Pseudohypoaldosteronism type 1 (PHA-1) is a rare genetic disorder that presents as an unresponsiveness to aldosterone, becoming apparent in newborns with hyperkalemia, hyponatremia, and metabolic acidosis. Protheragen is a premier research service provider specializing in rare kidney diseases, with a dedicated focus on PHA-1. With us, pharmaceutical and biotechnology companies that require support in accelerating drug discovery and development for PHA-1 will find full-service solutions tailored to their needs. Our experienced scientists incorporate advanced technologies to provide custom-tailored diagnostic, therapeutic, and disease modeling development services.
Overview of Pseudohypoaldosteronism Type 1 (PHA-1)
Pseudohypoaldosteronism type 1 (PHA-1) is a disorder that results from renal tubules resisting the action of the hormone aldosterone, leading to complications in sodium regulation. It is a rare, diverse disorder of insufficient mineralocorticoid action leading to a disorder of insufficient secretion of potassium and hydrogen. Estimated to affect roughly 1 in 80,000 live births, PHA-1 is indeed very rare. PHA-1 results in salt wasting, failure to thrive, and can lead to dehydration and even circulatory shock.
Fig.1 Renal ultrasound of the individual. (Kim, S. J.,
et al., 2021)
Pathogenesis of Pseudohypoaldosteronism Type 1 (PHA-1)
Autosomal dominant and autosomal recessive forms of PHA-1 are associated with mutations in one of four different genes that regulate sodium. Genetic variations linked to dominant PHA-1 are acquired through mutations in the NR3C2 gene, which is responsible for encoding the mineralocorticoid receptor protein. Autosomal recessive PHA-1 is associated with mutations in the SCNN1A, SCNN1B, or SCNN1G genes. Each of these genes encodes for one of the subunits that form the protein complex known as the epithelial sodium channel (ENaC).
Fig.2 Diagram of the individual's and parents' exon 7-9 deletion. (Kim, S. J.,
et al., 2021)
Alterations in the NR3C2 gene result in either a nonfunctional or dysfunctional mineralocorticoid receptor protein that fails to adequately control the specialized proteins that manage the transport of sodium and potassium. Changes to the SCNN1A, SCNN1G, and SCNN1B genes result in either nonfunctional ENaC channels or diminished functioning ENaC channels. Similar to autosomal dominant PHA1, the diminished or lack of ENaC function within the kidneys causes hyperkalemia and hyponatremia.
Therapeutics Development for Pseudohypoaldosteronism Type 1 (PHA-1)
| Therapeutics |
Targets |
Key Findings/Mechanism |
Research Stage |
| Sodium polystyrene sulfonate |
Potassium Ions |
Binding potassium ions in the GI tract and exchanging them for sodium ions promotes potassium excretion and reduces hyperkalemia. |
Approved |
| Fludrocortisone |
Mineralocorticoid Receptor |
Functions as a replacement for mineralocorticoids to promote sodium reabsorption and potassium excretion. |
Approved |
Disclaimer: Protheragen focuses on providing preclinical research services. This table is for information exchange purposes only. This table is not a treatment plan recommendation. For guidance on treatment options, please visit a regular hospital.
Our Services
Along with supporting PHA-1 drug development from early discovery to the preclinical stage, Protheragen offers a full spectrum of services. We identify new genetic mutations and confirm the disease pathology through our cutting-edge diagnostic development services. Strong in-house capabilities in medicinal chemistry and pharmacology back our therapeutic development services. Considering the unique aspects of PHA-1 drug research, we provide a comprehensive portfolio of preclinical and pharmacokinetic analyses and safety evaluations.
Therapeutic Development Platforms for PHA-1
Disease Models Development for PHA-1
Accurate disease models are essential for grasping the pathology of PHA-1 and for evaluating possible therapies. My group is focused on developing and characterizing sophisticated models that capture the salient features of the human disease. We provide distinct cell, organoid, and animal models to assist in your research, spanning from high-throughput drug screening to in vivo efficacy assessment.
- Primary renal cells
- Cell line development
- Patient-derived kidney organoids
- iPSC-derived kidney organoids
- And more
PHA-1 animal models are developed by genetic engineering technology, disrupting the genes that encode the subunits of the ENaC.
Drug Pharmacokinetics & Safety Evaluation Services
In Vitro ADME Services
- Renal Clearance Assay
- Drug-Transporter Interaction Screening
- Metabolic Stability Assay
- CYP Inhibition Screening
- Plasma Protein Binding
In Vivo Pharmacokinetics
- PK Studies in Renal Impairment Models
- Kidney Tissue Distribution Study
- Blood-to-Plasma Ratio
- Metabolite Profiling
Protheragen's integrated approach to PHA-1 research and development combines knowledge in genetics, molecular biology, and preclinical science to provide comprehensive solutions in drug discovery. We assist pharmaceutical companies and researchers in progressing PHA-1 therapies. Reach out to us today to benefit from our unique capabilities and accelerate your PHA-1 research projects.
Reference
- Kim, Su Jin et al. "A Neonate with Autosomal Dominant Pseudohypoaldosteronism Type 1 Due to a Novel Microdeletion of the NR3C2 Gene at 4q31.23." Children (Basel, Switzerland) 8.12 (2021): 1090.
All of our services and products are intended for preclinical research use
only and cannot be used to diagnose, treat or manage patients.
