Propionic Acidemia (PA)
Propionic acidemia, or propionic aciduria, is an uncommon metabolic disorder inherited in an autosomal recessive manner. It arises from a lack of propionyl-CoA carboxylase, which disrupts the normal metabolism of branched-chain amino acids and odd-chain fatty acids. At our company, we've assembled a team of seasoned professionals with a wealth of experience in navigating drug and therapy development challenges specific to Propionic Acidemia.
Introduction to Propionic Acidemia
Propionic acidemia is an uncommon genetic metabolic disorder resulting from mutations in the PCCA or PCCB genes, which lead to a deficiency of the enzyme propionyl-CoA carboxylase. This enzyme shortfall causes a buildup of harmful metabolites, resulting in severe metabolic disturbances. The global prevalence of PA varies, typically affecting between 1 in 100,000 and 1 in 250,000 people.
Pathophysiology of Propionic Acidemia
Fig. 1 The scheme of propionyl-CoA metabolism. (Marchuk, H., et al., 2023)Propionic acidemia results from mutations in the propionyl-CoA carboxylase (PCC) enzyme, which impairs the conversion of propionyl-CoA to methylmalonyl-CoA in the tricarboxylic acid cycle. This leads to the accumulation of toxic metabolites, causing oxidative stress and mitochondrial dysfunction. Elevated levels of propionyl-CoA and its byproducts disrupt various metabolic pathways, contributing to severe complications like cardiac, neurological, and renal dysfunctions.
Biomarkers of Propionic Acidemia
In the context of PA, biomarkers are most valuable for early evaluations of efficacy and safety. These include in vitro studies using tissue samples, in vivo research with animal models, and initial phase clinical trials to demonstrate proof of concept.
Primary Metabolites
Key biomarkers for PA include organic acids such as propionic acid, 3-hydroxypropionic acid, and 2-methylcitric acid (2-MCA), as well as glycine conjugates like propionylglycine and tiglylglycine.
Methylcitric Acid (MCA)
MCA is produced from the condensation of propionyl-CoA and oxaloacetic acid by citrate synthase. Plasma MCA levels are considered a useful biomarker for diagnosing and monitoring PA, as they correlate directly with disease burden.
Secondary Metabolites
Secondary metabolites in PA and methylmalonic acidemia (MMA) individuals include intermediates of the tricarboxylic acid (TCA) cycle (such as citric, ketoglutaric, succinic, and malic acids), acetyl-CoA, lactate, and ammonium.
Gene Therapy Development of Propionic Acidemia
Gene therapy has shown significant potential in the therapy of propionic acidemia particularly through the use of Adeno-Associated Virus (AAV) vectors, messenger RNA (mRNA) therapies.
Fig. 2 Gene therapy strategies. (Maestro, S., et al., 2021)- Adeno-Associated Virus (AAV) Gene Therapy: AAV can infect both dividing and non-dividing cells, enabling long-term gene expression within the body. Different AAV serotypes have demonstrated high specificity for various tissues and organs, making AAV an ideal tool for treating PA.
- Messenger RNA (mRNA) Therapy: mRNA therapy is an emerging treatment approach that delivers mRNA encoding the target protein, enabling gene expression within cells. This method can achieve transient expression of therapeutic genes, correcting metabolic defects. Recent research demonstrated that dual mRNA therapy could restore metabolic function in a mouse model of Propionic Acidemia.
Our Services
Our company adopts a collaborative approach, partnering closely with clients to create tailored and innovative therapy strategies for Propionic Acidemia. Our focus on customized strategies ensures that we meet your individual needs with the highest level of support and guidance.
Platforms of Propionic Acidemia Therapy Development
Animal Models of Propionic Acidemia
We have considerable expertise in developing and employing animal models that accurately replicate the disease characteristics and therapeutic responses seen in Propionic Acidemia. These models are instrumental in investigating the underlying mechanisms and assessing the safety and effectiveness of prospective therapies with precision.
Non-Genetically Engineering Models
They are biological systems used in research that do not involve the manipulation or alteration of an organism's genetic material.
Optional Models: Methyl Propionate Inhalation Model; Ammonium Propionate Injection Model; Sodium Propionate Injection Model
Genetically Engineering Models
Genetically engineering models involve the manipulation of genetic material to study specific disease mechanisms and therapeutic interventions.
Optional Models: Pccadel/del Mice Model; Mmut−/− Mice Model; Pccadel/del TgCAG-PCCA(p.A138T)IRES-GFP Mice Model
Moreover, we provide a variety of detailed animal model services focused on particular signaling pathways and molecular targets.
If you are interested in our services, please don't hesitate to contact us.
References
- Marchuk, H., et al., "Pathophysiological mechanisms of complications associated with propionic acidemia." Pharmacol Ther, (2023). 249: p. 108501.
- Maestro, S., et al., "Novel vectors and approaches for gene therapy in liver diseases." JHEP Rep, (2021). 3(4): p. 100300.
- Chandler, R.J. and Venditti, C.P., "Gene therapy for organic acidemias: Lessons learned from methylmalonic and propionic acidemia." J Inherit Metab Dis, (2024). 47(1): p. 63-79.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.