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Senior Investigator

Medical Genomics and Metabolic Genetics Branch


Organic Acid Research Section


B.S. Massachusetts Institute of Technology, 1988

M.D., Ph.D. Pennsylvania State University, 1996


Dr. Charles P. Venditti received a S.B. from the Massachusetts Institute of Technology in 1988 and was an M.D., Ph.D. scholarship recipient at Penn State University. After graduation in 1996, he completed a pediatrics residency at Massachusetts General Hospital/Harvard Medical School (1996-1999) and a combined clinical and biochemical genetics fellowship (1999-2003) at the Children's Hospital of Philadelphia/University of Pennsylvania School of Medicine. After his fellowship, he joined NHGRI as a member of the Physician-Scientist Development Program (2003-2008) and then as a tenure track investigator in the Genetics and Molecular Biology Branch (2008-current).

He is board-certified in pediatrics, clinical genetics and biochemical genetics and is an attending physician at the Mark O. Hatfield Clinical Center at NIH, where he has initiated a translational research program to study the natural history and clinical phenotype(s) of the hereditary methylmalonic acidemias (MMA) and cobalamin metabolic disorders. The clinical research studies are paralleled by laboratory investigations that have focused on the development of experimental systems to study the genetics, genomics and biochemistry of organic acid metabolism in model organisms, including roundworms, mice and zebrafish. Using a translational research approach, Dr. Venditti and his colleagues have published a number of papers that connect disease pathophysiology in MMA to mitochondrial dysfunction and prove the efficacy of gene therapy as a treatment for both methylmalonic acidemia and propionic acidemia.

In 2009, he was the recipient of a Presidential Early Career Award for Scientists and Engineers (PECASE), the U.S. government's highest honor for early-career scientists. Other awards include selection as an Outstanding New Investigator from the American Society of Gene and Cell Therapy in 2010 and election into the American Society of Clinical Investigation (ASCI) in 2012. Dr. Venditti is a member of numerous professional organizations in the fields of inborn errors of metabolism, genetics and gene therapy and serves on the medical advisory board of the Organic Acid Association (OAA).

Scientific Summary

The research interests of the section surround the genetics, pathophysiology and treatment of the hereditary methylmalonic acidemias and disorders of intracellular cobalamin metabolism. These inherited enzymopathies belong to the organic acidemia category of metabolic disease, and represent a group of collectively common inborn errors of metabolism. Affected patients are medically fragile and suffer from multisystemic complications, including severe metabolic instability, stroke of the basal ganglia, pancreatitis, end stage renal failure, growth impairment, osteoporosis and developmental delay. Despite intensive study since the early 1960s, few patients with MMA have survived into adulthood and evidence for effectiveness of current medical therapies is lacking, a fact that stands in stark contrast to the practice of screening all U.S. newborns for MMA. Because these disorders also feature pathology that can be seen in many common conditions, such as vitamin B12 deficiency, stroke syndromes, pancreatic dysfunction, diabetes, chronic kidney disease, osteoporosis, obesity and retinal degeneration, it is likely that the careful elucidation of patient phenotypes will provide new insights into the pathophysiology of more complex and prevalent disorders, and perhaps, suggest new pathways to target for therapeutic interventions in these more common conditions.

An overview of the pathway of cobalamin uptake, transport and intracellular metabolism.

Figure 1: An overview of the pathway of cobalamin uptake, transport and intracellular metabolism.

Through our natural history protocol, "Clinical and Basic Investigations of Methylmalonic Acidemia and Related Disorders" (ClinicalTrials.gov Identifier: NCT00078078), the Venditti lab has enrolled the largest single-center patient cohort. In the past few years, they have described dental manifestations in MMA, whole-body energetics in MMA, and a new treatment approach for cobalamin C deficiency. They have delineated the neurocognitive phenotype displayed by MMA patients and described the natural history of renal growth in MMA. The team has authored a series of comprehensive reviews on the clinical phenotype and treatment of isolated MMA, cobalamin disorders, and propionic academia, as well as numerous book chapters related to the diagnosis and management of patients with branched chain amino acid oxidation disorder.

Clinical investigations conducted by the section have enabled the identification of two new inborn errors of metabolism: combined malonic-methylmalonic acidemia (CMAMMA) and cblX deficiency. These discoveries have led to the demonstration of a new metabolic pathway for organic acid metabolism in humans and defined the first example of transcriptional dysregulation as the cause of a classical inborn error of metabolism. Both examples serve to further emphasize the novel insights into intermediary metabolism that can be achieved through the study of MMA. The longer-term goals of our clinical efforts are to study the correlations between enzymatic, genotypic, clinical and metabolic variables with phenotype, disease manifestations and outcomes in MMA and cobalamin disorders; to critically evaluate current treatment practices and develop evidence-based guidelines; and to discover and characterize novel patient phenotypes.

