Rare Disease Day Spotlight

 

RARE DISEASE DAY 2021 SPOTLIGHT

I would like to thank two amazing human beings that have helped Vivienne along her journey with Propionic Acidemia. First, I would like to thank Ms. Heather, who is Vivienne’s Nutritionist/Dietician. Since she took on Vivienne’s case, Vivi’s health has improved. She has made such a difference in Vivienne’s life! Now, I know why so many parents emphasized the importance of a great dietician! Ms. Heather has been very caring, very attentive,a great listener and very committed to Vivi’s case!

Second, I would like to thank Dr. Baker! Dr. Baker has been an extraordinary geneticist! His dedication and amazing care has helped Vivi stay away from many hospital stays. I feel so blessed in having both Dr. Baker and Ms.Heather as Vivienne’s care team. They both have gained my confidence. Dr. Baker and Heather truly made a difference in Vivienne’s life!

Thank you from the Lopez Family!

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Nalani has been lucky to have some amazing people in her life helping her along in her journey. She has been attending a weekly social group at Coeur Academy in Missouri for about 6 years now. They get together, talk about their week, plan activities and play games. They cook a “Thanksgiving feast” and exchange gifts on Christmas. They go shopping and go out to eat together. She is the only girl and tells everyone she meets that she has 4 boyfriends. Nalani is extremely social and this program has given her a group of true friends. I am so thankful to them. I don’t know what she would do without Ann, Sarah and her boyfriends at social group! – Angela  (picture of Nalani and her Teacher)

 

PAF Awards Initial Research Grant Houten DeVita

PAF Awards $50,000 New 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”

Amino acid metabolism and in particular the degradation of valine and isoleucine are a significant source of propionyl-CoA, the substrate of propionyl-CoA carboxylase. Current treatment of propionic acidemia aims to decrease the degradation of valine and isoleucine through medical diets and avoidance of fasting. Drs Houten and DeVita, the investigators on this project, aim to develop a pharmacological substrate reduction therapy for propionic acidemia that limits the degradation of these amino acids. They propose to inhibit short/branched-chain acyl-CoA dehydrogenase (SBCAD) and isobutyryl-CoA dehydrogenase (ACAD8), which are involved in isoleucine and valine degradation, respectively. Inhibition of these enzymes is thought to be safe because in contrast to propionic acidemia, inherited defects of SBCAD and ACAD8 are thought to be benign conditions. In cell line models, inhibition of SBCAD using a genetic KO or an inhibitor was efficacious and led to a pronounced decrease in the propionyl-CoA carboxylase substrate. The investigators anticipate to find a few hit inhibitors of SBCAD and ACAD8 that can be further optimized and serve as a starting point for a broader translational drug discovery program for treatment of propionic acidemia.

Progress Update April 2022

In January 2021, we were grateful to receive a research grant from the PAF, which allowed us to start the development of pharmacological substrate reduction as a novel therapeutic approach for propionic acidemia. For this project, we hypothesize that we can achieve a clinically relevant reduction in the accumulation of propionyl-CoA carboxylase substrates by inhibiting enzymes that play a role in the degradation of branched-chain amino acids. Specifically, we propose to inhibit short/branched-chain acyl-CoA dehydrogenase (SBCAD) and isobutyryl-CoA dehydrogenase (ACAD8), which are involved in isoleucine and valine degradation, respectively. Inhibition of these enzymes is predicted to be safe because inherited defects of SBCAD and ACAD8 are thought to be benign conditions. In cell line models, inhibition of SBCAD using a genetic KO or an inhibitor was efficacious, leading to a pronounced decrease in propionyl-CoA derived metabolites. Inhibition of ACAD8 was less efficacious, which may be explained by overlap in substrate specificity between different acyl-CoA dehydrogenases. The goal of this project is to identify small molecule inhibitors of SBCAD and ACAD8 that can be further validated to serve as starting points for a broader translational drug discovery program for treatment of propionic acidemia. In order to achieve this goal, we used the research grant from the PAF to develop the in vitro biochemical and cellular assays useful to screen for chemical matter to establish if a small molecule has possibility to be an effective SBCAD or ACAD8 inhibitor. We have also performed a virtual screening to generate a list of candidate inhibitor molecules for SBCAD and ACAD8. Of these potential SBCAD inhibitors, 91 were purchased and tested in the SBCAD assay. Unfortunately, none of the compounds were able to inhibit SBCAD with high affinity likely as a result of limitations to the computational modeling of the enzyme structure. This result indicates that a larger unbiased high throughput screening is necessary to identify hit small molecule inhibitors for SBCAD. Our enzyme assay seems well suited for this approach and this approach has been successfully applied to two other enzyme targets under investigation by the team (DHTKD1 [1] and LOR domain of AASS (unpublished)).

