PROPIONIC ACIDEMIA FOUNDATION CURRENTLY FUNDED RESEARCH

PI: Ala’a Siam, RPh PhDc MRes*, University College London, UK
Summary






PROJECT: Systemic Lentiviral Gene Therapy for Propionic Acidaemia

PRINCIPAL INVESTIGATORS: Ala’a Siam, RPh PhDc MRes*, University College London, UK

John Counsell, PhD, University College London, UK

This pilot research project is expected to result in the necessary proof-of-concept data for the examination of novel disease-modifying gene therapies for PA. Such hepatotropic gene therapies would provide a substitute to liver transplantation. Unlike the latter, this modality bypasses the need for matched liver grafts, risks of surgical complications and requirement for lifelong immunosuppression. It would also enable treatment shortly after diagnosis, thereby arresting the development of complications early on. The permanent nature of gene therapy would ensure continuous expression of PCCA. This aspect bypasses the shortcomings of mRNA nanoparticles, which include the need for repeated dosing at specialised centers and association with high risks of infusion-related reactions. In summary, the gene therapies developed as part of this project are expected to result in clinical outcomes that are similar to those of paediatric liver transplantation, but with a significantly enhanced quality of life and simplified patient access.

PI: Bart Bijnens
ICREA Research Professor
Universitat Pompeu Fabra
Barcelona, Spain
Summary report


DETAILED CARDIAC FUNCTIONAL AND ELECTRICAL PHENOTYPING IN PROPIONIC ACIDEMIA

PI: Bart Bjinens, ICREA Research Professor, Universitat Pompeu Fabra, Barcelona, Spain

“Detailed Cardiac Functional and Electrical Phenotyping in Propionic Acidemia”

In Winter 2023, PAF awarded a $46,000 Initial Research Grant for 3/1/24-2/28/25. Summary of Project

Experience has shown that individuals with Propionic Acidemia (PA) can get Heart Failure (HF) or experience a Sudden Cardiac Death (SCD), induced by cardiac arrhythmias. Given the rarity of PA, little is known about how having the disease, or being a carrier of PA, affects the heart, so treating cardiologists often rely on general guidelines for Heart Failure, associated with the enlargement of the heart and potential decrease in Ejection Fraction; or SCD, often associated with a prolongation of the QT interval on the electrocardiogram (ECG).

However, preliminary assessment of more detailed echocardiographic studies, and individual experience about the lack of improvement using standard therapies, suggests that the PA heart might not behave in a similar way as the majority of HF and SCD patients. Therefore, we have started with the collection of an extended cohort of PA patients, carriers and non-carrier family members, in which we performed comprehensive echocardiograms and ECGs, as well as extended genetic testing.

In this study, we propose to analyze the available imaging and electrical information in detail to study if indeed there is a specific PA cardiomyopathy, that explains both HF and SCD, and how this is expressed in different individuals. To ensure the most comprehensive quantification, we will use contemporary Machine Learning, besides classical cardiological parameters.

If successful, this could open possibilities for a better and more personalized assessment of the PA heart, as well as improved follow-up and (medical and dietary) management to reduce the risk of HF and SCD.

PI: Pawel Swietach
Professor of Physiology
Anatomy & Genetics, University of Oxford, England
Summary report

PAF Grant: Reducing the toxicity of propionyl-CoA in propionic acidemia: a case for revising dietary supplementation guidelines
PI: Pawel Swietach, DPhil, University of Oxford, UK

PROJECT: Reducing the toxicity of propionyl-CoA in propionic acidemia: a case for revising dietary supplementation guidelines

SUMMARY: Studying the epigenetic actions of propionyl-CoA and finding dietary ways of controlling its impact have been highlighted as priority areas by the PA research community. Our latest findings highlight two trajectories for the next project. The first relates to the potential benefit of increasing cardiac beta-alanine levels by dietary supplementation. We propose that higher beta-alanine availability raises carnosine levels, an important anti-oxidant in the heart. Since there is no ‘ceiling effect’ to levels of beta-alanine attained in the heart, it is plausible that even better outcomes can be attained safely with more dietary beta-alanine. Better anti-oxidant protection reduces PA severity, which we inferred from observations on PA mice where the disease was less severe among males. Sexually mature male mice accumulate higher beta-alanine stores through an effect of testosterone. As a pediatric condition, PA patients will not benefit from this exact mechanism, but there are alternative ways of raising beta-alanine levels. The most plausible intervention is dietary. Indeed, carnosine supplements are routinely used by athletes, and similar formulations could be re-purposed for PA patients. The second direction is to investigate histone methylation, and potential for correcting this by restricting methionine in the diet. The striking increase in liver histone methylation may indicate excessive levels of SAMe, caused by the lack of checks and controls on methionine assimilation, a feature of essential amino acids. Here, the challenge is to titrate a level of methionine that can safely control methylation without causing malnutrition. Our goal is to develop up-to-date dietary guidelines for PA, incorporating new scientific insights into disease mechanisms to deliver immediate benefits to patients.

