenza B pneumonia requiring veno-arterial extra-corporeal membrane oxygenator for refractory shock. In the absence of response to conventional therapy, we have inserted a Cytosorb® cartridge within the extra-corporeal membrane oxygenator circuit. A spectacular decrease in vasopressor requirements followed. Since clindamycin, a key component of Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus treatment, might be removed by Cytosorb® hemoadsorption, we have performed serial plasma concentrations measurements of the drug. Based on these measurements, we were able to develop a pharmacokinetic model incorporating variable plasma clearance. Patient's exposure was estimated before, during and after Cytosorb® hemoadsorption. According to this model, Cytosorb® hemoadsorption did not seem to result in significant clindamycin removal. Cytosorb® hemoadsorption during Panton-Valentine leucocidin producing methicillin-resistant Staphylococcus aureus infection appears safe and feasible and no adaptation of clindamycin dosage seems necessary.