The progress made with the PAF funds enabled us to propose this research project for the NIH Small Grant Program (R03) of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD). This grant was awarded in September 2021, which allowed us to continue this work for the next 2 years. In collaboration with Drs. Vockley and Mohsen (University of Pittsburgh), we also applied for an NIH Research Project Grant (R01; The therapeutic potential of inhibition of acyl-CoA dehydrogenases involved in valine and isoleucine degradation). This proposal is currently under consideration.

PAF Awards $49,953 New Research Grant – Swietach

PAF Awards $49,953 New Research Grant  in 2021

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”

The challenge placed on our hearts – to contract and relax in a correct sequence and with adequate strength – is formidable.  The elegant biological solution to this mechanical problem is an organ that pumps millions of liters of blood to support life for many decades.  However, the quality and span of a person’s life is strongly linked to cardiac health.  Thanks to scientific breakthroughs, better treatments are now available for cardiac disease, allowing patients to live longer and happier lives.  Our goal at Oxford University’s British Heart Foundation Centre of Research Excellence is to ensure that scientific progress addresses a wide spectrum of disorders, irrespective of their incidence.

Cardiac problems are common in propionic acidemia (PA).  Sadly, dilated cardiomyopathy and long-QT syndrome are often the cause of childhood death.  In order to treat and prevent these cardiac problems, we must first understand the underlying mechanisms.  Once these processes are described, our aimis to identify targets for drugs or interventions.  We believe that this ambition is achievable thanks to the wealth of knowledge about the heart and the vast repertoire of drugs approved for therapy in various other cardiac conditions.  Many of these drugs could be “repurposed” for PA-associated disorders, giving hope to many families for a timely treatment.

For this PAF-funded project, we have assembled a consortium of scientists who are eager to devote their expertise to studying PA.  My laboratory’s expertise is in cardiac cellular physiology in the context of acid-base disorders. We are joined by Tom Milne who is Associate Professor in Epigenetics at Oxford, Holger Kramer, an expert on proteomics, and Steve Krywawych, principal biochemist at Great Ormond Street Hospital in London. Resources and facilities made available to this project include a mouse model of PA, courtesy of Michael Barry and Lourdes Desviat, methods to characterise cardiac function from the cell to organ level, as well as measurements of changes at the protein and gene level.  This interdisciplinary but focused approach allows us to identify potential targets for PA treatment.  Indeed, our preliminary findings point to one such enzyme, and the aim of this project is to test and validate our hypothesis.

PA is associated with major metabolic changes, and many of these substances are not merely intermediates in a chain of events, but can have strong biological actions that are not always intuitive to predict.  Our project will investigate how the build-up of propionate affects cardiac genes through a chemical reaction that causes DNA scaffolds (called histones) to “open up” genes that should not normally be expressed in a healthy heart.  Many genes will be affected by this, but some are more closely linked to the cardiac disorder.  After identifying these lead genes, we will test the extent to which blocking these could be curative. In parallel, we will investigate if propionate can also react with other targets in the cell, such as proteins underpinning contraction.  Indeed, our work suggests that a promising avenue for research relates to so-called excitation-contraction coupling, a process that converts cardiac electricity to a mechanical response.

