Gene therapy for cross-correction of somatic organs and the CNS in mucopolysaccharidosis II in rodents and non-human primates.

Mucopolysaccharidosis II (MPS II) is a rare lysosomal storage disease characterized by deficient activity of iduronate-2-sulfatase (I2S), leading to pathological accumulation of glycosaminoglycans (GAGs) in tissues. We used iduronate-2-sulfatase knockout ( KO) mice to investigate if liver-directed recombinant adeno-associated virus vectors (rAAV8-LSP-h) encoding human I2S (hI2S) could cross-correct I2S deficiency in KO mouse tissues, and we then assessed the translation of mouse data to non-human primates (NHPs). Treated mice showed sustained hepatic hI2S production, accompanied by normalized GAG levels in somatic tissues (including critical tissues such as heart and lung), indicating systemic cross-correction from liver-secreted hI2S.

Myostatin and activin blockade by engineered follistatin results in hypertrophy and improves dystrophic pathology in mdx mouse more than myostatin blockade alone.

Background: Myostatin antagonists are being developed as therapies for Duchenne muscular dystrophy due to their strong hypertrophic effects on skeletal muscle. Engineered follistatin has the potential to combine the hypertrophy of myostatin antagonism with the anti-inflammatory and anti-fibrotic effects of activin A antagonism.

Methods: Engineered follistatin was administered to C57BL/6 mice for 4 weeks, and muscle mass and myofiber size was measured.

Protein Engineering on Human Recombinant Follistatin: Enhancing Pharmacokinetic Characteristics for Therapeutic Application.

Follistatin (FS) is an important regulatory protein, a natural antagonist for transforming growth factor-β family members activin and myostatin. The diverse biologic roles of the activin and myostatin signaling pathways make FS a promising therapeutic target for treating human diseases exhibiting inflammation, fibrosis, and muscle disorders, such as Duchenne muscular dystrophy. However, rapid heparin-mediated hepatic clearance of FS limits its therapeutic potential.

Expression of major histocompatibility complex class I proteins and their antigen processing chaperones in mouse embryonic stem cells from fertilized and parthenogenetic embryos.

Embryonic stem (ES) cells are pluripotent cells with the potential to differentiate into cells or tissues that may be used for transplantation therapy. Parthenogenetic ES (pES) cells have been recently derived from both mouse and human oocytes and hold promise as a cell source that is histocompatible to the oocyte donor. Because of the importance of major histocompatibility complex (MHC) antigens in mediating tissue rejection or acceptance, we examined levels of mRNA and protein expression of MHC class I proteins, as well as several MHC class I antigen processing and presentation chaperones in mouse ES cells derived from both fertilized (fES) and parthenogenetic (pES) embryos.