For a long time, a treatment for dominant genetic disorders has appeared remote. Now in a recent issue of Nature Medicine, two groups reported evidence of success in an animal model for one such disorder, amyotrophic lateral sclerosis (ALS) using RNA interference (RNAi), 1, 2 raising the hope that RNAi therapy for diseases caused by dominant, gain-of-function mutations may be available in the not-too-distant future. People with dominantly inherited diseases carry one normal allele and one mutant allele of the gene that causes the disease. The mutant allele could cause the disease by loss of function, that is, this allele has lost its function and the normal allele is insufficient to compensate for the lost function. The mutated gene could also cause the disease by gain of function, which could be a novel function or enhancement of an existing function. In principle, the delivery of a normal copy of the gene to the patient’s body can treat loss-offunction mutations. However, a conceptual solution to gain-of-function diseases is less obvious. ALS (also known as Lou Gehrig’s disease), which is characterized by motor neuron degeneration, paralysis and death, is one such disease that can be caused by gain-of-function mutations. Specifically, mutations in SOD1 cause a subset of

ALS cases. The mutated gene produces a protein with an undefined toxic property that kills motor neurons. 3 Because the pathway through which the mutant protein kills motor neurons is incompletely understood, rational design of therapy has been difficult. No cure is known. However, recent breakthroughs in RNAi have provided a conceptual basis for developing a new therapy for this disease.