 Figure 2: Growth and phenotypic correction after AAV8-mMut gene therapy, adapted from Chandler and Venditti (2010) Mol Ther 18: 11-16
Figure 2: Growth and phenotypic correction after AAV8-mMut gene therapy, adapted from Chandler and Venditti (2010) Mol Ther 18: 11-16. Download as PDF

Other than dietary management, no therapeutic alternative to elective liver or liver-kidney organ transplantation exists for patients with isolated MMA. We have therefore studied the efficacy of gene therapy as a treatment for MMA. After preliminary/feasibility experiments of gene correction using lenti- and adenovirus-mediated gene delivery, the section engineered a series of adeno-associated viral (AAV) vectors to express the methylmalonyl-CoA mutase (Mut) gene systemically or only in hepatocytes. The results in all the studies are striking: while the untreated Mut-/- mice uniformly perish in early life, the Mut-/- mice that receive AAV gene therapy with any of the section's AAV vectors have near normal long-term survival, are phenotypically corrected and display sustained, low-level enzymatic activity for as long as one year after a single treatment with an AAV vector. Our gene therapy experiments also inspired the invention of a device and method to quantify whole-body Mut enzyme activity after gene therapy using 13C isotopomer metabolism. The gene delivery approach and monitoring platform the team has developed should be immediately translatable to a phase I/II gene therapy trial at the NIH Clinical Center using AAV to treat mut MMA patients and could provide precedence for the application of a similar approach to many other disorders of intermediary metabolism, particularly those that feature mitochondrial localization of the metabolic lesion.

In the laboratory, researchers in the section have generated a suite of clinically-relevant mouse models to dissect disease mechanisms in MMA. Using a knock-out allele of Mut, they have established that mitochondrial dysfunction is central to the pathology of MMA and have extended these observations using ion abrasion scanning electron microscopy to characterize hepatic mitochondria in MMA on the nanometer scale in 3-D. To recapitulate the organ specific pathology experienced by patients with MMA, they created a new mouse model, Mut-/-;TgINS-Alb-Mut, to replicate the renal manifestations seen in MMA, specifically progressive kidney failure associated with impairment of proximal tubular mitochondrial function. These mice, like MMA patients who have received a liver transplant, express the Mut enzyme only in the hepatocytes. RNA profiling of genes expressed in the mutant mouse kidneys has identified novel MMA-associated renal biomarkers that we have validated in our patient cohort and used to measure the response of MMA kidney disease to antioxidant therapy. This mouse model has also been used to develop and test new therapeutics and should be useful for the wider study of related medical conditions, especially chronic kidney failure caused by tubulointerstitial disease. Future efforts to apply murine and zebrafish modeling to other disorders in the pathway, including cblC deficiency, are in progress.


Chandler RJ, Venditti CP. Genetic and genomic systems to study methylmalonic acidemia. Mol Genet Metab, 86(1-2):34-43. 2005. [PubMed]

Chandler RC, Aswani V, Tsai M, Falk M, Wehrli N, Stabler S, Allen R, Sedensky M, Kazazian HH, Venditti CP. Propionyl-CoA and Adenosylcobalamin Metabolism in C elegans: Evidence for a Role of Methylmalonyl-CoA Epimerase in Intermediary Metabolism. Mol Genet Metab, 89(1-2) 64-73. 2006. [PubMed]

Chandler RJ, Sloan J, Fu H, Tsai M, Stabler S, Allen R, Kaestner KH, Kazazian HH, Venditti CP. Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle. BMC Med Genet, 8:64. 2007. [PubMed]

Chandler RJ, Zerfas PM, Shanske S, Sloan J, Hoffmann V, DiMauro S, Venditti CP. Mitochondrial dysfunction in mut methylmalonic acidemia. FASEB J, 23(4):1252-61. 2009. [PubMed]

Bassim CW, Wright JT, Guadagnini JP, Muralidharan R, Sloan J, Domingo DL, Venditti CP, Hart TC. Enamel defects and salivary methylmalonate in methylmalonic acidemia. Oral Dis, 15(3):196-205. 2009. [PubMed]

Carrillo-Carrasco N, Sloan J, Valle D, Hamosh A and Venditti CP. Hydroxycobalamin dose escalation improves metabolic control in cblC. J Inherit Metab Dis, 32:728-731. 2009. [PubMed]

Chandler RJ, Venditti CP. Long-term rescue of a lethal murine model of methylmalonic acidemia using adeno-associated viral gene therapy. Mol Ther, 18(1):11-6. 2010. [PubMed]

Murphy GE, Lowekamp BC, Zerfas PM, Chandler RJ, Narasimha R, Venditti CP, Subramaniam S. Ion abrasion scanning electron microscopy reveals distorted liver mitochondrial morphology in murine methylmalonic acidemia. J Struct Biol, 171(2):125-132. [PubMed]

Carrillo-Carrasco N, Chandler RJ, Chandrasekaran S, Venditti CP. Liver-directed rAAV gene delivery rescues a lethal mouse model of methylmalonic acidemia and provides long-term phenotypic correction. Hum Gene Ther, 21:1147-1154, 2010. [PubMed]

