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Currently Funded Research
Michael Barry, PhD, Mayo Clinic Rochester
"Feasibility of translating gene therapy for propionyl CoA carboxylase (PCCA) deficiency"
In September 2009, PAF awarded Dr. Barry a $20,000 grant to which begins a new chapter in designing an adenoviral gene therapy for PA to be used in clinical trials in the future. Dr. Barry's project will include expanding the number and types of PA mice for use in the adenoviral (Ad5) therapy. Specifically he will be generating new transgenic mice bearing patient PCCA mutations to compare to the PA mouse model previously designed by Dr. Miyazaki. One goal will be to extend the lifespan of the new PCCA mutant mice. A second goal will be to determine how much genetic correction will be needed to do this. The amount of PCC activity necessary for extending the lifespan and reducing symptoms of PA in mice is currently unknown, so this will be determined from both human and mouse cell lines as well as analyzing whole mice. Dr. Kraus at The University of Colorado School of Medicine will participate in the PCC analysis of the cell lines.
Kimberly Chapman, MD, Ph.D., Children's Hospital of Philadelphia.
"Gene Expression Profiles of Patients with Propionic Acidemia and their Carrier Parents"
In May 2009, PAF Awarded Dr. Chapman a $29,381 grant to study how the blockage of PCC (propionyl CoA carboxylase, the enzyme that is missing or deficient in PA patients), affects other genes in the body. Dr. Chapman's study is unique in that she will be looking at how a single gene malfunction like mutated PCCA or PCCB may influence other genes across the entire human genome to malfunction. Hers is the first research project that will take advantage of the newly formed PA Cell and DNA Repository at Coriell Institute for Medical Research. Dr. Chapman will use patient samples obtained from Coriell to compare RNA expression levels of PA patients and also their carrier parents. The data she generates may shed new light on why certain secondary complications are prone to develop in PA's, and will hopefully improve our understanding of how the whole body reacts when PCC is not functioning properly. The hope is that the data from this project will identify genes with altered functions that help explain some of the clinical symptoms in PA patients and possibly some unrecognized clinical risks for PA carriers. This is the first study of its kind to look at a clinical significance for PA carrier parents.
Jan P. Kraus, Ph.D. University of Colorado at Denver and Health Sciences Center,(UCDHSC) Denver, Colorado.
"Genotype-phenotype correlations in Propionic Acidemia" - In July 2008, PAF awarded Dr. Kraus a $40,000 grant. In July 2009, PAF awarded a continuation grant of 40,000.
"Crystallization and structure determination of human propionyl-CoA carboxylase" - In March 2008, PAF awarded Dr. Kraus a $30,000 grant. In May 2009, PAF awarded Dr. Kraus an extension grant of $30,000 to continue his study.
In May 2010, PAF awarded Dr. Kraus an extension grant of $30,000. This study seeks to purify and characterize human PCC, the enzyme that is missing or deficient in PA patients. Dr. Kraus's lab is in the process of purifying crystals of wild type (normal) and mutant human PCCs. The crystals will be analyzed using X-ray crystallography to determine the true structures of both functioning and non-functioning PCCs. Seeing actual 3-D images of the proteins will lead to a better understanding of how PCC functions and interacts in the human body. Once we can directly compare the structures of mutant PCC's to the normal PCC structure we will hopefully begin to understand the mechanisms by which PCCA and PCCB mutations disrupt PCC activity and cause disease.
Previously Funded Research
Jan P. Kraus, Ph.D. University of Colorado at Denver and Health Sciences Center,(UCDHSC) Aurora, Colorado. Grant 3/1/2006- 2/29/2008
"Therapeutic Approaches to Propionic Acidemia”
In 2006, PAF awarded Dr. Kraus a grant for $25,000 for his studies with chaperone proteins. An additional $30,000 was awarded in 2007. The enzyme propionyl-CoA carboxylase (PCC) is deficient in pathogenic cases of propionic acidemia. PCC is constructed from alpha and beta subunits encoded by the genes PCCA and PCCB respectively. To produce a functional enzyme the subunits must be assembled and folded into the correct conformation inside the body. Some mutant forms of PCC tend to aggregate or fold incorrectly resulting in inactive enzymes in some PA patients. Previous work has shown that when some misfolded mutant PCCs are expressed in the presence of the molecular chaperone proteins GroES and GroEL significant levels of PCC activity are produced. Treatment of this class of PCC mutants with chemical chaperones also restored PCC activity. This indicates that in a subclass of PCC mutations, the defect lies in the impaired folding or assembly of the enzyme rather than in its production. Dr. Kraus is currently treating specific PCC mutants in E. coli and in fibroblasts with molecular and chemical chaperones to identify mutants that may respond in vivo. If increased production of PCC is demonstrated, this work has the potential to open the doors to a new treatment strategy for some PA patients.
