FDA-approved drug may address a major cause of infertility

Good news! Nice example of drug repurposing!

"Primary ovarian insufficiency (POI), in which the ovaries don’t mature and release eggs properly, affects about 3% of women under age 40 and typically causes infertility. But a drug already approved to treat kidney disease may one day help some of these people [women] get pregnant, a research team reports today in Science. ..."

From the editor's summary and abstract:

"Editor’s summary

Premature ovarian insufficiency is associated with decreased numbers of ovarian follicles and decreased frequency of menstrual periods before age 40. This occurs in more than 1% of women and leads to what is generally considered to be irreversible infertility. By screening a library of approved drugs, Lin et al. identified a promising candidate in finerenone, a mineralocorticoid receptor antagonist used for kidney disease ... The authors demonstrated that finerenone decreased ovarian fibrosis in mouse models, facilitating follicular development and improving fertility, and other antifibrotic drugs showed similar effects. In a pilot clinical trial, patients treated with finerenone showed improvement in ovarian function and follicle maturation, some getting as far as in vitro fertilization, all without major side effects or risk of fetal exposure.

Structured Abstract

INTRODUCTION

Premature ovarian insufficiency (POI) affects approximately 1 to 3% of women under the age of 40. It is characterized by symptoms such as oligomenorrhea or amenorrhea, sex steroid deficiency, elevated follicle-stimulating hormone levels, and infertility. Currently, no effective treatments exist to restore fertility in patients with POI. This is because ovarian follicular development in these patients is insufficient, typically lacking ultrasound-detectable antral follicles that are hormone-responsive. ...

RATIONALE

... we established a platform and systematically screened 1297 compounds from an FDA-approved drug library and identified finerenone as a safe and potentially effective candidate for treating POI-associated infertility.

RESULTS

We first revealed that finerenone promoted ovarian follicular development in mice, with no observed adverse effects on oocyte quality, early embryonic development, or offspring health.

Furthermore, our pilot clinical trial showed that oral finerenone administration (20 mg, twice weekly) promoted the development of follicles in patients with POI, yielding mature eggs (oocytes) and viable embryos. Mechanistically, we found that finerenone reduced collagen deposition (fibrosis) within aged ovaries, thus reducing the stromal fibrosis-mediated restriction of follicular development and creating a more permissive microenvironment for follicle activation and growth.

Based on these findings, we further identified a series of FDA-approved oral antifibrotic drugs, including nintedanib, ruxolitinib, and other drugs with established antifibrotic activity but based on distinct antifibrotic mechanisms, which were effective in promoting ovarian follicle growth. ... This broader validation across antifibrotic drugs with different mechanisms of action supports the notion that ovarian stromal fibrosis is a central, druggable, pathological condition that suppresses follicle growth in POI.

CONCLUSION

Our findings provide a starting point showing that targeting the ovarian stroma—rather than the follicles themselves—represents an effective therapeutic strategy for POI-related infertility. We propose that alleviating ovarian stromal fibrosis through repurposed antifibrotic drugs, such as finerenone, nintedanib, ruxolitinib, or other FDA-approved oral agents, offers a possible promising intervention for restoring fertility in patients with POI."

FDA-approved drug may address a major cause of infertility | Science | AAAS

Antifibrotic drug finerenone restores fertility in premature ovarian insufficiency (no public access)

Schematic model of finerenone-mediated follicle growth.

Ovarian stromal collagen suppresses the development of small follicles (left), whereas finerenone reduces the fibrotic deposits (right), relieving stromal constraints and thus enabling follicle activation and development.

Repurposing of existing drugs/medications

This is a very exciting subject!

The more new drugs we invent, the more opportunities exist and become discovered to repurpose them.

We have now a more than 125 years of history of inventing pharmaceutical drugs, the potential for repurposing increases with every new drug.

The news of repurposed drugs to treat medical conditions also become more frequent. Here is just one very recent example: Uncovering Drivers of—and Possible Treatment for—Noonan Syndrome Heart Defects ("... additionally identifying a leukemia drug [dasatinib, FDA approved in 2006] that shows promise as a therapeutic ...")

Mouse study suggests a common diabetes drug may prevent leukaemia

Good news! Cancer is history (soon)! Are there more opportunities to repurpose drugs?

