Endometriosis study exposes disconnect between animal research and clinical investigation

18 August 2020

by Marcia Triunfol

Endometriosis is a debilitating condition in which tissue that normally lines the inside of the uterus invades other pelvic organs, resulting in significant pain that can diminish quality of life. The disease afflicts approximately 176 million women and girls globally; in the UK alone, around 1.5 million women (1 in 10) are currently living with the condition. Endometriosis can lead to infertility in up to 40% of women who suffer from it. Despite its prevalence, its causality is not well understood and there is no specific treatment.

An in-depth review by Dr Carla Piccinato and colleagues from Hospital Israelita Albert Einstein in São Paulo, Brazil, examined available preclinical models for endometriosis, including their translational efficacy and limitations. A fundamental challenge the authors identify is continuing scientific reliance on rodents to model a human disorder that does not develop naturally in these animals. Efforts to create an artificial animal model for human endometriosis resort to invasive surgery to transplant endometrial cells into rodents’ abdominal cavity. This approach produces only superficial lesions compared with the clinical manifestations in humans.

The review found that drugs developed to treat endometriosis, which appeared efficacious in preclinical testing, failed at a rate of more than 80% in human clinical trials. For example, the drug Resveratrol showed promising results in reducing inflammation and inhibiting angiogenesis in rodents, yet failed when tested in patients. The authors further document that among 18 complete clinical trials for new therapeutic interventions for endometriosis, all were in fact drugs approved by the U.S. FDA for treatment of other diseases—none of which were products of preclinical studies using animal models of endometriosis.

“We were surprised to see that most approaches using animals focus on lesion regression, as if it was an important endpoint in endometriosis research when in fact lesion regression has never been picked as an end-point of clinical studies in endometriosis,” says Dr Carla Piccinato.

Indeed, the medical community seems to agree that finding ways to mitigate symptoms of endometriosis is the desired goal in order to offer patients a better quality of life.

New human-centered technology and predictive modeling approaches are increasingly supplanting animal models to study endometriosis and its association with pain. Large-scale integrated genome-wide RNA sequencing, miRNA analysis associated with pelvic pain, tissue-specific expression analysis of patients’ samples by laser capture microdissection, genetic associations between endometriosis and obesity-related traits are but a few examples of contemporary approaches yielding relevant results. In vitro studies using patients’ biopsy tissues have revealed that progesterone-resistance may play a role in endometriosis and have opened a new window into development of progestins, a class of drugs that inhibit inflammation, angiogenesis and oxidative stress in the endometrium cells.  And genome-wide association studies (GWAS) have shed additional light, revealing an association between endometriosis and specific gene pathways that may be targets for drug discovery.

The promise of such research and the obvious limitations of animal modeling for endometriosis suggest that stronger investments are warranted in the development of non-animal methods and techniques and better clinical investigation and research focusing on patient symptoms and response to treatment.

The review, Endometriosis: current challenges in modeling a multifactorial disease of unknown etiology, sponsored by BioMed21 Collaboration partner Humane Society International, was published in August 2020 edition of the Journal of Translational Medicine. The authors provide a road map into the future research of endometriosis in which they contemplate the use of AI and 3D blood vessel printing to further advance understanding of the disease and develop treatments to offer hope to the millions of women suffering from this debilitating condition.

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