Gene Therapies and Molecular Studies: Developing New Treatments for PA
PARnet is actively engaged in dialog with the following researchers and laboratories to promote new gene therapies and other forms of drug treatment for PA patients. Advances in research do not happen overnight, so ongoing support for these projects is critical for new PA treatments to be developed. PARnet is working with the Genetic Alliance, NORD, EURORDIS, NIH and other organizations who promote translational research in an effort to accelerate new treatments coming to market for patients of rare disorders.
Funding Applications: Interested in Applying for Funds?
Please contact email@example.com or firstname.lastname@example.org to receive information about applying for a grant from the Propionic Acidemia Foundation and to receive a research funding proposal form. Your initial contact should include a brief description of your project including how your studies would improve the lives of PA patients.
Adeno-associated virus serotype 8 gene transfer rescues a neonatal lethal murine model of propionic acidemia.
Dr. Charles Venditti, Organic Acid Research Section, Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Propionic acidemia (PA) is an autosomal recessive disorder of metabolism caused by a deficiency of propionyl-coenzyme A carboxylase (PCC). Despite optimal dietary and cofactor therapy, PA patients still suffer from lethal metabolic instability and experience multisystemic complications. A murine model of PA (Pcca(-/-)) of animals that uniformly die within the first 48 hr of life was used to determine the efficacy of adeno-associated viral (AAV) gene transfer as a potential therapy for PA. An AAV serotype 8 (AAV8) vector was engineered to express the human PCCA cDNA and delivered to newborn mice via an intrahepatic injection. Greater than 64% of the Pcca(-/-) mice were rescued after AAV8-mediated gene transfer and survived until day of life 16 or beyond. Western analysis of liver extracts showed that PCC was completely absent from Pcca(-/-) mice but was restored to greater than wild-type levels after AAV gene therapy. The treated Pcca(-/-) mice also exhibited markedly reduced plasma levels of 2-methylcitrate compared with the untreated Pcca(-/-) mice, which indicates significant PCC enzymatic activity was provided by gene transfer. At the time of this report, the oldest treated Pcca(-/-) mice are over 6 months of age. In summary, AAV gene delivery of PCCA effectively rescues Pcca(-/-) mice from neonatal lethality and substantially ameliorates metabolic markers of the disease. These experiments demonstrate a gene transfer approach using AAV8 that might be used as a treatment for PA, a devastating and often lethal disorder desperately in need of new therapeutic options.
The Use of Chaperones to Enhance PCC Assembly and Expression
Dr. Jan P. Kraus, Ph.D. Dept. of Pediatrics, University of Colorado School of Medicine, UCDHSC, Aurora, CO
Hua Jiang K., Sudhindra Rao, Vivien C. Yee, and Jan P. Kraus. Characterization of Four Variant Forms of Human Propionyl-CoA Carboxylase Expressed in Escherichia coli. (2005) J. Biol. Chem., Vol. 280, No. 30, 27719-27727.
Efforts are underway in the Kraus lab to understand how the enzyme PCC is assembled in vivo and to find options for correcting PA mutations that are defective in PCC assembly.
Correction of Novel Splicing Mutations in PCCA and PCCB
Dr. Magdalene Ugarte Ph.D., Dpto. Biologia Molecular, Centro do Biologia Molecular "Severo Ochoa", CSIC-UAM, Universidad Autonoma de Madrid, Madrid, Spain
Sonia Clavero, Belen Perez, Ana Rincon, Magdalene Ugarte, Lourdes Desviat. Qualitative and Quantitative Analysis of the Effect of Splicing Mutations in Propionic Acidemia Underlying Non-Severe Phenotypes. (2004) Hum. Genet. 115: 239-247.
The Ugarte lab has a long history of PA mutation identification and DNA analysis. Patients with splicing mutations in PCCA or PCCB have the potential of being treated if drugs can be developed to correct certain cellular splicing defects.