A five-year-old patient was brought to the emergency room with recurrent polymicrobial lung infections, only 29% small airway function and was unresponsive to antibiotics.

The patient’s medical records included a genetics report from age 1, which showed a 1p34.1 chromosomal duplication encompassing 1.9 Mb, including the PRDX1 gene, which encodes Peroxiredoxin 1. The gene has been linked to airway disease in both rats and humans, and is known to act as an agonist of toll-like receptor 4 (TLR4), a pro-inflammatory receptor. In addition, two patients at another clinic were found to have 1p34.1 duplications:

• One patient with a duplication including PRDX1 died with similar phenotypes
• One patient with a duplication that did NOT include PRDX1 showed no airway disease phenotype

While recurrent lung infections are typically treated with antibiotics, this patient was unresponsive to standard treatments. The patient’s earlier genetics report and data from other patients with similar duplications gave the physician evidence that PRDX1 may play a role in the disease, but no treatments directly related to the gene were known. With this information in mind, the physician asked a researcher familiar with Translator to try to find possible treatments for this patient.

How Might Translator Help?

The patient’s duplication of the 1p34.1 region of chromosome 1 gave Translator researchers a good place to start. Since PRDX1 is an agonist of TLR4, the duplication of the PRDX1 gene likely causes overexpression of PRDX1, which could lead to overactivity of both of the gene products. The researcher decided to try to find drugs that could be used to reduce the activity of those two proteins. An exhaustive search of chemical databases and PubMed to find safe drug options could take days to weeks.

For a known genetic mutation, can Translator be used to quickly find existing modulators to compensate for the dysfunctional gene product?

Initial Insight: dioscin and naltrexone

Translator returned many drug options, but the most promising PRDX1 inhibitor, as chosen by the researcher, was dioscin, a steroid that induces cell death and DNA damage. The researcher also chose one of several returned TLR4 blockers, naltrexone, which is an opioid antagonist.

Dioscin and naltrexone were returned to the clinician as potential treatment options, but the physician felt that these drugs may introduce too much risk to the patient.

The researcher then decided to search for other targets upstream of PRDX1.

Subsequent Translator Insight: Dietary Supplements

Translator also returned several genes that upregulate PRDX1, including NFE2L2, which is a transcription factor associated with some immunodeficiency disorders and cancers. A search for an NFE2L2 inhibitor returned two dietary supplements: ascorbic acid and luteolin.

These results were returned to the clinician, and the clinician decided to recommend the supplements to the patient.

Result

After taking ascorbic acid and luteolin for three months, small airway function increased from 29% to 70%, a significant improvement in quality of life!