PAF Grant: “New paradigm in alleviating the cardiac consequences of propionic acidemia: diverting excess propionate towards the heart’s beta-alanine store”
Grant period: June 1, 2023 to May 31, 2024
PI: Pawel Swietach

“New paradigm in alleviating the cardiac consequences of propionic acidemia: diverting excess propionate towards the heart’s beta-alanine store”.

Spring of 2023, PAF awarded a new grant of $50,000 for 6/2023-5/2024 
No cost extension granted through 2/28/25.
June 2024 Progress Report

Progress report

Thank you for supporting our research through a $50,000 grant to support staff time, consumables, and animal costs.

The project had three aims:

Aim 1: Trace the incorporation of 13C-labelled propiogenic substrates (i) into the beta-alanine pool, (ii) as canonical propionate metabolites, and (iii) as propionylated proteins in male and female PA mice, and relate these carbon-flows to genetic readouts relevant to PA;
Aim 2: Relate plasma beta-alanine levels with the size of the cardiac beta-alanine pool in mice, and use this information to evaluate the prognostic value of beta-alanine measurements in PA patient serum;
Aim 3: Test interventions that stimulate propionate incorporation into the beta-alanine pool in cultured myocytes and benchmark their efficacy to alleviate PA pathology using disease-relevant cellular readouts.

We are pleased to report progress in all areas. As with long-term research programmes, some work is on-going but we have a schedule for completion.

Work under Aim 1, and some aspects of Aim 2 and 3 were published in a high-profile publication:
“Disrupted propionate metabolism evokes transcriptional changes in the heart by increasing histone acetylation and propionylation”
Nat Cardiovasc Res. 2023 Dec;2(12):1221-1245

This publication resulted in considerable attention from the field and attracted an editorial from the journal. I will be presenting the results at an epigenetics conference in Oxford in September. One of the deliverables is that beta-alanine can improve processing of propionyl-CoA and confer a degree of protection. The link to the paper is available here:

https://pubmed.ncbi.nlm.nih.gov/38500966

As you know, we sought possible industrial collaborations to refine PA diets, leveraging on our evidence for a beneficial effect of beta-alanine. Despite our efforts, supported by you, none of the PA-providers, including Nutricia/Danone, were willing to engage with us. We therefore undertook an animal trial in our laboratory for safety and efficacy of beta-alanine.

This work completes Aim 3 and is on-going. We have obtained and secured the diet, and have placed animals on a 5-week diet, after weaning. The challenge is that a minimal number of knockout mice is necessary in order to place these in a cage with modified diet. Some litters do not yield enough mice, which is why these experiments are difficult to plan and slow to execute. The table below summarises our progress:

Animal group Samples requiredSamples obtainedEstimated completion time
Control diet 8 8 Complete
Diet enriched in beta-alanine 8 4 November 2024
Diet enriched in carnosine, a  beta-alanine derivative8 4 November 2024 

We are delighted to report that thus far, the diets are safe, in that they do not reduce growth of mice. Once the samples are prepared, we will be in position to assess their outcomes on metabolism and epigenetics.

Additionally for Aim 2, we have been preparing a plasma assay for beta-alanine. This is now ready but is waiting for plasma samples for testing. We are collecting samples for a time line of measurements. Our plan is to collect paired heart and plasma samples, and then process these for measurements of beta-alanine and histone modifications. The time line of samples is as follows:

Age Wild-type   femaleWild-type   malePA female PA male 
4 week old 0 out of 4 0 out of 4 4 out of 4 3 out of 4
8 week old 0 out of 4 0 out of 4 2 out of 4 4 out of 4
12 week old 0 out of 4 0 out of 4 4 out of 4 4 out of 4

Collection of samples from wild-type mice will be easier to complete because of simpler breeding, and we anticipate this will be complete by the end of Aug 2024. This work is supported by two postdoctoral workers, Eleanor Gill and Gul Simsek who aim to complete this work on this until Jan 2025.
We have now a gap between the completed grant (ended May 2024) and the next one. We will be able to support research in this period from other sources. Once the samples are prepared, we shall be sending these for processing with Sophie Trefely and Steve Krywawych, our collaborators.

