Mucopolysaccharidoses type I gene therapy.

Mucopolysaccharidoses type I (MPS I) is an inherited metabolic disease characterized by a malfunction of the α-l-iduronidase (IDUA) enzyme leading to the storage of glycosaminoglycans in the lysosomes. This disease has longtime been studied as a therapeutic target for those studying gene therapy and many studies have been done using various vectors to deliver the IDUA gene for corrective treatment. Many vectors have difficulties with efficacy and insertional mutagenesis concerns including adeno-associated viral (AAV) vectors. Studies of AAV vectors treating MPS I have seemed promising, but recent deaths in gene therapy clinical trials for other inherited diseases using AAV vectors have left questions about their safety. Additionally, the recent modifications to adenoviral vectors leading them to target the vascular endothelium minimizing the risk of hepatotoxicity could lead to them being a viable option for MPS I gene therapy when coupled with gene editing technologies like CRISPR/Cas9.

Combining angiotensin receptor blockade and enzyme replacement therapy for vascular disease in mucopolysaccharidosis type I.

Vascular involvement in the genetic disorder mucopolysaccharidosis type I (MPS I) has features of atherosclerotic disease near branch points of arterial vasculature, such as intimal thickening with disruption of the internal elastic lamina, and proliferation of macrophages and myofibroblasts. Inflammatory pathways are implicated in the pathogenesis of vascular disease in MPS I animal models, evidenced by cytokines like CD18 and TGF-ß within arterial plaques. The angiotensin II-mediated inflammatory pathway is well studied in human atherosclerotic coronary artery disease. Recent work indicates treatment with the angiotensin receptor blocker losartan may improve vascular MPS I disease in mouse models. Here, we combined losartan with the standard therapy for MPS I, enzyme replacement therapy (ERT), to measure effects on cytokines in serum and aortic vasculature. Each treatment group (losartan, ERT, and their combination) equally normalized levels of cytokines that were largely differential between normal and mutant mice. Some cytokines, notably CD30 ligand, Eotaxin-2, LIX, IL-13, IL-15, GM-CSF, MCP-5, MIG, and CCL3 showed elevations in mice treated with ERT above normal or mutant levels; these elevations were reduced or absent in mice that received losartan or combination therapy. The observations suggest that losartan may impact inflammatory cascades due to MPS I and may also blunt inflammation in combination with ERT.