Methylmalonic Acidemia (MMA) is a metabolic disorder affecting 1 in 25,000 to 48,000 individuals globally. MMA is characterized by increased acidity in the blood and tissues due to toxic accumulation of protein and fat by-products resulting in seizures, strokes, and chronic kidney failure. About 60% of MMA cases stem from mutations in the methylmalonyl CoA mutase (MUT) gene encoding a key enzyme required to break down amino acids and lipids. Previous efforts to develop mice with null mutations in MUT have been unsuccessful, as such mutations result in neonatal death.

One of four deaths in the United States is due to cancer despite an emphasis on prevention, early detection, and treatment that has lowered cancer death rates by 20% in the past two decades. Further improvements in survival rates are likely to come from improving the limits of detection sensitivity at earlier stages of cancer. New approaches that rely heavily on genomic information, however, may change future testing strategies.

Investigators at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) are seeking collaborators to further develop gene therapy to treat Niemann-Pick Disease Type C (NPC). NPC is a rare, autosomal recessive, neurodegenerative disease. Approximately 95% of patients with NPC have mutations in NPC1, a gene implicated in intracellular cholesterol trafficking. Mutations of NPC1 cause intracellular accumulation of unesterified cholesterol in late endosomal/lysosomal structures and marked accumulation of glycosphingolipids, especially in neuronal tissue.

Methylmalonic Acidemia (MMA) is a metabolic disorder characterized by increased acidity in the blood and tissues due to toxic accumulation of protein and fat by-products resulting in seizures, strokes, and chronic kidney failure. A significant portion of MMA cases stem from a deficiency in a key mitochondrial enzyme, methylmalonyl-CoA mutase (MUT), required to break down amino acids and lipids. Currently, there are no treatments for MMA and the disease is managed primarily with dietary restriction of amino acid precursors and liver-kidney transplantation in severe cases.

Niemann Pick Disease Type C (NPC) is a rare and fatal, autosomal recessive, neurodegenerative disease that can present in infants, children, or adults. Most patients with NPC have mutations in NPC1, a gene implicated in intracellular cholesterol trafficking, which results in intracellular accumulation of unesterified cholesterol in late edosomal/lysosomal structures and of glycosphingolipids, especially in neuronal tissue. No curative therapy exists at present.

Niemann-Pick Disease, type C (NPC) is a rare, autosomal recessive, neurodegenerative disease. Approximately 95% of patients with NPC have mutations in NPC1, a gene implicated in intracellular cholesterol trafficking. Mutation of NPC1 causes intracellular accumulation of unesterified cholesterol in late endosomal/lysosomal structures and marked accumulation of glycosphingolipids, especially in neuronal tissue. Thus, NPC patients generally present with hepatosplenomegaly (enlargement of liver and spleen) and neurological degeneration.

Double-stranded RNA (dsRNA) has been shown to trigger sequence-specific gene silencing in a wide variety of organisms, including plant, nematode and invertebrate species. Recent intense work in the field has shown that small dsRNAs mediate sequence specific RNA degradation in the process known as RNA interference (RNAi).

This invention provides for synthetic dsRNAs (20-25 nucleotides in length) and methods that can inhibit gene-specific expression in mammalian cells.

Isolated Methylmalonic Acidemia (MMA) comprises a relatively common and heterogeneous group of inborn errors of metabolism. Most affected individuals display severe multisystemic disease characterized by metabolic instability, chronic renal disease, and neurological complications. Patients with the cobalamin A (cblA) subtype of MMA can have variable presentations, spanning the full spectrum of MMA associated symptoms and pathology, yet always harbor an element of clinical and biochemical responsiveness to injectable vitamin B12.

Isolated Methylmalonic Acidemia (MMA) and the related disorder Propionic Acidemia (PA) comprise a relatively common and heterogeneous group of inborn errors of metabolism. NHGRI scientist discovered that in isolated MMA, a novel inhibitory PTM, methylmalonyllysine, is generated and inactivates protein targets through the failure of SIRT-mediated deacylation, and identified a series of antibodies for PTM specificity.