IN-DEPTH: MEDICATION AND THERAPEUTICS FOR RACEHORSES


mercially available are untested but nonetheless en- dorsed through anecdotal statements posted online suggesting they have many different applications, including to increase muscle mass, decrease fat, decrease injury recovery time, restore structural maladies, stimulate glucose uptake, and treat acute/ chronic illness. The ample supply of these com- pounds provides unrestricted access to anabolic peptides for abuse by dishonest trainers. Biological emerging threats are listed below:


1. Equine somatotrophin—Elevate insulin-like growth factor (IGF)-1 and insulin-like growth factor binding protein 3 (IGFBP3) production.


2. GH-releasing hormones (GHRH)—elevate GH production.


3. GH-releasing peptides—Mimics GHRH production.


The ideal goal, to counter these illegal biological agents, would be to understand the specific cellular processes that are affected when the drugs are ad- ministered to the horses. To achieve this goal, the biology of the drug class needs to be understood. This is often done through the study of interaction networks. The studies to establish effect must be performed on a large cohort to evaluate each bio- marker’s specificity. Then, an initial screening method could be used to identify ideal biomarker candidates without having to know the specific drug (within a class) that was administered. The bio- marker screening would include a specific panel of targets (proteins in known pathways) from the en- tire equine proteome and indicate critical changes by identifying up/down regulation from what is con- sidered the baseline proteome.


Biotherapeutics


Over the past 15 to 20 years, biological therapeutics have become a large portion of the pharmaceutical and biotech drug development pipelines. The num- ber and variety of new, large molecule therapeutics will continue to increase in the next decade. The human market has many biotherapeutics targeting arthritis, inflammation, and pain that are all local targets for equine biotherapeutic molecules. This expansion in the human field has led to a surge in therapeutics in specialized veterinary disciplines. Canine and feline oncology have already made prog- ress with the introduction of numerous species- specific therapeutics. The market is much smaller, but the global players in equine healthcare are actively adding new drugs into their development pipeline. Large molecules present unique challenges for anti-doping laboratories. Unlike the detection of small molecules, which are often based on their physical and chemical characteristics, biotherapeu- tics frequently require extensive clean-up proce- dures consisting of tryptic digestion and/or immunochemical methodologies, such as antibody


376 2020  Vol. 66  AAEP PROCEEDINGS


purification. Further complicating matters, large- molecule therapeutics often have endogenous coun- terparts in matrix (e.g., erythropoietin). The size of the analytical molecule (molecular weight) alone presents an obstacle very different than small- molecule drugs. For example, some biologics are produced by cell culture, and each batch generates unique outcomes; therefore, individual production lots will vary slightly in terms of the molecular structure, which will affect the end products. Con- sequently, analytical method validation must be linked to reference materials prior to validation ex- periments, making the traceability of reference standards even more important.


Genetic Practices (Gene Editing/Gene Doping)


Gene editing is a type of gene engineering, whereby DNA is inserted, deleted, modified, or replaced within the genome of a living organism. Gene ed- iting is most commonly considered within the realm of gene therapy research, with the aim of curing disease by altering malfunctional genes. To date, over 2300 gene therapy clinical trials have been completed in humans focused on the treatment of cancer and cardiovascular disease. However, like pharmacological therapies, gene therapy has the po- tential for misuse, specifically to enhance perfor- mance in athletes. This has been recognized as a risk to human sports for approximately the last 15 years. Gene doping poses a significant threat to the integrity of horseracing, and without the develop- ment of new methods, will go undetected. When viral vectors carrying genes encoding certain pro- teins are introduced into cells of the equine athlete, those cells will begin to produce these proteins. The cell will use endogenous components to pro- duce these proteins, making the products virtually indistinguishable from their endogenous counter- parts. The most frequently used technique is the so-called CRISPR/Cas9-system, which has fast tracked a wide variety of applications including ba- sic biological research and the development of new therapeutics. Developing analytical methods to de- tect gene doping has been particularly slow and problematic since both the doping gene and the pro- tein produced are likely highly homologous, if not identical, to their organically occurring counter- parts. To overcome this imminent threat, novel methods must be developed, such as monitoring the number of copies of gene within the cell. Baseline data from genetically unmanipulated horses should be collected, and the “normal” number of copies for each gene of interest should be predetermined. Candidate genes that may be targeted would likely include those which 1) induce desirable changes in the muscle phenotype to increase strength and im- prove sprinting ability, 2) may increase oxygen de- livery or blood flow to working muscles for enhanced capability, 3) alleviate pain to resist fatigue and improve post-race recovery, and 4) target mental aptitude, e.g., proopiomelanocortin (POMC) gene.


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