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).
Mucopolysaccharidosis 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 hyaluronidase 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 pre-treatment in increasing the immune response.
Friso
A
A
Gene Therapy Laboratory, Centre for Rare Diseases and Dept of Pediatrics, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.
Tomanin
R
R
Zanetti
A
A
Mennuni
C
C
Calvaruso
F
F
La Monica
N
N
Marin
O
O
Zacchello
F
F
Scarpa
M
M
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D002417:Cattle; D004558:Electric Stimulation / Q000379:methods; D005240:Feasibility Studies; D015316:Genetic Therapy / Q000379:methods*; D006023:Glycoproteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006025:Glycosaminoglycans / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006821:Hyaluronoglucosaminidase / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016532:Mucopolysaccharidosis II / Q000235:genetics / Q000628:therapy*; D052097:Quadriceps Muscle / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D006023:Glycoproteins; D006025:Glycosaminoglycans; C018322:IDS protein, human; D011994:Recombinant Proteins; D006821:Hyaluronoglucosaminidase