Generalized Arterial Calcification of Infancy (GACI)
Generalized arterial calcification of infancy (GACI) is a genetic disorder that is characterized by severe arterial calcification of the medium-sized arteries, which affects mainly the media with prominent intimal proliferation, and ectopic mineralization of the perivascular structures. Rare cardiovascular disease research, such as GACI, needs dedicated knowledge and holistic solutions. As a specialized preclinical research service provider, Protheragen offers high-quality one-stop drug discovery and development services exclusive to these crippling conditions.
Introduction to Generalized Arterial Calcification of Infancy (GACI)
Generalized arterial calcification of infancy (GACI) is, as the name suggests, arterial calcification of an infantile onset that usually manifests as widespread arterial calcification of the major arteries and/or stenoses of the large/medium-sized arteries with resultant cardiovascular findings (which can include heart failure, respiratory distress, edema, cyanosis, hypertension, or cardiomegaly). The frequency of the disease is approximately one in 200,000 pregnancies, that of carriers one in 223.
Fig.1 Rare monogenic diseases associated with vascular calcification. (Kawai, K., et al., 2022)Pathogenesis of Generalized Arterial Calcification of Infancy (GACI)
GACI can either be caused by ENPP1 deficiency (ENPP1-GACI) or by a deficiency in ABCC6 (ABCC6-GACI), when biallelic pathogenic variants in ENPP1 or ABCC6 are present, respectively.
ENPP1 cleaves the phosphodiester bonds of extracellular nucleotides. Its major known substrate is ATP, which is hydrolyzed to AMP and inorganic pyrophosphate. Impairment of ENPP1 function, therefore, results in low levels of both AMP and inorganic pyrophosphate. Pyrophosphate is the principal inhibitor of hydroxyapatite deposition and its deficiency causes formations ectopically, while AMP and downstream adenosine, defect causes intimal proliferation, and thence arterial stenosis.
Fig.2 Photos of GACI individuals with vascular calcifications. (Boyce, A. M., et al., 2020)Therapeutics Development for Generalized Arterial Calcification of Infancy (GACI)
| Drug Name | Mechanism of Action | Targets | NCT Number | Research Phase |
|---|---|---|---|---|
| INZ-701 | Substitution for deficient ENPP1 enzyme activity and elevated extracellular pyrophosphate to suppress pathological arterial calcification. | ENPP1 | NCT06739980 | Phase II |
| ENPP1-Fc | ENPP1, which is specifically bound to the Fc region of human IgG1, ameliorated mortality and vascular calcification and improved blood pressure and heart function in mice. | ENPP1 | / | Preclinical |
| Pamidronate | Serves as a bisphosphonate to interfere with the deposition of hydroxyapatite crystals and prevent arterial calcification. | FDPS | / | Approved |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a therapy plan recommendation. For guidance on therapy options, please visit a regular hospital.
Our Services
By integrating diagnostics, therapeutics, and disease model development services, we consolidate the entire development process for our clients. Our full range of preclinical testing services, including pharmacokinetic studies and drug safety assessments enable every aspect of your program to be handled with precision and attention to detail. Not only does this integrated model save time, but it also improves the quality and effectiveness of results. With dedicated disease focuses and solution services, we expedite your path from concept to execution using personalized approaches that matter.
Therapeutic Development Services
Animal Model Development for GACI
Animal models help researchers understand the disease process and facilitate the testing of potential therapeutic targets as well as the efficacy and safety of investigational drugs. Our company provides customized animal model development as an efficient tool for GACI research based on our expertise in its development, and all animal models we develop are available for GACI research.
Genetically engineered animal models of GACI involve introducing specific genetic mutations to replicate the human disease.
- Enpp1-/- model
- Other models
- Enpp1asj mutant mouse model
Leveraging cutting-edge technologies and methodology, Protheragen is committed to delivering results that meet industry standards. When you work with us, we bring expertise and a focused team that will help drive your research and development. Get in touch with us today to learn how our unique services can help, progress your project needs.
References
- Kawai, Kenji et al. "Generalized Arterial Calcification of Infancy (GACI): Optimizing Care with a Multidisciplinary Approach." Journal of multidisciplinary healthcare 15 (2022): 1261-1276.
- Boyce, Alison M et al. "Generalized Arterial Calcification of Infancy: New Insights, Controversies, and Approach to Management." Current osteoporosis reports 18.3 (2020): 232-241.
For research use only, not for clinical use.