Sarah Venezia, M.S. and Jan P. Kraus, Ph.D.  University of Colorado at Denver and Health Sciences Center,(UCDHSC) Denver, Colorado.

"Enzyme Replacement Therapy for Propionic Acidemia" -  In August 2011, PAF awarded a $32,000 grant.  The main objective of this project is to develp a therapeutic treatment of PA by enzyme replacement therapy. 

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.  In October, 2010, PAF awarded a continuation grant of $28,000.

Research Studies in PA - Dr. Kraus Update - 11/2011  

Mutation analysis in 54 propionic acidemia patients. 2011 Oct 27

Previously Funded Research

"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 project deals with the three dimensional structure of the enzyme using crystallization and X-ray diffraction.  Why is this important?  Solving the structure of the enzyme is essential for at least two reasons:  first, the structure would allow prediction of the impact of each mutation on the function onf the enzyme; second, any meaningful design of treatment drugs should be based on the enzyme's structure.  We are working on this project in collaboration with Dr. Vivien Yee who is an expert crystallographer and is based at the Case Western University in Cincinnati." - update Dr. Kraus 10/2010

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.

Adeno-associated virus serotype 8 (AAV8) Gene Transfer Rescues a Neonatal Lethal Murine Model of Propionic Acidemia

Randy Joseph Chandler, Suma Chandrasekaran, Nuria Carrillo-Carrasco, Julien Simon Senac, Sean Hofherr, Michael A Barry, Charles Paul Venditti.

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 results showed that over 300 of these genes respond differently to low glucose in individuals with PA than in individuals without PA. This is the first study of its kind to look at a clinical significance for PA carrier parents. 

Chapman Study Update in Autumn 2010 Newsletter, Page 2.

Poster presented at 2011 SIMD Annual Meeting.

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

Survey of health status and complications among propionic acidemia patients registered with the Propionic Acidemia Foundation

See the Fall 2010 Newsletter for some preliminary data on surveys received.  55 surveys have been received.  Dr. Pena finished collecting surveys in May 2011.

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

• Advertisement letter

Nicholas Ah Mew, Robert McCarter, Yevgeny Daikhin, Itzhak Nissim, Marc Yudkoff, and Mendel Tuchman
N-carbamylglutamate Augments Ureagenesis and Reduces Ammonia and Glutamine in Propionic Acidemia
Pediatrics, Jul 2010; 126: e208 - e214.

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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