As part of the project, we have also worked with a drug delivery company called EVOX to seek ways of targeting the heart. This work has found a new way for exosomes, small delivery vehicles, to selectively reach the heart. We are in the process of writing this up for publication and hope this could help target therapies specifically to the heart.

Thank you for your generous support,

Pawel Swietach

PI: Guofang Zhang, PhD, Duke University

“Propionyl-CoA and propionylcarnitine mediate cardiac complications
in patients with propionic acidemia”
Summary report


Guofang Zhang, PhD, Duke University

“Propionyl-CoA and propionylcarnitine mediate cardiac complications
in patients with propionic acidemia”

Spring 2019, PAF awarded a $48,500 grant.  
No cost extension awarded through 8/31/2020
Continuation grant for $51,500 awarded 9/2020-8/32021
No cost extension awarded through 1/31/2023
Continuation grant of $50,000 awarded for 4/23-3/31/24
No cost extension awarded through 5/31/25
Summary April 2023

Update March 2023

Cardiac disease has a high prevalence among patients with propionic acidemia (PA). The pathological mechanism remains largely unknown, particularly due to the nature of chronic development. It is challenging to predict the cardiac diseases development in PA patients simply by the PCC mutations, propionyl-CoA carboxylase (PCC) enzyme activity or acute metabolic changes in plasma or urine because no strong correlation between cardiac phenotype (severity of disease) and genotype, metabolic decompensations or residual enzyme activity has been observed from the clinical cases.

Fatty acids with various chain-lengths are major fuels for heart. Our previous data demonstrated that propionate rather than amino acids is a major source of cardiac propionyl-CoA. In addition, the deficiency of PCC reduces the hepatic disposal of microbiome-derived propionate and promotes odd-chain fatty acid synthesis, both of which impose metabolic stress on heart. Propionyl-CoA accumulation derived from propionate and odd-chain fatty acids could interrupt cardiac energy metabolism. The low ATP further inhibits propionyl-CoA carboxylation according to our recent ischemia study. The impaired energy metabolism and propionyl-CoA accumulation forms a vicious circle.

With a third-year grant support from PAF, we will collaborate with Drs Eva Richard Rodríguez and Lourdes R. Desviat from Universidad Autónoma de Madrid on how energy metabolism in PCCA- or PCCB- iPSC-cardiomyocytes derived from human patients is altered by stable isotope analysis, particularly under the stress of propionate and odd-chain fatty acids.  Another Aim is to improve cardiac energy metabolism by targeting propionate and odd-chain fatty acid metabolism.

Update August 2020

Cardiac disease is one of complications often associated with propionic acidemia (PA). Understanding the pathological mechanism is essential to prevent the development of complication. Our previous research has shown that propionyl-CoA accumulation inhibits the metabolism of fatty acid which is a major fuel for cardiac energy. The loss of fuel switch flexibility could interfere with cardiac energy metabolism and potentially develop cardiac complications particularly under various stresses. Our research was funded by PAF to investigate the pathological mechanism of cardiomyopathy associated with PA in 2019. In the year 1 of PAF award, we started to map out the metabolic source of propionyl-CoA in heart. Surprisingly, the amino acids (isoleucine, threonine, methionine, valine) and protein which are known to be substrates of propionyl-CoA have negligible contribution to propionyl-CoA production in heart. However, our data does not exclude the possibility that these amino acids substantially contribute to propionyl-CoA production in other organs, like liver. Circulating propionate is a major source of cardiac propionyl-CoA. It also fits the observation that heart prefers fatty acids including short-chain fatty acids as energy substrates. More than 99% propionate originating from microbiome is efficiently removed/metabolized at its first pass through liver in healthy rodents. Therefore, circulating propionate maintains at very low level after liver. The deficiency of PCC attenuates hepatic ability of disposing propionate and increases circulating propionate level, which exacerbates propionyl-CoA accumulation in heart. Our results show the “metabolic filtering” role of liver in maintaining efficient cardiac energy metabolism. 

