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Charles Venditti: To Treat a Metabolic Disorder

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Title: Head, Organic Acid Research Section, National Human Genome Research Institute
Education: PhD, Pennsylvania State University, 1996
Recommended by: Eric Green, National Human Genome Research Institute

When he was a fellow at the Children's Hospital of Philadelphia, Charles Venditti helped diagnose and treat infants and children with hereditary metabolic diseases. Some of these conditions, like methylmalonic acidemia, lacked efficacious therapies. "That the patients needed better therapies, the disease mechanisms were poorly defined, and the prognosis for the affected was poor ... made me acutely aware of the need for scientific and clinical research to improve the outcomes," he says.

Now, Venditti and his team at NHGRI study metabolic disorders that cause increased accumulation of methylmalonic acid and homocysteine in body fluids, with the hope of better defining the natural history of the conditions and their biological bases. "We use stable isotopes and metabolic tracers to monitor in vivo metabolism by mass spectrometry and magnetic resonance spectroscopy," Venditti says. "By examining a mouse model of vitamin B12-non-responsive MMA that displays neonatal lethality, we have determined that mitochondrial dysfunction is a cardinal feature of the disorder and may underlie the tissue-specific manifestations seen in patients."

Venditti and others at NHGRI plan to use whole-exome and whole-genome approaches to identify novel disease-associated genes.

If he could imagine one thing to simplify his research, it would be "a widely accepted, inexpensive, and orally bioactive gene delivery agent that could offer tailored tissue trophism," as it would be useful for the treatment of numerous genetic conditions. "I think something like that would be as close to a magic bullet as possible," he adds.

Looking ahead

A major challenge that Venditti faces is finding easy-to-use bioinformatic platforms for analyzing large data sets such as those that arise from exome and whole-genome analysis. Looking forward, Venditti says, high-throughput screening will quickly be incorporated into medical practice, perhaps even as part of screening newborns for many more disorders in a second-tier diagnostic and confirmatory fashion.

Papers of note

In October, Venditti and his group published a paper in Human Gene Therapy demonstrating a murine model of the metabolic disorder propionic acidemia, which they used to determine the efficacy of adeno-associated viral gene transfer as a potential therapy. In it, the team suggests that a gene transfer approach using AAV8 might serve as a treatment for acidemia.

And the Nobel goes to ...

If he were to win the Nobel Prize, Venditti says he'd like it to be for making discoveries that lead to improved therapies for patients with methylmalonic acidemia and of organic acid metabolic disorders.

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