Hypophosphatasia (HPP)
Animal models of hypophosphatasia (HPP) provide researchers with valuable tools for studying the disease and developing potential therapies. Our company is dedicated to helping our clients create animal models of human disease that accurately simulate human characteristics at the onset of disease. Our disease modeling services and preclinical research capabilities provide a unique advantage in developing effective HPP therapies.
Background
HPP is a rare genetic bone metabolism disorder characterized by impaired bone and/or tooth mineralization. It is caused by mutations in the gene encoding tissue non-specific alkaline phosphatase (TNSALP), the enzyme responsible for regulating the mineralization of bones and teeth. Its manifestations vary from mild cases that may present only with pathological fractures of the lower extremities in adulthood to severe cases that may result in stillbirths without mineralized bone. Due to the rarity of this disease, the development of effective therapies has been challenging.
Animal models of disease are essential for understanding the pathophysiology of various human diseases, including HPP. To date, most animal models of HPP have been designed in rodents. Researchers have obtained HPP mice through genetic engineering modifications. However, these engineered models have limitations because they do not faithfully represent the broad range of human HPP manifestations. Recently, the development of large animal models of HPP has improved the consistency and utility of animal models for studying rare bone diseases.
Fig. 1 Skeletal muscle histological phenotype in ALPL c.1077 C > G targeted sheep. (Williams D K, et al., 2018)
Our Services
We offer disease modeling services for a variety of genetic diseases, such as HPP. Our disease modeling services use the latest gene editing technologies, such as CRISPR/Cas9, to generate animal models that exhibit similar symptoms to HPP, including skeletal abnormalities and dental problems. Our disease modeling services include, but are not limited to:
- Generation of HPP mouse model
We generate Tnsalp-/- mouse models for our clients to simulate a severe form of HPP. In this model, phenotypically abnormal biochemical parameters such as elevated concentrations of plasma pyridoxal-5ʹ-phosphate and urinary phosphoethanolamine can be used as readouts to assess ERT efficacy. - Generation of HPP sheep model
The development and replacement of teeth as well as skeletal organization and bone remodeling in sheep are highly similar to those in humans compared to mice. Our expert team helps clients generate large animal models of HPP by introducing a single-point mutation in the TNSALP gene (ALPL) in sheep using CRISPR/Cas9. - Provision of HPP canine model
We provide our clients with Karelian bear dog models with diseases associated with autosomal recessive defects in the alkaline phosphatase gene ALPL. This is a spontaneous animal model of human HPP.
Our Solutions
Our animal models of HPP can be used extensively in preclinical research to investigate potential therapies for the disease and provide valuable data for drug development. Our solutions include:
- Development of animal models for HPP pathophysiology research
- Development of animal models for preclinical validation of enzyme replacement therapy (ERT) for HPP using recombinant mineral-targeting TNAP
- Development of animal models for preclinicalvalidation of enzyme replacement for HPP using viral vector delivery of mineral-targeting TNAP
Our disease modeling and preclinical research capabilities enable us to test the efficacy and safety of potential HPP therapies in animal models before they are tested in humans. This helps to reduce the risk of adverse effects in human trials and increases the likelihood of success. If you are interested in our disease modeling services, please contact us for more information.
Reference
- Williams, D. K.; et al. Genetic engineering a large animal model of human hypophosphatasia in sheep. Scientific reports, 2018, 8(1): 16945.
All of our services and products are intended for preclinical research use only and cannot be used to diagnose, treat or manage patients.
