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The Journal of Neuroscience, May 15, 2003, 23(10):4164-4172

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Increased Expression of Brain-Derived Neurotrophic Factor Preserves Retinal Function and Slows Cell Death from Rhodopsin Mutation or Oxidative Damage

Godwin Okoye,¹ Joelle Zimmer,¹ Jennifer Sung,¹ Peter Gehlbach,¹ Tye Deering,¹ Hiroyuki Nambu,¹ Sean Hackett,¹ Michele Melia,¹ Noriko Esumi,¹ Donald J. Zack,^1,2 and Peter A. Campochiaro¹

Departments of ¹Ophthalmology and Neuroscience and ²Departments of Molecular Biology and Genetics, and Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287-9277

There are no effective treatments for inherited retinal degenerations, which are prevalent causes of visual disability. Several proteins promote the survival of various types of neurons, and increasing expression of one or more of these survival factors is a promising strategy for a new treatment. Studies examining the effects of intravitreous injections of brain-derived neurotrophic factor (BDNF) in models of inherited retinal degenerations have suggested that BDNF has little survival-promoting activity for photoreceptors. In this study, we generated double transgenic mice with doxycycline-inducible expression of BDNF in the retina. In a model of primary rod photoreceptor degeneration, expression of BDNF resulted in significant delay in photoreceptor cell death and maintenance of retinal function assessed by electroretinogram recordings. Expression of BDNF also caused strong protection of photoreceptors from oxidative damage-induced cell death. These data suggest that continuous expression of BDNF, unlike intravitreous injections, results in morphologic and functional benefit in animal models of inherited retinal degeneration. Double transgenic mice with inducible expression of survival factors provide valuable tools for selection of survival factor candidates for gene therapy.

Key words: BDNF; gene transfer; inducible transgenics; neurotrophic factors; oxidative damage; retinal degenerations

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Received Dec. 11, 2002; revised Mar. 3, 2003; accepted Mar. 4, 2003.

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