Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.2.1.23 (beta-galactosidase)
 14,648 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adenoviral vector-mediated gene transfer to skeletal muscle is a promising potential treatment for Duchenne muscular dystrophy. However, the immunological response to viral antigens and the therapeutic protein expressed by the delivered gene could prevent effective treatment. In this study, we investigated the immune response induced by adenoviral and dystrophin antigens presented by high-capacity adenoviral vector-mediated dystrophin and beta-galactosidase delivery to skeletal muscle of a mouse model that is both dystrophin-deficient and lacZ transgenic. Direct intramuscular gene delivery of the high-capacity adenoviral vector encoding full-length murine dystrophin resulted in stable expression of recombinant dystrophin for 5 months in mice treated as neonates and for 4 weeks in mice treated as adults. We observed neutralizing antibody to adenoviral antigens only in mice treated as adults and not in mice treated as neonates. This suggested that adenoviral antigens were only presented at the time of vector administration when the neonatal immune system was not yet mature. In contrast, antibodies to dystrophin were observed both in mice treated as neonates and in mice treated as adults. The development of an anti-dystrophin antibody response in mice treated with the high-capacity adenoviral vector as neonates suggested that dystrophin antigens were presented to the immune system at a time remote from the gene delivery, when the immune system was mature. Interestingly, an antibody response against beta-galactosidase developed late in the course of mice treated with the high-capacity adenoviral vector as neonates, suggesting a loss of tolerance to beta-galactosidase, a self-antigen in these transgenic mice. Our results suggest that future human trials of dystrophin gene delivery will need to address the potential for immunity induced by ongoing segmental degeneration of partially treated muscle fibers and presentation of recombinant dystrophin antigens in the context of a Duchenne muscular dystrophy patient.
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PMID:Immune response to full-length dystrophin delivered to Dmd muscle by a high-capacity adenoviral vector. 1223 Nov 72

Duchenne muscular dystrophy (DMD) is a lethal, X-linked, recessive disease caused by a defect in the dystrophin gene. No effective therapy is available. Dystrophin gene transfer to skeletal muscle has been proposed as a treatment for DMD. However, successful treatment for DMD requires restoration of dystrophin in the affected muscle fibers to at least 20% of the normal level. Current gene transfer methods such as intramuscular injection of viral vector or naked DNA can only transfect a small area of muscle, and therefore is of little clinical utility. We have developed a semisystemic method for gene transfer into skeletal muscle of mdx mice, an animal model for DMD. Naked DNA was injected through the tail artery or vein of mice, in which the aorta and the vena cava were clamped at the location just below the kidneys. The DNA solution was thus forced into the blood vessels of both legs. Luciferase gene expression was detected in all muscle groups in both legs. The effects of injection speed, injection volume, and ischemia time on gene expression were also optimized. LacZ staining was used to check the spread of gene expression in muscle. Although the percentage of transfected fibers was modest (approximately 10%), beta-galactosidase was found in all muscle groups of both legs. Finally, plasmid DNA encoding full-length dystrophin gene was injected into mdx mice and widespread restoration of dystrophin protein was observed in all muscles of both hind limbs. In conclusion, these results demonstrate that the semisystemic delivery of naked DNA is a potential approach towards the long-term goal of gene therapy for DMD.
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PMID:Restoration of dystrophin expression in mdx mice by intravascular injection of naked DNA containing full-length dystrophin cDNA. 1498 86

In utero gene delivery could offer the advantage of treatment at an early stage for genetic disorders such as Duchenne muscular dystrophy (DMD) in which the inevitable process of muscle degeneration is already initiated at birth. Furthermore, treatment of fetal muscle with adenoviral (Ad) vectors is attractive because of a high density of Ad receptors, easy vector accessibility due to immaturity of the basal lamina and the possibility of treating stem cells. Previously, we demonstrated the efficient transduction of fetal muscle by high-capacity Ad (HC-Ad) vectors. In this study, we compared HC-Ad and first-generation Ad (FG-Ad) vectors for longevity of lacZ transgene expression, toxicity and induction of immunity after direct vector-mediated in utero gene delivery to fetal C57BL/6 mice muscle 16 days after conception (E-16). The total amount of beta-galactosidase (betagal) expressed from the HC-Ad vector remained stable for the 5 months of the study, although the concentration of betagal decreased due to muscle growth. Higher survival rates that reflect lower levels of toxicity were observed in those mice transduced with an HC-Ad vector as compared to an FG-Ad vector. The toxicity induced by FG-Ad vector gene delivery was dependent on mouse strain and vector dose. Animals treated with either HC-Ad and FG-Ad vectors developed non-neutralizing antibodies against Ad capsid and antibodies against betagal, but these antibodies did not cause loss of vector genomes from transduced muscle. In a mouse model of DMD, dystrophin gene transfer to muscle in utero using an HC-Ad vector restored the dystrophin-associated glycoproteins. Our results demonstrate that long-term transgene expression can be achieved by HC-Ad vector-mediated gene delivery to fetal muscle, although strategies of vector integration may need to be considered to accommodate muscle growth.
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PMID:Comparison of high-capacity and first-generation adenoviral vector gene delivery to murine muscle in utero. 1548 68


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