August 2006 Progress Update as seen in the PAF Newsletter
About PCC
List of PCCA Mutations
List of PCCB Mutations
Jon Wolff, University of Wisconsin Madison, Wisconsin
"Muscle directed gene therapy for Propionic Acidemia"
In 2007, PAF awarded Dr. Wolff a $30,000 grant. More information is available in the April 2007 newsletter. July 2008 Update
Dr. Michael Barry, Ph.D. Mayo Clinic, Rochester, MN
"Gene Therapy for Propionyl CoA Carboxylase Deficiency"
Preclinical studies by Dr. Miyazaki and liver transplantation in PA patients suggest that correction of the defective genes of PCC in the liver can temper some of the metabolic problems due to the disease. Based on this, Dr. Michael Barry is testing the feasibility of performing liver-directed gene therapy using adenoviral and adeno-associated virus gene delivery vectors using PA mice constructed by Dr. Miyazaki. Work is underway to determine if these liver-directed approaches can mitigate the metabolic defects in the mice and how long the genetic correction will last. While at Baylor College of Medicine, Dr. Barry's project was funded $58,489.04. (2004-2006) An additional $25,000 was awarded to Dr. Barry for 1/1/2007-12/31/2007 to continue his studies at Mayo Clinic.
Short-term Rescue of Neonatal Lethality in a Mouse Model of Propionic Acidemia by Gene Therapy. Hofherr S, Senac JS, Chen CY, Palmer D, Ng P, Barry MA. Hum Gene Ther. 2008 Nov 24. [Epub ahead of print] PMID: 19025475
Mayo Clinic - Barry Lab (Vector and Vaccine Engineering)
August 2006 Progress Update as seen in the PAF Newsletter
Dr. Toru Miyazaki, M.D., Ph.D. The University of Texas Southwestern Medical Center, Dallas, Texas
Other Important PA Research/Studies
PA Survey Poster at NUCDF Satellite Symposium - August 2009
Dr. Mendel Tuchman, Children's National Medical Center, Washington, D.C. : NEW DRUG STUDY FOR PATIENTS WITH HYPERAMMONEMIA
N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers.
N-carbamylglutamate can potentially improve hyperammonemia in patients with propionic and methylmalonic acidemia - From the August 2006 PAF Newsletter.
For information from a family that has participated, email paf@pafoundation.com
You can still participate in this study.
Dr. Nicola Longo, University of Utah
Anaplerotic Therapy in Propionic Acidemia - The objective of this project is to define whether nutritional
supplements (ornithine alphaketoglutarate,
glutamine, or citrate)
capable of filling-up the citric acid cycle
(anaplerotic therapy) can improve
hyperammonemia, glutamine levels, and
outcome in patients with propionic
acidemia. You can read more in the Spring 2008 newsletter on the Sites of Interest Page.
Current Research List
This document contains a list of journal articles with information on Propionic Acidemia.
PA Current Research List (new web page with links to articles-click on authors to link to the article)
PA Current Research List (PDF) - so you can print it.
The Importance of Research (click HERE)
Interested in Applying for Research Funds?
In addition to scientific studies, PAF is looking for clinical studies on complications of propionic acidemia including:
Cardiomyopathy
Genotype phenotype studies
Long QT
Hyperammonemia
Neutropenia
Pancreatitis
Secondary immune deficiency
Treatment
Gut microbial flora control
Gastrointestinal motility
In order to encourage clinical studies, PAF is working with Coriell to help establish a public worldwide repository of DNA and clincal data. We encourage all investigators working towards a cure or better treatments for propionic acidemia to contact the Propionic Acidemia Foundation for possible funding. Grant applications may be downloaded by clicking on Format for PAF Research Funding Proposals.
Grant applications should be submitted by October 1st. All applications will be reviewed by the Propionic Acidemia Foundation Medical Advisory Board. Grant determinations will be made in January.
If you have any additional questions regarding applications and funding regulations, please email research@pafoundation.com
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