Genzyme

About: Genzyme is a based out in . It is known for research contribution in the topics: Enzyme replacement therapy & Population. The organization has 3085 authors who have published 3472 publications receiving 177632 citations. The organization is also known as: Sanofi Genzyme.

Lung transplantation in idiopathic pulmonary fibrosis: a systematic review of the literature

Abstract: Idiopathic pulmonary fibrosis (IPF) is a distinct form of interstitial pneumonia with unknown origin and poor prognosis. Current pharmacologic treatments are limited and lung transplantation is a viable option for appropriate patients. The aim of this review was to summarize lung transplantation survival in IPF patients overall, between single (SLT) vs. bilateral lung transplantation (BLT), pre- and post Lung Allocation Score (LAS), and summarize wait-list survival. A systematic review of English-language studies published in Medline or Embase between 1990 and 2013 was performed. Eligible studies were those of observational design reporting survival post-lung transplantation or while on the wait list among IPF patients. Median survival post-transplantation among IPF patients is estimated at 4.5 years. From ISHLT and OPTN data, one year survival ranged from 75% - 81%; 3-year: 59% - 64%; and 5-year: 47% - 53%. Post-transplant survival is lower for IPF vs. other underlying pre-transplant diagnoses. The proportion of IPF patients receiving BLT has steadily increased over the last decade and a half. Unadjusted analyses suggest improved long-term survival for BLT vs. SLT; after adjustment for patient characteristics, the differences tend to disappear. IPF patients account for the largest proportion of patients on the wait list and while wait list time has decreased, the number of transplants for IPF patients has increased over time. OPTN data show that wait list mortality is higher for IPF patients vs. other diagnoses. The proportion of IPF patients who died while awaiting transplantation ranged from 14% to 67%. While later transplant year was associated with increased survival, no significant differences were noted pre vs. post LAS implementation; however a high LAS vs low LAS was associated with decreased one-year survival. IPF accounts for the largest proportion of patients awaiting lung transplants, and IPF is associated with higher wait-list and post-transplant mortality vs. other diagnoses. Improved BLT vs. SLT survival may be the result of selection bias. Survival pre- vs. post LAS appears to be similar except for IPF patients with high LAS, who have lower survival compared to pre-LAS. Data on post-transplant morbidity outcomes are sparse.

Carbohydrate-remodelled acid α-glucosidase with higher affinity for the cation-independent mannose 6-phosphate receptor demonstrates improved delivery to muscles of Pompe mice

Abstract: To enhance the delivery of rhGAA (recombinant GAA, where GAA stands for acid α-glucosidase) to the affected muscles in Pompe disease, the carbohydrate moieties on the enzyme were remodelled to exhibit a high affinity ligand for the CI-MPR (cation-independent M6P receptor, where M6P stands for mannose 6-phosphate). This was achieved by chemically conjugating on to rhGAA, a synthetic oligosaccharide ligand bearing M6P residues in the optimal configuration for binding the receptor. The carbonyl chemistry used resulted in the conjugation of approx. six synthetic ligands on to each enzyme. The resulting modified enzyme [neo-rhGAA (modified recombinant human GAA harbouring synthetic oligosaccharide ligands)] displayed near-normal specific activity and significantly increased affinity for the CI-MPR. However, binding to the mannose receptor was unaffected despite the introduction of additional mannose residues in neo-rhGAA. Uptake studies using L6 myoblasts showed neo-rhGAA was internalized approx. 20-fold more efficiently than the unmodified enzyme. Administration of neo-rhGAA into Pompe mice also resulted in greater clearance of glycogen from all the affected muscles when compared with the unmodified rhGAA. Comparable reductions in tissue glycogen levels in the Pompe mice were realized using an approx. 8-fold lower dose of neo-rhGAA in the heart and diaphragm and an approx. 4-fold lower dose in the skeletal muscles. Treatment of older Pompe mice, which are more refractory to enzyme therapy, with 40 mg/kg neo-rhGAA resulted in near-complete clearance of glycogen from all the affected muscles as opposed to only partial correction with the unmodified rhGAA. These results demonstrate that remodelling the carbohydrate of rhGAA to improve its affinity for the CI-MPR represents a feasible approach to enhance the efficacy of enzyme replacement therapy for Pompe disease.

Parathyroid hormone treatment induces dissociation of type IIa Na+-Pi cotransporter-Na+/H+ exchanger regulatory factor-1 complexes

Abstract: The type IIa Na+-Pi cotransporter (NaPi-IIa) and the Na+/H+ exchanger regulatory factor-1 (NHERF1) colocalize in the apical membrane of proximal tubular cells. Both proteins interact in vitro. Here...

Novel anti-VEGF chimeric molecules delivered by AAV vectors for inhibition of retinal neovascularization.

Abstract: Vascular endothelial growth factor (VEGF) is important in pathological neovascularization, which is a key component of diseases such as the wet form of age-related macular degeneration, proliferative diabetic retinopathy and cancer. One of the most potent naturally occurring VEGF binders is VEGF receptor Flt-1. We have generated two novel chimeric VEGF-binding molecules, sFLT01 and sFLT02, which consist of the second immunoglobulin (IgG)-like domain of Flt-1 fused either to a human IgG1 Fc or solely to the CH3 domain of IgG1 Fc through a polyglycine linker 9Gly. In vitro analysis showed that these novel molecules are high-affinity VEGF binders. We have demonstrated that adeno-associated virus serotype 2 (AAV2)-mediated intravitreal gene delivery of sFLT01 efficiently inhibits angiogenesis in the mouse oxygen-induced retinopathy model. There were no histological observations of toxicity upon persistent ocular expression of sFLT01 for up to 12 months following intravitreal AAV2-based delivery in the rodent eye. Our data suggest that AAV2-mediated intravitreal gene delivery of our novel molecules may be a safe and effective treatment for retinal neovascularization.