# Effective treatment of cystinuria with a novel engineered cyst(e)ine-degrading human enzyme therapy

> **NIH NIH R21** · UNIVERSITY OF TEXAS AT AUSTIN · 2024 · $437,761

## Abstract

Project Summary
Cystinuria is a rare disease characterized by chronic, recurrent lithiasis (stone formation) in the urinary tract due
to accumulation of high concentrations of cystine in the urine. This accumulation results from impaired
reabsorption of the amino acid cysteine and its poorly-soluble, oxidized form, cystine, from the kidney back into
systemic circulation. Current therapeutic strategies involve lowering the effective cystine concentration or
increasing its solubility in the urine, but patient compliance is low due to treatment burden and unfavorable side
effect profiles. Chronic kidney disease is common and surgical intervention is a necessary and recurrent event
in the lives of these patients. For these reasons, the disease burden due to cystinuria represents an unmet
clinical need. In short, both the disease and its narrow range of treatment options exact a heavy toll on cystinuria
patients, resulting in greatly diminished quality-of-life. Therefore, there is an urgent need to provide safe,
effective therapies that not only prevent or slow the growth of cystine kidney stones, but also carry a low
treatment burden and thus promote adherence to therapy.
Human enzyme therapy represents an attractive, tractable means of combatting metabolic disorders that
manifest as metabolite imbalances in the systemic circulation or in tissue compartments that are addressable
through manipulation of the systemic circulation. In principle, cystinuria fits this treatment modality, as cysteine
and cystine (cyst(e)ine) derived from the blood are filtered into the urine where they concentrate due to defective
reabsorption mechanisms, leading to lithiasis. Lowering circulating levels of cyst(e)ine to concentrations that
will normalize urine metabolite levels but not affect cyst(e)ine homeostasis should prevent or reduce the rate of
stone formation, even in the context of impaired reabsorption of these amino acids. Therapeutic enzyme-
mediated normalization of amino acid levels has been clinically validated for other diseases.
This project seeks to determine if a human enzyme therapeutic that degrades cyst(e)ine can prevent or slow
lithiasis and mitigate associated kidney pathology in the Slc3a1 knockout mouse model, a translationally-relevant
model of human cystinuria. Changes in stone volume and multiplicity will be assessed by computed tomography
and values will be compared to controls and baseline values as appropriate. Importantly, the long-term safety
of this approach will also be evaluated by chronically dosing human cyst(e)inase in mice and undertaking a
rigorous health assessment of treated animals, including body weight and behavioral measurements, blood-
based measures of physiological function, and metabolomics.

## Key facts

- **NIH application ID:** 10939186
- **Project number:** 1R21TR005156-01
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** GEORGE Georgiou GEORGIOU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $437,761
- **Award type:** 1
- **Project period:** 2024-08-01 → 2026-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10939186

## Citation

> US National Institutes of Health, RePORTER application 10939186, Effective treatment of cystinuria with a novel engineered cyst(e)ine-degrading human enzyme therapy (1R21TR005156-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10939186. Licensed CC0.

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