In order to understand the pathological mechanism of cardiac complication associated with PA, a PA-mediated cardiac complication model is essential. In year 2 of PAF award, we will first develop and confirm a mouse model with cardiac complication before pathological mechanism study. With the collaboration with Dr. Michael Barry, we will characterize cardiac function and metabolic phenotype of Pcca-/-(A138T) mouse that is a PA animal model created by Dr. Michael Barry. We will induce cardiac complication with Pcca-/-(A138T) mice by diets or stresses if it is necessary. After that, we will examine how cardiac energy metabolism is disturbed using stable isotope-based metabolic flux and RNA-Seq approaches. Furthermore, we will further investigate how propionylcarnitine expansion in the heart could deplete cardiac acetylcarnitine, acetyl-CoA buffer, and affects cardiac acute energy demanding. The long-term goal of our research is to find a therapeutic target on cardiac propionyl-CoA metabolism to mitigate cardiac complication

PREVIOUSLY FUNDED RESEARCH BY PAF

PI: Eva Richard, Associate Professor Universidad Autónoma de Madrid, Spain
PI: Eva Delpon, Professor Universidad Complutense de Madrid, Spain 

“Elucidation of cardiac electrophysiological alterations in propionic acidemia: Towards the identification of targets for therapeutics”

PI: Grant Mitchell, MD CHU Saint-Justine, Montreal, Canada

“New approaches to understanding and treating propionic acidemia”

In Spring 2024, PAF awarded a $50,000 Initial Research Grant for 4/1/24-3/31/25

PI: Ken Maclean, PhD, University of Colorado Denver

“Chemical Chaperone Treatment to Restore Enzyme Activity in Folding Mutations of Propionyl-Co-A Carboxylase: Towards a Personalized Therapeutic Strategy in Propionic Acidemia (PA)” – In Summer 2020, PAF awarded a $50,000 grant.  In Spring 2022, PAF awarded a $50,000 continuation grant. No cost extension through 12/31/23.

PI: Rajavel Elango, PhD, University of British Columbia

“Optimizing amino acids in medical foods to manage propionic acidemia” – In Spring 2020, PAF awarded a  $44,253 grant.  A no cost extension was granted through June 30, 2022.

PI: Pawel Swietach, Professor of Physiology, Department of Physiology, Anatomy & Genetics, University of Oxford, England

“Aberrant protein propionylation and distinct histone marks in propionic acidemia: new disease mechanisms and risk factors for cardiac disease” In Spring 2021, PAF awarded $49,953 Initial Research Grant.

PI: Sander Houten, Ph.D., Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, NY, US
Co-PI: Robert J. DeVita, Ph.D., Department of Pharmacological Sciences, Drug Discovery Institute, Icahn School of Medicine at Mount Sinai, NY, US

“Substrate reduction as a novel therapeutic strategy for propionic acidemia”  In Spring 2021,  PAF awarded $50,000 Initial Research Grant

PI: Eva Richard, PhD, Universidad Autonoma de Madrid, Spain

“Cardiomyocytes derived from induced pluripotent stem cells as a new model for therapy development in propionic acidemia” – In Spring 2019, PAF awarded a $33,082.12 grant.   In Spring 2020, PAF awarded a continuation grant for $30,591  See 4 publications below.

Co-PIs: Oleg Shchelochkov, M.D. and Charles P. Venditti MD, PhD, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD

“Diversion of Isoleucine and Valine Oxidative Pathway to Reduce the Propionogenic Load in Propionic Acidemia.” – 2018, PAF awarded a $32,912 grant.

PI: Hilary Vernon, MD, PhD, Johns Hopkins University

“Targeting Serine and Thiol Metabolism in Propionic Acidemia” – In July 2017, PAF awarded a $43,645 grant.   In the research project, entitled “Targeting Serine and Thiol Metabolism in Propionic Acidemia”, we will define the role of novel pathways of cellular dysfunction in Propionic Acidemia. It has been known for several decades that the genetic cause of Propionic Acidemia is an abnormality in one of the genes encoding for propionyl-CoA carboxylase, leading to accumulation of propionic acid and it’s metabolites. However there is still a limited understanding of how this causes cellular dysfunction.