We are excited to be part of the PA research family and wish to take this opportunity to invite patients, carers, and supporters to our lab for a visit.


Update 8/2022 – Final Report

ABERRANT PROTEIN PROPIONYLATION AND DISTINCT HISTONE MARKS IN
PROPIONIC ACIDEMIA: NEW DISEASE MECHANISMS AND RISK FACTORS FOR

CARDIAC DISEASE
Final Report – August 2022
PI: Pawel Swietach (Oxford University)

Non-confidential report for dissemination

Patients affected by propionic acidemia (PA) present with disturbances in the levels
of metabolites, notably propionate. This small (three-carbon) molecule is normally produced
from the breakdown of substances in the diet, such as branched-chain amino acids and odd-
numbered fatty acids. In PA, however, genes responsible for propionate processing are
inactivated by inherited mutations. A long-standing view postulates that the ensuing
biochemical milieu is responsible for the dysfunction of multiple organs affected in PA.
Understanding how the heart is affected in PA is particularly important, because many
childhood deaths have been linked to cardiac disease. However, the precise mechanism
linking the metabolic disturbance with heart disease in PA is unclear. Without this detailed
information, it is difficult to propose new cures and improve disease management before
viable gene therapies are available. Moreover, knowledge of the molecular mechanisms has
broader impact on cardiac health, because elevations of propionate have also been
described in other diseases, such as diabetes.

The aim of our PAF project was to investigate how the metabolic derangements in
PA affect proteins through so-called post-translational modifications, i.e. chemical ‘editing’
that can affect their functions. Using a mouse model of PA, we showed that histones, the
protein scaffold of DNA, undergo two types of modifications in the heart: propionylation and
acetylation. We then demonstrated how these actions affect the expression of genes in the
heart. Strikingly, we found that several genes, previously implicated in cardiac disease,
become aberrantly activated in PA, and we speculate that dampening this PA-driven genetic
response may alleviate the pathological changes experienced by patients. Through our
observations of the mouse model of PA, we identified a novel biochemical pathway that
offers an alternative means of processing excess propionate in the heart. Activation of this
pathway was associated with a less severe disease presentation in mice. We hypothesize
that this pathway could be exploited therapeutically in PA patients, and our immediate aims
for the future are to identify the best approach for exploiting this protective reservoir for
propionate in the heart.

In summary, the PAF project has (i) delivered novel mechanistic insights into how
propionate affects the heart using state-of-the-art methods in metabolomics, transcriptomics,
chromatin biology, and physiology, and (ii) revealed new pathways for propionate processing
that by-pass the mutated enzymes in PA patients.

 

PAF Awards Continuation Grant to Guofang Zhang at Duke University

Guofang Zhang, PhD, Duke University

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

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 associated with PA.

PAF Grant Maclean

PAF Awards $50,000 New Research Grant

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.”  

Propionic acidemia (PA) is a severe life-threatening disease for which there is currently no truly effective treatment. The disease is caused by mutation in one of the two genes that code for the enzyme propionyl-CoA carboxylase (PCC). This enzyme is made up of two different proteins that fold around each other into a complex structure with six of each of these two molecules. This is a very unusual and complex structure for a metabolic enzyme and recent work in our laboratory has found that a number of specific mutations that cause PA cause problems by interfering with the protein folding and/or assembly process leading to a non-functional enzyme and thus the disease. In cells, proteins with complicated folding patterns are often assisted in their folding by other proteins called chaperones. We have observed that a number of mutant forms of PCC can be restored to normal activity if they are helped to fold correctly using these chaperone proteins. In our study, we will examine a number of chemicals that can also function as chaperones and assist with protein folding with a view towards restoring full activity in mutant forms of PCC. This work will initially occur in a bacterial PCC expression system to identify promising compounds and then depending upon progress, move into treating human PCC patient derived cells. These studies have the potential to serve as an initial first step in the rational design of a personalized medicine strategy for patients with specific mutations causing PA.