Chandler RJ, Chandrasekaran S, Carrillo-Carrasco N, Senac JS, Hoferr SE, Barry MA, and Venditti CP. Adeno-associated virus serotype 8 (AAV8) Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia. Hum Gene Ther, 22(4):477-81. 2011. [PubMed]

Hauser NS, Manoli, I, Graf JC, Sloan J, and Venditti CP. Variable dietary management of methylmalonic acidemia: metabolic and energetic correlations. Am J Clin Nutr, 93(1):47-56. 2011 [PubMed]

Sloan JL, Johnston JJ, Manoli I, Chandler RJ, Krause K, Carrillo-Carrasco N, Chandrasekaran SD, Sysol JR, O'Brien K, Hauser NS, Sapp JC, Dorward HM, Huizing M, NISC, Barshop BA, Berry SA, James PM, Champaigne NL, de Lonlay P, Valayannopoulos V, Geschwind MD, Gavrilov DK, Nyhan WL, Biesecker LG, and Venditti CP. Exome sequencing identifies ACSF3 as the cause of Combined Malonic and Methylmalonic Aciduria. Nat Genet, 43(9):883-6. [PubMed]

Sénac JS, Chandler RJ, Sysol JR, Li L, and Venditti CP. Gene therapy in a murine model of Methylmalonic Acidemia (MMA) using rAAV9 mediated gene delivery. Gene Ther, 19(4):385-91. 2012. [PubMed]

Carrillo-Carrasco N, Chandler RJ, and Venditti CP. Combined methylmalonic acidemia and homocystinuria, cblC type I Clinical presentations, diagnosis and management. J Inherit Metab Dis, 35(1):91-102. 2012. [PubMed]

Carrillo-Carrasco N and Venditti CP. Combined methylmalonic acidemia and homocystinuria, cblC type II Complications, pathophysiology and outcomes. J Inherit Metab Dis, 35(1):103-14. 2012. [PubMed]

O'Shea CJ, Sloan JL, Wiggs EA, Pao M, Gropman A, Baker EH, Manoli I, Venditti CP, and Snow J. Neurocognitive Phenotype of Isolated Methylmalonic Acidemia (MMA). Pediatrics, 29(6):e1541-51. 2012. [PubMed]

Kruszka PS, Manoli I, Sloan JL, Kopp JB, and Venditti CP. Renal growth in isolated methylmalonic acidemia. Genet Med, 15(12):990-6. 2013. [PubMed]

Manoli I, Sysol J, Li L, Houillier P, Wang C, Zerfas P, Cusmano-Ozog K, Young S, Trivedi NS, Cheng J, Sloan JL, Chandler RJ, Abu-Asab M, Tsokos M, Elkahlooun AG, Rosen S, Enns GM, Berry GT, Hoffman V, DiMauro S, Schnermann J, and Venditti CP. Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia. Proc Natl Acad Sci USA, 110(33):13552-7. 2013. [PubMed]

Yu HC, Sloan JL, Scharer G, Brebner A, Quintana,A, Achilly NP, Manoli I, Coughlin CRII, Geiger EA, Schneck U, Watkins D, VanHove JL, Fowler B, Baumgartner MR, Rosenblatt DS, Venditti CP, and Shaikh TH. An X-linked cobalamin disorder caused by mutations in transcriptional coregulator HCFC1. Am J Hum Gen, 93(3):506-514. 2013. [PubMed]

Venditti CP. Methylmalonic acidemia. In: GeneReviews at GeneTests, Unversity of Washington, Seattle: Medical Genetics Information Resource, 2005. [Full Text]

Adams D, Venditti CP. Disorders of intracellular cobalamin metabolism. In: GeneReviews at GeneTests, Unversity of Washington, Seattle: Medical Genetics Information Resource, 2008. [Full Text]

Organic Acid Research Section Staff

Randy Chandler
Randy Chandler, Ph.D.
  • Staff Scientist
  • Organic Acid Research Section
Susan C. Ferry
Susan C. Ferry
  • Research Nurse Specialist
  • Organic Acid Research Section
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Lina Li
  • Research Scientist
  • Organic Acid Research Section
Irini Manoli
Irini Manoli, M.D.
  • Staff Clinician
  • Organic Acid Research Section
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Kelsey C. Murphy
  • Organic Acid Research Section
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Alexandra R. Pass
  • Postbaccalaureate IRTA
  • Organic Acid Research Section
Jessica L. Schneller
Jessica L. Schneller
  • Predoctoral IRTA Fellow
  • Organic Acid Research Section
Oleg A. Shchelochkov
Oleg A. Shchelochkov
  • Staff Clinician
  • Organic Acid Research Section
Jennifer L Sloan
Jennifer L. Sloan
  • Protocol Coordinator and Genetic Counselor
  • Organic Acid Research Section
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Stephanie N. Smith
  • Biologist
  • Organic Acid Research Section

Last updated: March 14, 2017