In our preliminary work, we defined novel differences in the way that cells affected with Propionic Acidemia produce defenses against oxidative stress, and in the way that these cells utilize serine, a central amino acid for cellular growth. In this current research project, we will use a new cell model of propionyl-CoA carboxylase deficiency developed in our laboratory to fully define these pathway differences, and how they alter the response to stress. We hope that in defining these new pathways of cellular dysfunction in Propionic Acidemia, we will offer new areas for potential therapeutic intervention and therapeutic monitoring. We are excited to begin this research, and are grateful to the Propionic Acidemia Foundation for funding this research.

PI: Nicola Brunetti-Pierri, MD, Fondazione Telethon, Italy

“Novel Therapies for Propionic Acidemia” – In June 2017, PAF awarded a $50,000 grant. Propionic acidemia (PA) is an inborn error of metabolism caused by deficiency of propionyl-CoA carboxylase (PCC). There is no cure for PA and available therapies are often unsatisfactory. Elective liver transplantation is being increasingly used to reduce metabolic crises and temper some of the most severe symptoms of the disease. However, liver transplantation is invasive, has high morbidity, and requires long-term immunosuppression. Therefore, more effective and safer therapies for PA are highly needed. We generated a PA model in the medaka fish (Oryzias latipes) that recapitulate the pathological and biochemical abnormalities observed in human patients, and has reduced locomotor activity and survival. As disease model, the fish has several advantages including easy handling, low costs, large number of progeny per generation, a relatively short generation time, and a small and well-draft genome. We propose to perform a high-throughput drug screening in this animal model using the reliable and clinically relevant endpoint of locomotor activity as first-tier read-out. Positive hits will be confirmed for their effect on biochemical abnormalities and survival.

PI: 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.  A continuation grant for $28,898 was awarded for January 1, 2013- June 30, 2016.   The main objective of this project is to develop a therapeutic treatment of PA by enzyme replacement therapy.

PI: Loren Pena, M.D., PhD. Duke University

PAF awards a $21,200 Grant to Dr. Loren Pena on her study titled:  “A prospective study of biochemical parameters reflective of metabolic control in propionic acidemia”  in January 2013.    In March, 2014 PAF awarded a $28,697 grant.  In February, 2015  PAF awarded an additional $18,159 grant for year 3 of the study.  Study completed February 2017.

PI: Michael A. Barry, Ph.D, Mayo Clinic College of Medicine

PAF awards $39,572 Grant to Dr. Barry for his study titled:  “Neurologic Phenotypes and Therapy in Propionic Acidemia Mice.”

PI: Andrea Gropman, M.D., FAAP, FACMG, FAAN Children’s National Medical Center,  Washington, D.C.

“Biomarkers for Neurological Injury in PA” – In January 2012, PAF awarded a $27,000 grant.   If you have Propionic acidemia and are between the ages of 6-40 years, you may be able to participate in an MRI study at Children’s National Medical Center and Georgetown University.  Unspent funds of $26,940 returned August 2019 due to difficulty in recruitment.

PI: Kimberly Chapman, M.D. Ph.D and Kristina Cusmano-Ozog, M.D., Children’s National Medical Center, Washington, D.C.

“Is there energy deficiency in Propionic Acidemia”.  In January 2012, PAF awarded a $15,500 grant.

PI: Marisa Cotrina, Ph.D. University of Rochester, Rochester, NY
“The impact of pa on brain astrocytes: an in vitro model to test mitochondrial therapy in PA”   In January 2012, PAF awarded a $27,000 grant.  In March 2013, PAF awarded a $27,000 continuation grant.

PI: Holmes Morton, MD. Clinic for Special Children, Strasburg, PA“The Biochemical Basis fo Keto-Acidemia, Encephalopathy, Metabolic Strokes, Heart Failure & Long QTc, and a Discussion of Current Therapies” -In September 2012, PAF awarded a $5000 grant for the workshop held on September 14, 2012.

PI: 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.

“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

PI: 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.

PI: 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.

PI: 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.

PI: 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

PI: 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.

OTHER CLINICAL PROJECTS WHERE INDIVIDUALS WITH PA CAN PARTICIPATE

See Clincial Trials Tab

Previous Projects

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

NOTE:  PI stands for Principal Investigator

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