Mutant mammalian RPE65 proteins and portions thereof, and nucleic acids encoding the mutants, for use in treating a condition related to retinal degeneration in a subject, the mutant mammalian RPE65 proteins or portions thereof having isomerohydrolase activity. A gene therapy method of treating a condition related to retinal degeneration in a mammalian subject in need of such treatment, comprising administering to the subject a therapeutically- effective amount of a vector comprising a nucleic acid encoding a mutant mammalian RPE65 protein or a portion thereof. A method of treating a condition related to retinal degeneration in a subject in need of such treatment, comprising administering to the subject a therapeutically-effective amount of at least one of a mutant mammalian RPE65 protein or a portion thereof.