Research Summary: Dr. Charles Venditti's research at ASGCT 2026
Dr. Charles Venditti is a Senior Investigator and Head of the Organic Acid Research Section at the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health. A physician-scientist with extensive experience in rare metabolic disease, Dr. Venditti has focused his career on the development of gene and RNA therapies for methylmalonic acidemia (MMA) and propionic acidemia (PA).
What distinguishes Dr. Venditti’s approach is his commitment to grounding laboratory research in real patient data. Drawing on natural history studies, long-term observations of how MMA and PA progress in actual patients, his team uses that clinical insight to build and refine mouse models that more accurately reflect the human disease. This patient-data-driven methodology means that when new gene therapies and RNA-based treatments are tested in the lab, they are evaluated against a biological backdrop shaped by the lived experience of the OA community itself.
The result is a research program that keeps patients at its center, from the first experimental model to the clinic. OAA has awarded Dr. Venditti a $50,000 research grant to support development of a circular RNA treatment for MMA and PA.
Recently Dr. Venditti and his team members presented their research at the 2026 American Society for Gene and Cell Therapy (ASGCT) Conference. Below is a brief explanation of their work summarized from the conference abstracts:
- Development of a circular RNA-LNP platform for the treatment of Organic Acidemias
- Translational Journey of an AAV Gene Therapy Product for PCCA-Related Propionic Acidemia, First Candidate in the Platform Vector Gene Therapy PaVe-GT
- Preclinical Development and proof-of-concept studies supporting a first in human AAV9-hPCCB gene therapy trial for Propionic Acidemia caused by PCCB Deficiency
- Preclinical Development of scAAV9-MMAB Gene Therapy for Cobalamin B-Type Methylmalonic Acidemia
Development of a circular RNA-LNP Platform for the Treatment of Organic Acidemias
Justine Wagaman, Pamelasara Head, Eun-Young Choi, Jennifer L. Sloan, Charles P. Venditti
So far, preclinical and clinical studies of mRNA therapies for MMA caused by MMUT variants have shown promising results, however, limitations exist. First, mRNA therapeutics do not have a long half-life. This means that the body breaks down the mRNA quickly, meaning patients may need more frequent infusions to make the treatment effective. Since mRNA therapies are often given through intravenous (IV) injections, treatment can cost a lot of money and time spent going to a clinic.
The relatively short half-life of mRNA therapeutics is because mRNA is a single, linear strand of nucleotides. The beginning and end of the RNA strand have chemical groups that are “free” and open to reacting with other nearby molecules and proteins. Enzymes naturally use these free ends to break down the mRNA. To increase the half-life of RNA therapies, some researchers are looking at circular RNA, or circRNAs. The beginning and end of these circular nucleotide strands are connected to each other, making it much more difficult for enzymes to break them down.
Dr. Venditti’s group has designed and begun testing circRNA for the treatment of MMA and cobalamin disorders caused by variants in MMUT, MMAB, and MMACHC. Studies in cells that carry variants in those three genes show that a lower dose of circRNA than mRNA is needed for cells to produce functional protein. Additionally, circRNA treatment makes cells produce functional protein for 7 days as compared to the 5 days for mRNA treatment. Studies in mouse models show that circRNA treatment leads to protein expression and changes in biomarker levels that are closer to mice without any variants. Together, these experiments provide evidence that circRNA may successfully treat MMA and cobalamin disorders at lower doses and with less frequent treatments than with more traditional mRNA therapeutics.
