Molybdenum cofactor deficiency type B knock-in mouse models carrying patient-identical mutations and their rescue by singular AAV injections.

Molybdenum cofactor deficiency is an autosomal, recessively inherited metabolic disorder, which, in the absence of an effective therapy, leads to early childhood death due to neurological deterioration. In type A of the disease, cyclic pyranopterin monophosphate (cPMP) is missing, the first intermediate in the biosynthesis of the cofactor, and a biochemical substitution therapy using cPMP has been developed. A comparable approach for type B of the disease with a defect in the second step of the synthesis, formation of molybdopterin, so far has been hampered by the extreme instability of the corresponding metabolites. To explore avenues for a successful and safe gene therapy, knock-in mouse models were created carrying the mutations c.88C>T (p.Q30X) and c.726_727delAA, which are also found in human patients. Recombinant adeno-associated viruses (rAAVs) were constructed and used for postnatal intrahepatic injections of MoCo-deficient mice in a proof-of-concept approach. Singular administration of an appropriate virus dose in 60 animals prevented the otherwise devastating phenotype to a variable extent. While untreated mice did not survive for more than 2 weeks, some of the treated mice grew up to adulthood in both sexes.

Rheumajecta and vasolastine in the treatment of rheumatoid arthritis--the results of a placebo-controlled, double-blind trial of a complementary treatment.

The so called "enzymatic preparations" Rheumajecta and Vasolastine (R & V) belong to the complementary treatments. The preparations have been used for many years in the treatment of patients with rheumatic conditions such as rheumatoid arthritis (RA) in the Netherlands and other countries of Europe, although a proper study showing efficacy was never performed. Therefore a double-blind, placebo-controlled, modified cross-over trial during two periods of 3 months was performed in 34 patients with RA. They were allocated at random to R & V or to placebo injections, all intramuscular. After 3 months of therapy each patient could opt for cross-over in the event of lack of subjective improvement. Clinical assessments including Ritchie's articular index, grip strength, the DUTCH-AIMS questionnaire, ESR and CRP were performed. R & V did not prove to be more effective than placebo. No serious side-effects were seen.