Gene therapy of Hunter syndrome: Evaluation of the efficiency of muscle electro gene transfer for the production and release of recombinant iduronate-2-sulfatase (IDS)

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1782

Article

Friso, A.^1,2  Tomanin, R.^1,2  Zanetti, A.^1,2  Mennuni, C.³  Calvaruso, F.³  La Monica, N.³  Marin, O.⁴  Zacchello, F.^1,2  Scarpa, M.^1,2 

[1] Univ Padua, Ctr Rare Dis, Gene Therapy Lab, I-35128 Padua, Italy

[2] Univ Padua, Dept Pediat, I-35128 Padua, Italy

[3] Ist Ric Biol Mol P Angeletti, Dept Oncol, I-00040 Rome, Italy

[4] Univ Padua, Dept Biochem, I-35100 Padua, Italy

关键词: Hunter syndrome;    Iduronate-2-sulfatase;    Electro gene transfer;    Hyaluronidase;    Muscle;    Gene therapy;   

DOI  :  10.1016/j.bbadis.2008.07.001

来源: Elsevier

【 摘 要 】

Mucopolysacchariclosis type II (MPSII) is an inherited disorder due to a deficiency of the lysosomal enzyme iduronate-2-sulfatase (IDS). The disease is characterized by a considerable deposition of heparan- and dermatan-sulfate, causing a general impairment of physiological functions. Most of the therapeutic protocols proposed so far are mainly based upon enzyme replacement therapy which is very expensive. There is a requirement for an alternative approach, and to this aim, we evaluated the feasibility of muscle electro, gene transfer (EGT) performed in the IDS-knockout (IDS-ko) mouse model. EGT is a highly efficient method of delivering exogenous molecules into different tissues. More recently, pre-treatment with bovine hyraluronidase has shown to further improve transfection efficiency of muscle EGT. We here show that, by applying such procedure, IDS was very efficiently produced inside the muscle. However, no induced IDS activity was measured in the IDS-ko mice plasma, in contrast to matched healthy controls. In the same samples, an anticipated and rapidly increasing immune response against the recombinant protein was observed in the IDS-ko vs control mice, although reaching the same levels at 5 weeks post-injection. Additional experiments performed on healthy mice showed a significant contribution of hyaluronidase pretreatment in increasing the immune response. (C) 2008 Elsevier B.V. All rights reserved.

【 授权许可】

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