Translational Journey of an AAV Gene Therapy Product for PCCA-Related Propionic Acidemia, First Candidate in the Platform Vector Gene Therapy PaVe-GT
Rodica Stan, Richa M. Lomash, Venkata Mangalampalli, Randy J. Chandler, Eun-Young Choi, Irini Manoli, Jennifer L. Sloan, Oleg Shchelochkov, Xin Xu, Erik J. Wagner, Amy Q. Wang, Pramod Terse, Malar Durai, Carolina Galarreta-Aima, Susan Ferry, Carol Van Ryzin, Pj Brooks, Carsten G. Bonnemann, Charles P. Venditti, Elizabeth A. Ottinger
The PaVe-GT program is an NIH sponsored effort to create four different gene therapies, including one to treat propionic acidemia and another to treat methylmalonic acidemia. The PaVe-GT program is designed to identify steps of clinical gene therapy development that can be made more efficient. Gene therapies are designed to provide cells with a working copy of a specific gene. Because inheritable disorders are caused by thousands of different genes, hundreds or thousands of gene therapies are needed to treat each of those inheritable disorders. Proof of concept studies, drug manufacturing, toxicology screening, regulatory submissions, and initial clinical trial planning have already been completed for one of the four gene therapies, specifically propionic acidemia caused by mutations in PCCA. The lessons learned and tools developed to advance this gene therapy can then be passed along to make development of other gene therapies more efficient.
Preclinical Development and proof-of-concept studies supporting a first in human AAV9-hPCCB gene therapy trial for Propionic Acidemia caused by PCCB Deficiency
Randy J. Chandler, Christian Kim, Erik J. Wagner, Asvelt Nduwumwami, Xin Xu, Amy Q. Wang, Charles P. Venditti
As part of the work with the Bespoke Gene Therapy Consortium (BSGTC), a gene therapy for patients with propionic acidemia caused by variations in the PCCB gene has been tested in new mouse models. Using a gene editing technique called CRISPR-Cas9, several different mouse models with variants in PCCB were created. These models vary in the severity of their symptoms, which collectively represent the variability of disease severity in propionic acidemia patients. Preclinical gene therapy testing on models with differing disease severity for organic acidemias is important for predicting what the gene therapy effects will be on a range of patients with differing levels of disease severity i.e. patients who can manage their condition well with a protein restricted diet and supplements alone versus patients who need medical formula and may have had one or more metabolic decompensations.
Different gene therapy dosages were tested on the mouse models at different ages. The intermediate and high doses showed several benefits including weight gain in most of the mouse models for a year. There is evidence that mice receiving gene therapy produce functional PCCB protein in several different tissues including the liver. This indicates that gene therapy is successfully inserting the functional PCCB gene copy into cells throughout the mouse body and not just in one specific area. While propionic acidemia has a large effect on the liver, it is likely that providing functional copies of the gene throughout the body will better improve the patient’s condition. These preclinical tests yield promising results for this PCCB gene therapy.
Preclinical Development of scAAV9-MMAB Gene Therapy for Cobalamin B-Type Methylmalonic Acidemia
Eun-Young Choi, Karenna Choi, John M. Selser, Katelyn D. Leone, Jennifer L. Sloan, Asvelt Nduwumwami, Amy Q. Wang, Erik J. Wagner, Xin Xu, Charles P. Venditti
Dr. Venditti’s team is working to develop a gene therapy for Cobalamin B-type Methylmalonic Acidemia, an inherited metabolic disorder caused by mutations in the MMAB gene. Before the gene therapy is ready for clinical use, it needs pre-clinical development, which typically consists of testing the treatment a mouse model. Mouse models are developed by creating mutant mice that closely mimic the disease in humans. To inform mutations that would closely mimic human Cobalamin B-type MMA in mice, Dr. Venditti’s team looked at data from their ongoing natural history study, containing data from real patients living with Cobalamin B-type MMA. They found two common genetic variants from the natural history study data and created mouse models to mimic the disease severity caused by those and additional mutations. A gene therapy, scAAV9-MMAB were tested in these new mouse models. Mice who were treated with gene therapy showed increased enzyme activity and decreased plasma levels of methylmalonic acid. These results are promising and pave the way for future development of gene therapy for Cobalamin B-type MMA.
Full abstracts of these presentations can be found in the list of abstracts from the meeting.
If you or someone you care for may be interested in participating in Dr. Venditti’s ongoing natural history study research, reach out to the team at NHGRIVendittiClinical@mail.nih.gov
If you would like to financially support further development of treatments for organic acidemias, you can donate to the Organic Acidemia Association.