CblC Deficiency is a very rare disease (less than 100 individuals in the US) and as such, it is considered an “Orphan Disease”— a disorder that afflicts fewer than 200,000 individuals. Despite more than 7000 distinct rare or “orphan” diseases, which may in aggregate affect over 25 million people in the US, research in most disease types has lagged far behind other major areas due to a combination of technological and funding limitations. That is why Michael’s Fund is committed to promoting research, developing treatments, and providing support for patients diagnosed with rare inherited disorders of cobalamin (vitamin B12) metabolism.
All donations to Michael’s Fund are used to support highly trained personnel for CblC-specific research in the laboratory of Dr. Charles Venditti.With support from Michael’s Fund, Dr. Venditti has been able to expand his team and bring about groundbreaking advances in the understanding of CblC Deficiency.
Our Current Goal:Raise $100,000 by April 1st, 2015 to fund the salary of a research fellow for two years of dedicated CblC exploration within Dr. Venditti’s lab
Dr. Charles Venditti
Head of Organic Acid Research National Human Genome Research Institute at the NIH
Dr. Venditti studies a group of inherited metabolic disorders that cause increased methylmalonic acid and homocysteine to accumulate in body fluids. The conditions are generally caused by impaired intracellular metabolism of vitamin B12 or by defects in two enzymes — methylmalonyl-CoA mutase (MUT) and methionine synthase — that require the vitamin to function. Dr. Venditti and his colleagues conduct clinical research aimed at defining the natural history of these conditions, as well as laboratory studies that use metabolic, genetic and genomic approaches to better-understand the basic biology underlying these disorders. Isolated methylmalonic acidemia (MMA) is one of the most common inborn errors of organic acid metabolism. The American College of Medical Genetics recommends newborn screening for MMA. With diverse clinical manifestations, affected patients are medically fragile and suffer from multisystem complications ranging from developmental delay to metabolic stroke to end-stage renal failure. The frequency of these complications and their precipitants remains undefined. Aberrant intracellular metabolism of vitamin B12 produces another group of conditions that feature both increased MMA and/or hyperhomocysteinemia; these disorders are named after their corresponding cellular complementation class — either cobalamin C, D, E, F, or G — and are also clinically and biochemically heterogeneous.
Dr. Venditti conducts clinical research in pursuit of a comprehensive understanding of the natural history of these disorders while developing new insights into their pathophysiology. Future efforts will involve studying patients using stable isotopes and metabolic tracers to monitor in vivo metabolism by mass spectrometry and magnetic resonance spectroscopy.
In the laboratory, Dr. Venditti uses model organisms to study MMA pathophysiology. By examining a mouse model of vitamin B12-non-responsive MMA that displays neonatal lethality, his group has determined that mitochondrial dysfunction is a cardinal feature of the disorder and may underlie the tissue-specific manifestations seen in patients. In addition, Dr. Venditti has found that a large source of methylmalonic acid derives from skeletal muscle, which may explain the clinical observation of persistent MMA in patients after solid organ (liver or liver-kidney) transplantation. Dr. Venditti's group plans to use transgenic knockout and Mut-partial-deficiency mouse models to examine organ-specific contributions to methylmalonic acid metabolism and to further explore disease mechanisms.
Mouse models of MMA have also provided a platform for testing gene and cell therapies. Dr. Venditti's laboratory produced and validated lentiviral, adenoviral, and adeno-associated viral vectors for delivering the Mut gene to the liver and skeletal muscle in mice. They have also recently found evidence for viral correction in enzyme-deficient human liver cells and in Mut-knockout mice. Furthermore, gene-delivery studies using adeno-associated virus serotype 8 vectors have been successful in mice, and have encouraged the pursuit of similar approaches in patients. Dr. Venditti plans to undertake cell therapy experiments in future studies.
Another focus of Dr. Venditti's laboratory involves the study of cobalamin metabolism. In collaboration with the NHGRI Zebrafish Core and as an extension of previous efforts using C. elegans to study MMA and cobalamin disorders, Dr. Venditti and his colleagues have developed a zebrafish model of cobalamin C deficiency. The cobalamin C (cblC) disorder, a form of combined MMA and hyperhomocysteinemia, is thought to be the most common inborn error of intracellular cobalamin metabolism. While its clinical manifestations are diverse — ranging from intrauterine effects, such as congenital microcephaly, to cognitive deterioration in adulthood — the underlying explanation for the pathophysiology in patients is unknown. One particularly devastating disease-related complication is progressive retinal degeneration leading to medical blindness. This occurs in only some patients affected with cblC. Dr. Venditti plans to use the cblC zebrafish model for genomic and proteomic studies in an effort to shed light on this human disorder.
Click on the following link to see the most recent Official Press release by Dr. Venditti's Team-- NIH Researchers Tackle Thorny Side of Gene Therapy: http://www.genome.gov/27560180