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TRANSLATOR TIDBIT 04

Finding Marketed Drugs that Might Treat an Unknown Syndrome by Perturbing the Disease Mechanism Pathway

Some translational research questions start at the bedside, as opposed to the bench.

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TRANSLATOR TIDBIT 04

I want to what...

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!

The Power of Translator

Generating new hypotheses for potential investigation through clinical trials
Translator identified several potential treatments for an unknown respiratory disorder based on a known genetic mutation. Working closely with clinicians, an option with relatively low risk was identified and when tried, significantly increased airway function.

Process Details

Translator was queried to find drugs that could reduce the PRDX1 and TLR4 proteins. One of Translator’s reasoning tools, mediKanren, returned several potential treatments based on database assertions from the Semantic MEDLINE Datbase (SemMedDB). These included dioscin, a steroid that induces DNA damage and cell death and downregulates PRDX1, and naltrexone, an opioid agonist that blocks the action of TLR4. These two drugs were returned to the patient’s physician as a potential treatment option, but the physician was concerned about potential side effects from these two drugs, and asked the researcher to continue the search.

Since potential treatments to directly target PRDX1 and TLR4 were too risky, upstream regulators of these genes were investigated next. Translator was queried to find genes that regulate PRDX1, and erythroid-like nuclear factor 2 (NFE2L2) was returned, which is known to upregulate PRDX1. Reduction of NFE2L2 therefore can be assumed to also reduce PRDX1, so Translator was then queried to find drugs that can reduce NFE2L2, and a pair of dietary supplements, ascorbic acid and luteolin, were returned based on SemMedDB assertions. Since dietary supplements are not likely to cause major side effects, these supplements were returned to the patient’s clinician, who decided to recommend that the patient try the supplements. Three months after taking the supplements, the patient’s airway function had improved significantly, by 41%.

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Data Sources Connected

RTX

A reasoning tool created for Translator that integrates many different databases into a cohesive knowledge graph.

SemMedDB

A repository of semantic predications (subject-predicate-object triples) extracted by SemRep, a semantic interpreter of biomedical text. SemMedDB currently contains approximately 94.0 million predications extracted from PubMed.

MONARCH

A database linking model organism research to human disease allowing for the comparison of similar phenotypic profiles across species.

mediKanren

A reasoning tool created for Translator that can access knowledge graphs to find novel connections between data points.

References
https://www.nature.com/articles/s41598-017-06484-6
https://skr3.nlm.nih.gov/SemMedDB/dbinfo.html
https://monarchinitiative.org/

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