Antioxidant gene therapy can protect hearing and hair cells from ototoxicity.
ABSTRACT Aminoglycosides are commonly used antibiotics that often induce ototoxicity leading to permanent hair cell loss and hearing impairment. The ototoxic effects of aminoglycosides have been linked to oxidative stress. To determine the feasibility of antioxidant gene therapy for protecting the inner ear against aminoglycoside-induced oxidative stress, we used adenoviral vectors for overexpression of catalase, Cu/Zn superoxide dismutase (SOD1), and Mn superoxide dismutase (SOD2). We inoculated adenoviruses designated Ad.cat, Ad.SOD1, and Ad.SOD2 into the left guinea pig cochlea. Five days later, an ototoxic combination of kanamycin and ethacrynic acid was systemically administered. Artificial perilymph and adenovirus without a gene cassette (Ad.null) were used as controls. Biochemical analysis showed significant increase in catalase and a moderate elevation in SOD2 levels in tissues of the cochlea inoculated with the respective vectors. Auditory brain-stem responses were measured to monitor hearing thresholds. Animals were sacrificed 7 days after the ototoxic insult and their hair cells counted. Hair cells and hearing thresholds were significantly protected by Ad.cat and Ad.SOD2, while results with Ad.SOD1 were inconsistent. Control ears showed no significant protective effects. The results demonstrate that the expression of functional enzymes in the inner ear is feasible using adenoviral-mediated gene delivery. Furthermore, they confirm that reactive oxygen species contribute to aminoglycoside ototoxicity and suggest antioxidant gene therapy as a potential therapeutic strategy to reduce inner ear oxidative stress.
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ABSTRACT: This paper will focus on understanding the role and action of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in the molecular and biochemical pathways responsible for the regulation of the survival of hair cells and spiral ganglion neurons in the auditory portion of the inner ear. The pivotal role of ROS/RNS in ototoxicity makes them potentially valuable candidates for effective otoprotective strategies. In this review, we describe the major characteristics of ROS/RNS and the different oxidative processes observed during ototoxic cascades. At each step, we discuss their potential as therapeutic targets because an increasing number of compounds that modulate ROS/RNS processing or targets are being identified.Current Medicinal Chemistry 01/2010; 17(30):3591-604. · 4.86 Impact Factor
Article: The designer aminoglycoside NB84 significantly reduces glycosaminoglycan accumulation associated with MPS I-H in the Idua-W392X mouse.[show abstract] [hide abstract]
ABSTRACT: Suppression therapy utilizes compounds that suppress translation termination at in-frame premature termination codons (PTCs) to restore full-length, functional protein. This approach may provide a treatment for diseases caused by nonsense mutations such as mucopolysaccharidosis type I-Hurler (MPS I-H). MPS I-H is a lysosomal storage disease caused by severe α-L-iduronidase deficiency and subsequent lysosomal glycosaminoglycan (GAG) accumulation. MPS I-H represents a good target for suppression therapy because the majority of MPS I-H patients carry nonsense mutations, and restoration of even a small amount of functional α-L-iduronidase may attenuate the MPS I-H phenotype. In this study, we investigated the efficiency of suppression therapy agents to suppress the Idua-W392X nonsense mutation in an MPS I-H mouse model. The drugs tested included the conventional aminoglycosides gentamicin, G418, amikacin, and paromomycin. In addition, the designer aminoglycosides NB54 and NB84, two compounds previously designed to mediate efficient PTC suppression with reduced toxicity, were also examined. Overall, NB84 suppressed the Idua-W392X nonsense mutation much more efficiently than any of the other compounds tested. NB84 treatment restored enough functional α-L-iduronidase activity to partially reverse abnormal GAG accumulation and lysosomal abundance in mouse embryonic fibroblasts derived from the Idua-W392X mouse. Finally, in vivo administration of NB84 to Idua-W392X mice significantly reduced urine GAG excretion and tissue GAG storage. Together, these results suggest that NB84-mediated suppression therapy has the potential to attenuate the MPS I-H disease phenotype.Molecular Genetics and Metabolism 10/2011; 105(1):116-25. · 3.19 Impact Factor