 My name is Charles Venditti. I'm an investigator in the National Human Genome Research Institute here in the Intramural Research Program at the National Institutes of Health in Bethesda, Maryland. And I'm here with my colleague and collaborator Dr. Randy Chandler to discuss our recent developments in gene therapy for methylmalonic acidemia. This is a very grave metabolic disorder that mainly affects infants and children. And unfortunately, despite all conventional dietary and cofactor therapy, is lethal in many children. We're using adeno-associated virus to basically deliver the gene that's defective in methylmalonic acidemia. And the virus is just like a car that delivers a passenger, which is the correct gene sequence for the genetic defect. Our early studies, preclinical studies in our mouse model of methylmalic acidemia, which is an early lethal model of the disease. The mice die within the first 24 to 48 hours of life. Those experiments were quite successful. The mice survived after the treatment with the adeno-associated virus until adulthood. Unfortunately, we began to observe an increase in liver cancers in the mice treated with the AAV at levels that we hadn't observed in our control group of untreated mice. The mice fell up cancer at a rate of between 75 and 50 percent compared to the control mice, where only 3 out of 51 of the mice developed cancer. And notice that in the liver cancers, one locus, the rion locus, was overrepresented in the cancers versus the control tissue. The high early expression of this gene is a contributing factor for the AAV vector integrating into this locus and causing cancer in the mice. Most of the AAV integrations that caused liver cancer landed in a gene that is not found in the human genome. Some people would wonder whether or not the cancers we observed after AAV gene therapy were therefore a mouse specific phenomenon. So we designed a new vector using a different promoter enhancer system. And what we observed in a small number of mice is integrations in the same locus that we observed before without the occurrence of the liver cancer. So what we suspect may be happening here is that the new vector we have developed is not activating nearby genes in proximity to the integration, and therefore it's a safer vector. But since we've only studied this in 10 mice, we'll have to perform more studies before we can be sure that this is indeed a safer vector. What I think is important about our study is, you know, we've identified a risk in the mice, which may or may not be present in the humans, but it's an important risk to understand and to disclose to patients. There's been a great controversy in the field of AAV gene therapy about whether or not AAV could ever be associated with cancer. And our results clearly prove that it in fact can be. We feel that these studies will help us move forward to develop safer gene therapy for methylmalonic acidemia because we have defined a very important safety parameter related to the AAV gene therapy in our mouse models, which is critical to understand before we move to human patient trials.