Therapy Prospects for Mitochondrial DNA Maintenance Disorders.

Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited.

Darunavir and ritonavir total and unbound plasmatic concentrations in HIV-HCV-coinfected patients with hepatic cirrhosis compared to those in HIV-monoinfected patients.

Our objective was to describe the pharmacokinetic (PK) parameters of total and unbound darunavir and ritonavir concentrations in HIV-hepatitis C virus (HCV)-coinfected patients with cirrhosis, as ritonavir-boosted darunavir is mainly metabolized in the liver, and hepatic cirrhosis might modify darunavir-ritonavir concentrations. This was a prospective, case-control, and unicenter study. HIV-HCV-coinfected patients with compensated cirrhosis (cases) and HIV-monoinfected patients with normal liver function (controls) were included. Darunavir-ritonavir was given at 800/100 mg once daily. Patients were followed for 24 weeks to assess safety and efficacy. A steady-state 12-h PK study was performed. Total and unbound concentrations were determined by liquid chromatography-tandem mass spectrometry. The unbound fraction was obtained by ultrafiltration. The plasma area under the concentration-time curve (AUC) and oral clearance (CL/F) were assessed by noncompartmental models. Thirty patients (20 cases and 10 controls) were included. Among cirrhotic patients, the Child-Pugh score was C in 4 cases, B in 1 case, and A in 15 cases; the median (interquartile range) transient elastography values were 20 kPa (14 to 26 kPa), and 5 patients had prior clinical decompensations. There were no significant differences in the darunavir PK parameters between cases and controls except for longer time to maximum plasma concentrations (Tmax) and half-lives in the cirrhotic patients. There were no significant differences in ritonavir total concentrations, but the unbound concentrations were higher in cirrhotic patients. There were significant correlations between the darunavir total and unbound concentrations in both cirrhotic patients and controls. There were no differences in PK parameters based on Child-Pugh score, liver elasticity, gender, or use of concomitant medications. In conclusion, in HIV-HCV-coinfected patients with clinically compensated cirrhosis receiving darunavir-ritonavir at 800/100 mg once daily, the darunavir total and unbound concentrations are similar to those observed in noncirrhotic patients, and dose adjustments are not necessary.

Identification of the novel mutation m.5658T>C in the mitochondrial tRNA(Asn) gene in a patient with myopathy, bilateral ptosis and ophthalmoparesis.

We report a heteroplasmic novel mutation m.5658T>C in the mt-tRNA(Asn) gene in a patient who initially presented myopathy, bilateral ptosis and ophthalmoparesis and several years later developed a non-nephrotic proteinuria. The muscle biopsy showed cytochrome c oxidase (COX) negative and ragged red fibers and in the kidney biopsy that was taken in order to identify the causes of non-nephrotic proteinuria, a focal segmental glomerulosclerosis was observed. Using laser capture microdissection we isolated COX negative fibers and COX positive fibers from the muscle of the patient and determined that there was a clear increase in the mutation load in the COX negative muscle fibers. However, the low degree of mutation load found in the renal biopsy of the patient does not allow us to conclude that the m.5658T>C mutation is responsible for focal glomerulosclerosis. Additionally, we hypothesize that the mutated m.5658T nucleotide might be structurally relevant, as it is one of the fifteen nucleotides conserved in all the species analyzed and is situated contiguously to the discriminator base in the 3'end of the mt-tRNA, where the tRNase Z cleaves the 3' trailer sequence during mt-tRNA maturation.