PAF research summary Elango

PAF Awards $44,253 New Research Grant

Rajavel Elango, PhD, University of British Columbia

“Optimizing amino acids in medical foods to manage propionic acidemia”  

Propionic Acidemia (PA) is primarily caused by an enzymatic defect, propionyl-CoA carboxylase (PCC), in the catabolic pathway of valine, isoleucine and other propiogenic precursors. The dietary management of PA mainly depends on protein restriction from food to reduce supply of propiogenic amino acids, and the use of special medical foods. These medical foods contain all essential amino acids and nutrients, but no propiogenic compounds. Recently, concerns have been raised about their use, due to the imbalanced content of the Branched Chain Amino Acids (BCAA) – high leucine, to minimal or no valine and isoleucine. The imbalanced mixture of BCAA negatively impacts plasma concentrations of valine and isoleucine, and has been proposed to affect growth in pediatric PA patients. 

In an ongoing retrospective natural history study (n=4), patients with PA treated at our center from birth (or diagnosis) to age 18y, we observed that higher intake of medical food (compared to intact protein) results in lower ht-for-age Z scores. Based on these pilot data, we propose that there is an immediate need to determine the optimal amounts of leucine to be present in the medical foods.

Therefore, the specific objectives of the current study are to:

  1. Stable isotope studies
    1. Determine the ideal ratio among BCAA in children using the stable isotope-based indicator amino acid method to optimize protein synthesis in a Proof-of-Principle approach.
    2. Test the ratio among BCAA using the same stable isotope-based method in our cohort of PA patients to determine impact on protein synthesis, and plasma metabolite responses.
  2. Determine the impact of the use of natural (intact) vs formula (medical food) protein on anthropometric, biochemical and clinical outcomes via a retrospective natural history study of PA patients treated at BC Children’s Hospital.

Recent dietary guidelines for PA are discouraging the reliance on medical foods as a sole dietary source. However most individuals with PA are at risk for malnutrition and depend on these medical foods as an easy tolerable source of energy and protein. Thus, determining the optimal ratio of BCAA in PA medical foods is necessary to optimize protein synthesis, promote anabolism, growth and prevent the accumulation of toxic metabolites. 

Our laboratory, equipped with use of novel stable isotope tracers to examine protein and amino acid metabolism, is ideally suited to address the question of the ideal BCAA ratio to be used for dietary management of PA and potentially impact health outcomes.

 

PAF attends 2019 Abbott Nutrition Conference

17th Abbott Metabolic Conference: Advances in Management of Inherited Metabolic Disorders
Memphis, TN May 30-June 1, 2019
By Brittany S Smith, PAF Board Member & Treasurer

PAF had a table at the 2019 ABBOTT Metabolic Conference.

There were several presentations and debates that were relevant to the PA community. The first was Dr. Sufin Yap, MD, from Sheffield, UK, who spoke on Organic Acidemias. She described how she has observed her patients in a metabolic crisis and that their livers can enlarge very rapidly. Dr. Yap also described how she has used Carbaglu within a crisis situation and it has brought the ammonia levels down on her patients. The medication was also shown to improve the quality of life of patients with PA using the medication, this was shown by using the PedsQL, a quality of life survey tool. Carbaglu has been used in Europe for over 15 years.

Three dietitians gave a joint presentation on Emergency Preparedness, detailing the impacts of natural disasters on the clinics and staff and also families serviced by their clinics. Amy Cunningham, RD; Suzanne Hollander, RD; and Heather Saavedra, RD, each detailed natural disasters they have had in their areas of the country, which have included wild fires, hurricanes, flooding, droughts, and earthquakes. They have not only impacted families, but the clinic operations. In some cases the hospital and clinics were closed for months. Families, too, were significantly impacted and in one case, a family utilizing one of the clinics had only 5-10 minutes to flee their home. Overall, they indicated a need for all of the metabolic clinics and newborn screening offices to create Emergency Preparedness plans, as well as, helping affected families to prepare as well.

