Genomics guided drugs for Asthma

Some of the scariest experiences of our childhood in Montevideo, Uruguay, involved the sudden onset of dyspnea in the middle of the night, which made us gasp for air and scream for help. Fortunately, we could count on two caring parents that quickly burst into our room and proceeded to sit us up in bed, perform some maneuvers and give us a bronchiolar anti-spasm medication (the albuterol inhalers did not exist yet)

Asthma is basically an inflammatory disease that drastically remodels our airways, which provokes shortness of breath and wheezing due to the airway obstruction and hyper-responsiveness; it represents the leading childhood disease in developed nations and affects approximately 400 million people worldwide. Catastrophes like the wildfires in the state of California at present, will only exacerbate its incidence. The interaction between environmental factors and the genetic make-up of patients complicate their long-term treatment, with 5-10% of patients out of disease control.

In the past three decades, extensive research has identified the genetic risk factors for the disease, which consist of single-nucleotide polymorphisms (SNPs); they are genetic variants with an allele frequency of 1% in the general population. To allow the genotyping, and identification of the genes of the SNPs, an innovative assay technique called Genome-Wide Genotyping was designed in 2002; as a result, the Genome-Wide Association Studies (GWASs), that could involve thousands upon thousands of participants, were made possible, shedding light on Asthma genetics. In 2007, Moffatt et al. published a paper reporting that the genetic variation of chromosome 17q12-21 was associated with Childhood Asthma; asthma-associated SNPs in this locus were eventually associated with mRNA expression of ORMDL3 in lymphoblastic cell lines using eQTL mapping. Many more SNPs were later found.

In a paper published in The Lancet Respiratory Medicine, Zaid W El-Husseini et al. updated the list of 128 independent asthma-associated SNPs, which had been discovered mostly in populations of European descent; they emphatically argued that more studies of Non-European populations are necessary to study the genetic causes of Asthma. They said that: “Approximately 88% of the disease-associated variants acquired from GWASs reside in non-coding regions. eQTL analysis is able to identify genetic variation that is involved in gene expression withing a particular tissue or cell type. An SNP within a gene or in close vicinity (within 1 Mbp) of the gene that is associated with gene expression is called a cis-eQTL…161 target genes were significantly to the top asthma SNPs in one or more studies with 154 unique target genes and seven genes overlapping.” What is the utility of this information?

The authors proposed that the asthma target genes are clustered in networks that act in sync to provoke Asthma and that, if identified, can get a downstream intervention. Considering that drug development is a long, costly and risky endeavor, the authors state that: “For a drug to be effective, it needs to be targeted to a protein involved in the causal pathway of the disease or to a physiological repressor of such a casual pathway…A biomarker highly associated with the disease but not part of the causal mechanism is therefore not an appropriate drug target. GWASs can identify genes that causally implicated in a disease and thus provide a robust technique to validate existing targets and unveil novel drug targets.”

Considering the heavy financial and resource burden of developing brand new drugs, scientists and pharma companies are engaging in the search of drug repositioning. Drugs that were initially designed, or are being studied for, another disease might be eventually repurposed for another one, based on sophisticated genetic studies. Out of the 142 asthma target genes that the authors studied, 22 were also targets of drugs for other conditions, either approved by regulatory authorities or being developed. They claimed that the genetics-targeted approach might be useful in 3 scenarios:

  1. It could identify individuals with a risk genotype related to a target for an already available drug, which would facilitate their responses to it.
  2. The discovery of an Asthma risk allele might identify a biomarker to find the best candidates for a certain treatment.
  3. The genetic studies of sub-groups of patients might identify clinical features that are idiosyncratic to them, furthering the targeting of specific drugs.

The eventual treatment responses might vary amongst individuals and for the same patient in different circumstances, depending on time-specific and tissue-specific specific epigenetic effects, the local inflammatory conditions, the contribution of transformed tissue, as well as tissue specificities and the drug’s tissue concentration. Even though the genomic studies have contributed to drug repositioning in Asthma, the authors stated that the functional annotation of many Asthma genes is missing.

The authors said: “Finally, for many asthma genes, associated pathways are missing because the emergence of functional evidence is lagging behind gene discovery. Multi-disciplinary research that integrates genetic findings, functional evidence, and therapeutic intervention might offer a way to move forward in developing much-needed asthma therapies.”

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