"... Thanks to recent advances, individuals at high risk of AML [acute myeloid leukaemia] can be identified years in advance using blood tests and blood DNA analysis, but there’s no suitable treatment that can prevent them from developing the disease.

In this study ... investigated how to prevent abnormal blood stem cells with genetic changes from progressing to become AML. The work focused on the most common genetic change, which affects a gene called DNMT3A and is responsible for starting 10-15% of AML cases. ...

The research team examined blood stem cells from mice with the same changes in DNMT3A as seen in the pre-cancerous cells in humans. Using a genome-wide screening technique, they showed that these cells depend more on mitochondrial metabolism than healthy cells, making this a potential weak spot. The researchers went on to confirm that metformin, and other mitochondria-targeting drugs, substantially slowed the growth of mutation-bearing blood cells in mice. Further experiments also showed that metformin could have the same effect on human blood cells with the DNMT3A mutation. ..."

From the abstract:

"Somatic DNMT3A R882 codon mutations drive the most common form of clonal haematopoiesis (CH) and are associated with increased acute myeloid leukaemia (AML) risk.

Preventing expansion of DNMT3A-R882-mutant haematopoietic stem/progenitor cells (HSPCs) may therefore avert progression to AML.

To identify DNMT3A-R882-mutant-specific vulnerabilities, we conducted a genome-wide CRISPR screen on primary mouse Dnmt3aR882H/+ HSPCs. Amongst the 640 vulnerability genes identified, many were involved in mitochondrial metabolism and metabolic flux analysis confirmed enhanced oxidative phosphorylation usage in Dnmt3aR882H/+ vs Dnmt3a+/+ (WT) HSPCs. We selected citrate/malate transporter Slc25a1 and complex I component Ndufb11, for which pharmacological inhibitors are available, for downstream studies.

In vivo administration of SLC25A1 inhibitor CTPI2 and complex I inhibitors IACS-010759 and metformin, suppressed post-transplantation clonal expansion of Dnmt3aR882H/+, but not WT, LT-HSC.

The effect of metformin was recapitulated using a primary human DNMT3A-R882 CH sample.

Notably, analysis of 412,234 UK Biobank (UKB) participants revealed that individuals taking metformin had markedly lower prevalence of DNMT3A-R882-mutant CH, after controlling for potential confounders including glycated haemoglobin, diabetes and body mass index.

Collectively, our data propose modulation of mitochondrial metabolism as a therapeutic strategy for prevention of DNMT3A-R882-mutant AML."

Mouse study suggests a common diabetes drug may prevent leukaemia | University of Cambridge "Metformin, a widely used and affordable diabetes drug, could prevent a form of acute myeloid leukaemia in people at high risk of the disease, a study in mice has suggested. Further research in clinical trials will be needed to confirm this works for patients."

Mitochondrial metabolism sustains DNMT3A-R882-mutant clonal haematopoiesis (no public access)

Extensive study identifies over a dozen existing drugs as potential COVID-19 therapies

Good news! Very interesting research into whether existing drugs can be repurposed to treat e.g. Covid-19. 

"Mining the world’s most comprehensive drug repurposing collection for COVID-19 therapies, scientists have identified 90 existing drugs or drug candidates with antiviral activity against the coronavirus that’s driving the ongoing global pandemic.

Among those compounds, the Scripps Research study identified four clinically approved drugs and nine compounds in other stages of development with strong potential to be repurposed as oral drugs for COVID-19, according to results published June 3 in the journal Nature Communications. ...

the study tested more than 12,000 drugs in two different types of human cells infected with SARS-CoV-2. ...

In the ... study, the scientists treated two different types of laboratory-cultured SARS-CoV-2-infected human cells with each of the 12,000 drugs ... After 24 or 48 hours, they measured the level of viral infection in the cells to determine if the drugs prevented the virus from replicating. In some cases, they applied two drugs at a time to see if the compounds would work together against the virus. ..."

Extensive study identifies over a dozen existing drugs as potential COVID-19 therapies | Scripps Research FDA-approved drugs or experimental drugs with ample health data could be rapidly tested in humans for treatment of COVID-19.

Here is the link to the underlying research article:

Drug repurposing screens identify chemical entities for the development of COVID-19 interventions (open access)