Animal models of inherited metabolic diseases : proceedings of the International Symposium on Animal Models of Inherited Metabolic Disease held in Bethesda, Maryland, October 19-20, 1981 / editors: Robert J. Desnick, Donald F. Patterson, Dante G. Scarpelli.
- International Symposium on Animal Models of Inherited Metabolic Disease (1981 : Bethesda, Md.)
- Date:
- [1982]
Licence: Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Credit: Animal models of inherited metabolic diseases : proceedings of the International Symposium on Animal Models of Inherited Metabolic Disease held in Bethesda, Maryland, October 19-20, 1981 / editors: Robert J. Desnick, Donald F. Patterson, Dante G. Scarpelli. Source: Wellcome Collection.
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![logous bovine p-glucuronidase did not elicit an immune response following repeated intravenous administrations (Fiddler et_ al_., 1977). These studies also demonstrated that intravenously administered enzyme, whether entrapped in liposomes or erythrocytes, or unentrapped, was unable to cross the blood-brain barrier and gain access to the central nervous system. Thus, it was recognized that efforts to treat diseases with neurologic involvement required the develop ment of strategies to reversibly open the blood-brain barrier for neuronal enzyme uptake. Using the feline model of Gwp-gangliosidosis, Rattazzi et_ al_. (1979, 1980) eval uated the effectiveness of hyperbaric oxygen and intracaro tid air micro-embolism as methods to reversibly open the blood-brain barrier. Following exposure to hyperbaric oxygen, p-hexosaminidase A was injected into the femoral or carotid vein and neural uptake was determined. In order to prolong the half-life of exogenous enzyme in the circula tion and maximize its central nervous system exposure, hepatic clearance of the enzyme was partially inhibited by the infusion of receptor-blocking mannosaccharides (i.e., mannans). This inhibition resulted in a 3 to 5-fold in crease in neural enzyme uptake over that observed without blockage of the hepatic uptake receptors. However, hyper baric treatment followed by the intracarotid administration of large doses of enzyme resulted in the neural uptake of only about 1% of injected enzyme. More encouraging results were obtained in preliminary experiments of intracarotid air micro-embolization. Fol lowing the injection of small volumes of air, mannans and p-hexosaminidase A were administered intravenously into normal or G M?-gangliosidosis cats (Rattazzi et aK, 1979; Rattazzi, 19b0). One hour after enzyme injection, the exogenous P-hexosaminidase A activity reached 20-30% of the endogenous level in normal feline brain, suggesting that air micro-embolization or similar mechanical methods to open the blood-brain barrier will permit access to neuronal sites of substrate deposition by nonselective extravasation of plasma containing the administered enzyme. More recent ly, these investigators have improved their techniques, permitting increased amounts of injected enzyme to reach the central nervous system (see Rattazzi et a]_. and Baker et_ aj_., this volume). Clearly, animal models are essential for the development and evaluation of novel therapeutic](https://iiif.wellcomecollection.org/image/b18027842_0073.JP2/full/800%2C/0/default.jpg)