The last session that I wanted to mention was a debate session in which a team of doctors and dietitians each had to debate one side of a treatment suggestion. One was on liver transplantation and whether to encourage or discourage a metabolic family to investigate liver transplantation. While the debate was interesting, the discussion that followed was poignant; they were open to being corrected if they had misstated facts, one being using the livers from those with PA and UCDs in a “domino” transplant, and the other was that they all recommended encouraging their families to seek out information and go down a treatment route if the parents felt that was what was best.

 

The Propionic Acidemia Nutrition Guidelines are now published

Great News – The “Propionic Acidemia Nutrition Guidelines” Are Now Published!

The Nutrition Guideline Committee is happy to announce that the Organic Acidemia Workgroup has published the “Propionic Acidemia (PROP) Nutrition Guidelines” in the February, 2019 issue of Molecular Genetics and Metabolism. The article is available and can be downloaded at no cost at https://doi.org/10.1016/j.ymgme.2019.02.007.

Publication of the PROP/PA Nutrition Guidelines in Molecular Genetics and Metabolism brings the latest evidence- and consensus-based nutrition management recommendations to the attention of clinicians, researchers, policy makers, insurers, and patients.

The new Nutrition Management Guidelines for PROP/PA provide:

  • New directions including:
    • A greater emphasis on nutritional needs such as nutrient intake, nutritional interventions, supplementation, etc.
    • Less emphasis on  medical management which has been covered in previous publications;
    • Additional topics such as monitoring to ensure nutritional adequacy, nutritional issues with pregnancy and lactation, nutritional management for secondary complications such as pancreatitis, and finally a section addressing liver transplantation and the nutritional management before, during, and after the procedure.

 

Two consumer-oriented pieces, Frequently Asked Questions and a Consumer Summary, provide patients and families with information to use when interacting with their providers. The summary highlights key recommendations and suggests questions that patients and families may want to discuss with the metabolic team.

  • When patients and health care providers (HCPs) have the same information, they can work together as a team to identify the treatment that is best for the patient’s situation.
  • You can access these pieces at the Genetic Metabolic Dietitians International (GMDI) or Southeast Genetics Network websites located at http://www.Southeastgeneticsnetwork.org/ngp  and http://www.GMDI.org
  • The new guidelines should lead to greater consistency of care across centers.
    • There are several important resources included in the guidelines including recommended nutrient intakes, monitoring schedules, and nutritional interventions tables.
    • A web site that provides all the resources and references used to develop the guidelines is available so that health care clinicians and others can readily obtain the background information related to the guidelines at the websites listed above.
    • The guidelines development method utilized evidence from published research, practice-based medical literature and expert consensus processes.

SIMD 2019

PAF at SIMD 2019

Jill Chertow and Maria L. Cotrina represented PAF and the PA Community at the Society for Inherited Metabolic Disorders (SIMD) 41st Annual Meeting on April 6-9, 2019 in Bellevue, Washington.  Propionic Acidemia Foundation (PAF) partners with the National Urea Cycle Disorders Foundation (NUCDF) in sharing an exhbition booth.

Maria L. Cotrina shared her poster on “High Incidence of Autism/ASD in Propionic Acidemia: Data from the Propionic Acidemia and Urea Cycle Disorders Registries.”

 

 

Arianna F. Anzmann, MS was the recipient of  the SIMD Founders Award (Best Oral Presentation by a Trainee).  Her presentation “Multi-Omics Studies in Patient-Derived and CRISPR-Edited Cellular Models of Methylmalonc Acidemia and Propionic Acidemia Reveal Dysregulation fo Serine Metabolism: New Directions for Cellular Pathogenesis in Disorders of Branch Chain Amino Acid Metabolism.”  was a result of a 2017 PAF awarded grant to Hilary Vernon, MD, PhD, Johns Hopkins University for the project “Targeting Serine and Thiol Metabolism in Propionic Acidemia”.