Axcelead offers strong support for drug discovery for kidney diseases, from target validation and evaluation in animal models to bridging toward clinical development
The kidney is complicated organ composed of various cells with many different functions. Although there is an abundance of drugs for lifestyle diseases, they can not stop progression, leading to dialysis. Development of drugs that directly target the kidneys is still inadequate due to a lack of reliable biomarkers that can predict efficacy. We can support the development of drugs for kidney diseases from target identification / validation, drug efficacy study in kidney disease models, as well as the discovery of clinical biomarkers and bridging toward clinical development.
Identification of target molecules by comprehensive gene expression analysis using patient samples and disease model samples.
Validation of drug efficacy in kidney disease models using commercially available compounds, antibodies, etc. for target molecules.
Confirmation of ameliorative/detrimental effects on renal failure and fibrosis in target molecule KO mice.
We provide high-quality hit compounds for a wide range of targets using the largest industrial class, high-quality compound libraries, and a variety of high-throughput screening techniques.
HTS（High-Throughput Screening）
We can develop various cellular assays based on drug target in discussion with the clients.
From our various disease models of chronic kidney disease and acute kidney injury, we propose the most appropriate disease model and assay that meet the needs of the client, such as “to focus on glomerular lesions” or “to analyze fibrosis” can be proposed.
We also choose PD markers, which are combined with PK studies to clarify the drug profile.
Drug efficacy using the same biomarkers as in clinical settings can be evaluated.
Novel biomarker discovery and validation study that match your drug target can be designed.
Contribution to planning of clinical development strategy, from quantitative analysis combining PK/PD/efficacy analysis with modeling & simulation, can be provided.
Axcelead’s approach to various challenges in drug discovery for kidney diseases
— Are you experiencing a problem like this? —
Solution A: An optimal kidney disease model for evaluation of drug efficacy and mechanism of action analysis is proposed.
- We can propose the most appropriate disease model for chronic kidney disease (CKD)/acute kidney injury (AKI) to solve the client’s problems, and evaluate drug efficacy.
- We can set PD markers and select drugs and dosages to be examined in the disease model due to changes and duration of PD marker, in combination with PK studies. PK/PD studies are also conducted in order to prove drug efficacy based on MOA.
- New genetically engineered animals based on target molecules can be generated in a short period of time and used for evaluation of drug efficacy.
We can contribute to an improved clinical trial success rate by evaluation of drug efficacy in the best model
for your target molecule.
■Kidney disease models
■Characteristics of kidney disease models
1) Nephrol Dial Transplant 2021, 36, 631., 2) Atherosclerosis 1977, 27, 165.,
3) Scientific Reports 2019, 9, 15547.,4) Eur J Pharmacol. 2021, 894, 173852. ND：No Data
■AXCC mice: Axcelead’s original kidney disease model which exhibits CKD-like symptoms
(Axcelead DDP-generated Col4a5 R471X-Chronic kidney disease model mice)
This is our original genetically engineered mice with a Col4a5 R471X mutation derived from an Alport syndrome patient.
Albuminuria develops from young age due to abnormal glomerular basement membrane, leading to fibrosis and decreased renal function (glomerular filtration rate) via secondary tubulointerstitial injury.
The renoprotective effect of angiotensin II receptor blockers (ARBs) used in clinical settings can be detected.
Research achievements on AXCC mice
Poster presentation at the 42nd Annual Meeting of the Molecular Biology Society of Japan
Collaborative research with Tsukuba University has been published in Scientific Reports.
An in vivo study conducted in Axcelead have been published in Nature Communication.
Solution B: Clinically applicable biomarkers that can evaluate drug efficacy are proposed.
- We can propose various biomarkers that can reflect disease progression and drug efficacy, including biomarkers used in clinical settings such as glomerular filtration rate (GFR) and urine albumin/protein, according to the study purpose.
- In order to predict drug efficacy in clinical settings and prove that drugs act through the target, we can discovery for target-specific biomarkers .
By measuring biomarkers used for diagnosis and prognosis in clinical setting, discovery of new biomarkers, and bridging toward clinical setting, we can contribute to an improved success rate of drug discovery!
■Renal function = Glomerular filtration rate (GFR) measurement
We can measure GFR in mice and rats, which is important for evaluating renal function as a diagnostic criteria for CKD.
■Measurement of biomarkers in urine, blood, and kidneys
In drug efficacy studies, various urine and blood biomarkers used in the diagnosis and prognosis of CKD and AKI patients, are measured.
Biomarkers are measured depending on disease severity and the mechanism of action for the drug.
Biomarkers used in the diagnosis and prognosis
of CKD patients
・Urine albumin and protein
・Blood urea nitrogen and creatinine
Biomarkers reflected pathophysiological process
■Discovery of novel biomarkers using clinical and disease model samples and application to clinical setting
・Identification
In order to be highly sensitive to disease progression and drug efficacy, novel biomarker candidates are identified by omics analysis using clinical samples and kidney disease model samples (blood, urine, and tissue).
Introduction to omics analysis
・Validation
We validate the usefulness of biomarker candidates
(1) Evaluation of drug efficacy and changes in biomarker candidates in animals treated with the drug
(2) Evaluation of disease progression and changes in biomarker candidates in a kidney disease model
・Application
To increase the success rate in a clinical trial, modeling & simulation are combined with PK/PD analysis using known and novel biomarkers, thus contributing to the smooth bridge to clinical development.
Introduction to modeling & simulation
Solution C: Analysis of the complicated kidney structure
at the tissue/cell level
- The most advanced techniques in molecular biology are used to analyze the complicated structure of the kidney, breaking it down to the tissue/cell level.
- Validation study that combine results obtained from molecular biological methods with genetically engineered animals are proposed.
Experts analyze kidneys with complicated structures using various methods in order to support clients in solving problems such as MOA analysis of drug efficacy and toxicity and the identification of biomarkers, including PD markers!
