Stephen Zano - Modification of aspartoacylase for potential use in enzyme replacement therapy for the treatment of Canavan Disease

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      Publication Details (including relevant citation   information):

    Modification of   aspartoacylase for potential use in enzyme replacement   therapy for the treatment of   Canavan disease

      Stephen   Zanoa, Radhika Malika, 1, Sylvia Szucsb, Reuben Matalonb, Ronald E. Violaa, http://www.sciencedirect.com/science/article/pii/S1096719210003719#cr0005Corresponding Author Contact Information,  E-mail The Corresponding Author

     

                                 
            a              Department of Chemistry, University of Toledo, Toledo, OH         43606, USA      

     

                                 
            b              Department of Pediatrics, University of Texas Medical         Branch, Galveston, TX 77555, USA      

      Received 23 October 2010; Accepted 25 October 2010. Available   online 30 October 2010.

     

     

        Abstract  

     

            Canavan disease is a fatal neurological disease without     any effective treatments to slow the relentless progress of     this disorder. Enzyme replacement therapy has been used     effectively to treat a number of     metabolic disorders, but the presence of the         blood–brain-barrier presents an additional challenge in     the treatment of     neurological disorders. Studies have begun with the aim     of establishing a treatment protocol that can effectively     replace the defective enzyme in     Canavan disease patients. The     human enzyme,     aspartoacylase, has been cloned, expressed and purified,     and the surface lysyl groups modified through PEGylation. Fully     active modified enzymes were administered to     mice that are defective in this enzyme and that show     many of the symptoms of     Canavan disease. Statistically significant increases in         brain enzyme activity levels have been achieved in this     animal model, as well as decreases in the elevated substrate     levels that mimic those found in     Canavan disease patients. These results demonstrate that     the modified enzyme is gaining access to the     brain and functions to correct this metabolic defect.     The stage is now set for a long term study to optimize this     enzyme replacement approach for the development of a treatment     protocol.  

     

     
        

      Abbreviations:   ASPA,   aspartoacylase;   CD,   Canavan disease; ERT, enzyme replacement therapy;     NAA, N-acetyl-l-aspartate;   PEG,   polyethylene glycol

      Keywords:   Canavan disease;   Aspartoacylase; Enzyme replacement therapy; PEGylation;   Animal model

      Abstract:

        Canavan disease is a fatal neurological disease without   any effective treatments to slow the relentless progress of this   disorder. Enzyme replacement therapy has been used effectively to   treat a number of   metabolic disorders, but the presence of the   blood–brain-barrier presents an additional challenge in   the treatment of   neurological disorders. Studies have begun with the aim of   establishing a treatment protocol that can effectively replace   the defective enzyme in   Canavan disease patients. The   human enzyme,   aspartoacylase, has been cloned, expressed and purified,   and the surface lysyl groups modified through PEGylation. Fully   active modified enzymes were administered to   mice that are defective in this enzyme and that show many   of the symptoms of   Canavan disease. Statistically significant increases in     brain enzyme activity levels have been achieved in this   animal model, as well as decreases in the elevated substrate   levels that mimic those found in   Canavan disease patients. These results demonstrate that   the modified enzyme is gaining access to the   brain and functions to correct this metabolic defect. The   stage is now set for a long term study to optimize this enzyme   replacement approach for the development of a treatment protocol.

      Address (URL): http://www.sciencedirect.com/science/article/pii/S1096719210003719