Argininosuccinic aciduria (ASA)
Argininosuccinic aciduria is a rare inherited disorder marked by a deficiency or absence of the enzyme argininosuccinate lyase (ASL). This enzyme is one of six involved in the urea cycle, which is essential for breaking down and eliminating nitrogen from the body. 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 Argininosuccinic aciduria.
Introduction to Argininosuccinic aciduria
Argininosuccinic aciduria (ASA) is an autosomal recessive disorder caused by mutations in the argininosuccinate lyase (ASL) gene, characterized primarily by hyperammonemia. Urea cycle disorders are a set of uncommon conditions that impact the urea cycle, which is a sequence of biochemical reactions responsible for converting nitrogen into urea and expelling it from the body via urine. Nitrogen, produced during protein metabolism, becomes a waste product. When the body cannot properly process nitrogen, it leads to an abnormal buildup of ammonia in the bloodstream.
Fig. 1 Systemic phenotype in argininosuccinic aciduri. (Baruteau, J., et al., 2019)Pathogenesis of Argininosuccinic aciduria
Argininosuccinic aciduria (ASA) is caused by a deficiency in argininosuccinate lyase (ASL), which affects the conversion of argininosuccinate into arginine and fumarate in the urea cycle. This deficiency leads to hyperammonemia and a lack of arginine and its downstream metabolites, resulting in various metabolic disorders. The toxicity of argininosuccinate and guanidinosuccinic acid, along with nitric oxide (NO) deficiency, are key factors in the pathogenesis of ASA.
Fig. 2 Main pathophysiological mechanisms in argininosuccinic aciduria. (Baruteau, J., et al., 2019)Biomarkers of Argininosuccinic aciduria
- Argininosuccinic Acid: Individuals with ASA have significantly elevated levels of argininosuccinic acid (ASA) in their plasma and urine. This is the primary biomarker for ASA and is essential for diagnosis.
- ASL Enzyme Activity: Measuring the activity of the ASL enzyme (argininosuccinate lyase) in cultured fibroblasts or leukocytes. Individuals with ASA show significantly reduced ASL enzyme activity.
- ASL Gene Mutations: Identifying mutations in the ASL gene through genetic sequencing (e.g., Sanger sequencing or next-generation sequencing) is the gold standard for confirming ASA. The type and location of mutations can help predict the severity and presentation of the disease.
Gene Therapy of Argininosuccinic aciduria
(AAV) Vector-Based Therapy
This therapy utilizes AAV vectors to deliver a functional copy of the ASL gene to individual cells. In studies using AslNeo/Neo mice, which mimic human ASA, a single systemic injection of the gene therapy vector demonstrated long-term correction of both the urea cycle and the citrulline-nitric oxide cycle.
(LNP-mRNA) Therapy
This approach involves delivering nucleoside-modified mRNA encoding the ASL enzyme encapsulated in lipid nanoparticles. In mouse models, intravenous administration of this therapeutic mRNA significantly improved survival rates and demonstrated robust ASL protein expression with a favorable safety profile.
Our Services
Our company adopts a collaborative approach, partnering closely with clients to create tailored and innovative therapy strategies for Argininosuccinic aciduria. Our focus on customized strategies ensures that we meet your individual needs with the highest level of support and guidance.
Platforms of Argininosuccinic aciduria Therapy Development
Animal Models of Argininosuccinic aciduria
We have considerable expertise in developing and employing animal models that accurately replicate the disease characteristics and therapeutic responses seen in Mucolipidosis. 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: Hyperammonemia Induction Model; Amino Acid Restriction Model; Urease Injection Model
Genetically Engineering Models
Genetically engineering models involve the manipulation of genetic material to study specific disease mechanisms and therapeutic interventions.
Optional Models: ASL Knockout Mice Model; Hypomorphic AslNeo/Neo Mice Model; ASL Transgenic Rescue 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
- Baruteau, J., et al., "Argininosuccinic aciduria: Recent pathophysiological insights and therapeutic prospects." J Inherit Metab Dis, (2019). 42(6): p. 1147-1161.
- Wasim, M., et al., "Aminoacidopathies: Prevalence, Etiology, Screening, and Treatment Options." Biochem Genet, (2018). 56(1-2): p. 7-21.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.