# MPS Qualifications Section

> **NIH NIH U2C** · UNIVERSITY OF WASHINGTON · 2024 · $668,403

## Abstract

ABSTRACT – MPS Qualification Section
The failure rate for drugs entering clinical study between phase I/II and FDA submission approaches 90% with
40-50% of those failures attributed to lack of efficacy, 30% to unmanageable toxicity, and 10-15% to poor drug-
like properties (unfavorable pharmacokinetics). With an estimated expenditure of $1.3 billion (USD) to move a
therapeutic candidate from early drug discovery through Phase I trials, development of rigorous and
reproducible tools that can better predict compound liabilities and clinical characteristics are critical to improve
drug safety and efficacy.
In response to the critical unmet need for better preclinical models, our interdisciplinary team has pioneered
the development of the proximal tubule epithelial cell microphysiological system (PTEC-MPS) and the kidney
organoid. Once qualified these platforms can, with specific biomarkers as drug development tools, address the
three major causes of drug attrition during drug development. We believe that these technologies are robust
and reproducible, and within specific contexts of use, can be relied upon to have a specific interpretation and
application during drug development and regulatory review. We have proposed the following contexts of use
(COUs) for our technologies:
1. To demonstrate the utility of a PTEC-MPS device to reliably identify proximal tubule toxicity, as exhibited by
toxicity biomarkers KIM-1, HO-1, microRNA, and RNAseq, from drugs cleared by filtration (polymyxin B,
cisplatin) with reproducibility between freshly isolated PTECs and cryopreserved cells after 3 and 6 months of
storage.
2. To demonstrate the utility of a PTEC-MPS device to reliably identify proximal tubule toxicity, as exhibited by
toxicity biomarkers KIM-1, HO-1, microRNA, and RNAseq, from drugs cleared by tubular secretion (tenofovir,
drisapersen) with reproducibility between freshly isolated PTECs and cryopreserved cells after 3 and 6 months
of storage.
3. To demonstrate the ability of a physiologically-based pharmacokinetic (PBPK) model populated with PTEC-
MPS derived renal clearance parameters to predict maximum serum concentration (Cmax) and total drug
exposure (AUC) of filtered and secreted drugs (e.g., tenofovir, furosemide) in healthy subjects and subjects
with impaired kidney function.
4. To measure therapeutic efficacy for hereditary disorders in MPS by quantifying the effect of pharmacological
interventions on kidney disease phenotypes in genetic organoid models using biomarkers for two distinct
disease states: polycystic kidney disease and nephropathic cystinosis. The models will be rigorously quantified
to demonstrate reproducibility and batch-to-batch consistency in isogenic human kidney organoids with
disease-causative mutations, compared to isogenic control organoids. Correspondence between datasets of
organoid biomarkers vs. clinical biomarkers will be calculated to establish a correlative formula. Using
therapeutics with known clinical effects,...

## Key facts

- **NIH application ID:** 10816296
- **Project number:** 1U2CTR004867-01
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** EDWARD J KELLY
- **Activity code:** U2C (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $668,403
- **Award type:** 1
- **Project period:** 2024-02-01 → 2024-09-22

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10816296

## Citation

> US National Institutes of Health, RePORTER application 10816296, MPS Qualifications Section (1U2CTR004867-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10816296. Licensed CC0.

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