# Reducing Nephrotoxicity while enabling read through of missense stop codons by Gentamicin congeners

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2020 · —

## Abstract

Aminoglycoside antibiotics remain first line therapy for gram negative infections and are used in conjunction
with other antibiotics for certain gram positive organisms. Aminoglycosides, especially gentamicin, have also
been used to suppress premature stop codon termination of protein synthesis leading to monogenic diseases
like cystic fibrosis and Duchene's Muscular Dystrophy. Unfortunately, they still have an unacceptably high rate
of dose and duration-dependent nephrotoxicity, especially in the elderly and in patients with chronic kidney,
heart and liver disease. We have previously identified non-nephrotoxic, yet bactericidal, congeners of
gentamicin that we now propose to use to determine their efficacy in suppressing premature termination
codons (PTC). To do this we will use a human proximal tubule cell line with a novel FRET probe allowing for
ratiometric quantitation of readthrough of different embedded stop codons. This will be followed by in vivo
studies, again using the FRET probe, but now with 2-photon microscopy in kidney proximal tubule cells labeled
by subcapsular delivery of specifically designed plasmids based on the cell culture data. To test the clinical
potential of this approach we will study the mdx mouse and quantify dystropin synthesis in response to dose
and duration dependent therapy. Finally, we will develop a transgenic mouse for the most appropriate stop
codon, determined by the rat studies, and quantify readthrough in multiple tissues throughout the body. This is
particularly important as many solid tumor cancers have monogenic premature termination codons that lead to
malignant transformation of the cell type and these are also responsive to suppression therapy by
aminoglycosides. We hypothesize that gentamicin congeners, with markedly reduced nephrotoxicity,
will provide enhanced suppression of PTC leading to synthesis of functional proteins needed to
reduce and/or prevent multiple PTC diseases. The nontoxic congeners will allow us to directly compare
and contrast differences between toxic and nontoxic forms thereby leading to greater understanding of the
factors mediating premature termination codon suppression in multiple cell types. These studies will provide
the information necessary to enhance translation into clinical studies of multiple diseases.

## Key facts

- **NIH application ID:** 9898260
- **Project number:** 5I01BX001137-08
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** ROBERT L BACALLAO
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2011-10-01 → 2021-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898260

## Citation

> US National Institutes of Health, RePORTER application 9898260, Reducing Nephrotoxicity while enabling read through of missense stop codons by Gentamicin congeners (5I01BX001137-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9898260. Licensed CC0.

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