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Out with the Bad, in with the Good
Therapy silences disease gene, adds healthy one

Context: The usual goal of gene therapy is to supply missing instructions for creating a protein. A newer kind of gene therapy instead short-circuits problematic instructions. Supplying the missing protein has shown both promise and problems: it cured children of severe combined immunodeficiency, a rare genetic disease, but has also led to fatal leukemia and toxicity. The second approach improved symptoms in mice suffering from a disease similar to Huntington’s but is not yet ready to try in humans. If it proves safe, a more versatile option may be to combine both approaches, suppressing a problematic protein while creating a therapeutic one. That’s what Patrick Aebischer’s team at the Ecole Polytechnique Federale de Lausanne in Switzerland has done for a mouse with the rodent version of Lou Gehrig’s disease.

Methods and Results: Amyotrophic lateral sclerosis, or Lou Gehrig’s disease, kills muscle-controlling neurons; patients eventually become paralyzed and die. In some cases, mutations in a gene called SOD1 are responsible. Mice engineered with a mutant version of human SOD1 have trouble walking, breathing, and grooming themselves and eventually die. To silence this problem-causing gene, Aebischer’s team used a technique called RNA interference (RNAi). In RNAi, short strands of RNA match up with a gene’s messenger RNA, destroying it before it can take part in protein assembly. The researchers inserted instructions for RNA targeting SOD1 into a genetically modified virus. Then they injected the virus into mice. RNAi suppressed the mutant human SOD1 gene but ignored normal mouse SOD1. Though the treated mice still got sick and died, they remained healthy longer. However, in humans, RNAi would likely silence not just the mutant version of the SOD1 gene but also the healthy version. So Aebischer’s team genetically engineered a virus to deliver both instructions for RNAi and a gene for human SOD1 designed so that it would not be shut down by RNAi. Though the new virus has so far been tested only in cells, it is the first demonstration of a promising new technique.

Why it Matters: Aebischer’s technique could overcome a nagging limitation of RNAi. Particularly for diseases like Lou Gehrig’s, which can be caused by many different mutations in a particular gene, RNAi cannot be engineered to attack the disease-causing form of a gene without attacking its normal counterpart. By designing genes unaffected by RNAi and delivering them alongside instructions to silence the existing gene, Aebischer’s team has found a general way to use the technique against diseases in which the nontargeted gene must remain functional.

Source: Raoul, C., et al. 2005. Lentiviral-mediated silencing of SOD1 through RNA interference retards disease onset and progression in a mouse model of ALS. Nature Medicine (published online).

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Tagged: Biomedicine

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