 Hi, my name's Madeleine Arnold, I work in the Venditti Lab at NHGRI. Vitamins are important for maintaining our health. Whether it's vitamin A, vitamin C, or vitamin E, these are essential nutrients that we have to obtain through our diet since our bodies can't synthesize them. I study vitamin B12, also known as cabalamin. Vegetarians or vegans might be familiar with B12, since they are at a higher risk for being deficient. That's because we obtain vitamin B12 through meat and animal products in our diet. I study a specific form of vitamin B12 deficiency called cabalamin deficiency type C, or CBLC for short. It's a genetic disorder caused by mutations in the MMA-CHC gene. Patients with CBLC develop symptoms early in life, including developmental delay, cognitive impairment, anemia, and a progressive retinal degeneration that often results in blindness. There are treatments for patients with CBLC, including vitamin B12 injections. However, the current treatments fail to resolve many of the complications of the disorder. Therefore, my lab is working to develop new therapies for CBLC, including gene therapy using adeno-associated viral vectors. The first step in testing whether a new therapy could be successful is to develop an animal model of a disease. I've created a mouse model of CBLC using the genome-editing technique talons. As you can see in the photograph on the top right of the slide, mice with this mutation in a homozygous state are much smaller than their heterozygous littermates, and they have a severe clinical phenotype. I measured the survival of these mice over time and found that they perished by 30 days of life, as you can see in the gray line on the survival graph. The next step was to test whether vitamin B12 injections, the current treatment that patients receive, could correct the phenotype in the mice and improve their survival. I tested whether weekly injections of vitamin B12 would improve survival, and you can see that it did based on the red line in the survival graph. We can use this survival curve as a benchmark to test the success of new therapies. I created two adeno-associated viral vectors, one with the mouse MMA-CHC gene, and one with a human codon-optimized MMA-CHC gene. I injected mice with one of these two vectors in the neonatal period right after they're born. Then I measured their survival and compared it to that of vitamin B12 injections, and you can see based on the green and blue lines in the graph that this survival was greatly improved similar to vitamin B12. This is a promising result indicating that AAV could be a new therapy for CBLC, and we hope to use this mouse model to test other new therapies as well. Thank you.