The role of YAP1 in fibrosis explored through the surgical healing process.

Descrizione riassuntiva dello studio

After an injury, our body triggers a repair process aimed at healing the damaged area. However, in adult mammals, this process typically results in the formation of scar tissue, or fibrosis. This fibrosis is irreversible and often leads to impaired function of the affected organ. A significant portion of non-violent deaths in Western countries is due to fibrosis in the affected organ, highlighting the importance of better understanding the underlying process from both a scientific and medical perspective. To illustrate the fibrosis process, we can take the example of skin healing in adults. Unlike embryonic skin, which can completely regenerate after an injury without leaving a scar, adult mammalian skin repairs itself by forming fibrotic scar tissue. Therefore, adult skin provides an ideal model for studying fibrosis, as most stages of the healing process are visible to the naked eye. Fibroblasts, specific cells, play a key role in fibrosis. Studies have shown that there are two types of fibroblasts, and their conversion is regulated by a protein called YAP1. Verteporfin, a drug approved since 2000 for intravenous treatment in photodynamic therapy, is a YAP1 inhibitor and has repeatedly shown its anti-fibrotic effects not only in mouse models but also on human samples. These findings on YAP1 and its inhibition by verteporfin open up hypotheses about the potential to ultimately prevent or treat these fibrotic conditions. Verteporfin is approved for intravenous administration with a good safety profile, and we propose to study its anti-fibrotic potential by injecting a fraction of the approved dose locally into wounds.

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Intervento studiato

The first contact with potential participants will occur during their usual visit after the removal of a mole. During this visit, we will present the study to each patient for whom an additional excision with a safety margin of 5 mm is indicated due to in situ melanoma or severe dysplastic nevus located on the back (to ensure that all patients receive their excision with safety margin within the standard six-week timeframe, we will also accept patients requiring the procedure on another anatomical site if a particular batch cannot be filled within 4 weeks of enrolling its first patient).

The study intervention takes place on the day of the safety margin excision. Two biopsies of the initial scar will be taken for histological analysis and scRNA-seq. Then either the study drug (Verteporfin) or the placebo (NaCl 0.9%) will be injected into the surgical wound before suturing it.

Three days (+/- 2) after the surgical intervention, a brief consultation will be organized to measure vital signs and inquire about any safety issues and side effects.

Fourteen days (+/- 2) after the operation, the usual postoperative consultation will take place with photographic documentation of the operated site and measurements of clinical scores, vital signs, and a questionnaire aimed at assessing how a patient perceives the care outcomes.

A follow-up visit will take place 90 days (+/- 10) after the intervention, during which two new biopsies will be performed in the repaired tissue. Additionally, photographic documentation, clinical scores, and the questionnaire will be taken.

The second and final follow-up visit will occur 180 days (+/- 10) after the intervention with photographic documentation, clinical scores, and the questionnaire.

(BASEC)

Malattie studiate

After an injury, the body initiates a repair process to heal the damaged area. In adult mammals, this repair process results in the irreversible formation of fibrotic tissue. Fibrotic tissue is a scar tissue characterized by excessive deposition of collagen and other extracellular matrix components. It is a type of non-functional fibrotic tissue that often impairs the function of the affected organ to varying degrees. Non-violent deaths are generally due to organ failure. In developed countries, organ failures during non-violent deaths, whether related to kidney, liver, lung, heart disorders, or others, are primarily due to non-functional repair tissue called fibrosis. Therefore, it is crucial to understand the fibrosis process, both scientifically and medically, in order to develop prevention strategies or even treatments for these fibrotic states that can lead to loss of organ function. A good way to illustrate the fibrosis process is skin healing in adults. Unlike embryonic skin, which can completely regenerate after an injury, adult mammalian skin repairs itself by forming fibrotic scar tissue. Since almost the entire healing process is visible to the naked eye, adult skin is an ideal model for studying fibrosis. Fibrosis is primarily due to fibroblasts, which are the main cells contributing to the onset of fibrosis. Recently, researchers have identified two different types of fibroblasts based on their embryonic development: En1-positive fibroblasts (EPF) and En1-negative fibroblasts (ENF). ENFs are responsible for complete regeneration during embryonic development, but as fetal development progresses, EPFs become dominant, leading to wound repair with scar formation from birth. EPFs are considered responsible for scar formation (=fibrosis), while ENFs lead to complete regeneration without scarring in embryos. Experimental studies conducted on mice have confirmed this theory, showing that transplantation of ENFs into wounds leads to tissue repair without visible scarring. Another study on a mouse model analyzed the function of fibroblasts in scar formation and also showed that EPFs are primarily responsible for scar formation. Mekanotransduction signaling refers to the process by which cells detect mechanical tensions to respond. In the context of healing, mechanical tension can activate mechanotransduction pathways, leading to the conversion of ENFs into postnatal EPFs (pEPF). The activation of Yes-associated protein 1 (YAP1) plays an important role in this conversion process. YAP1 is involved in significant biological processes and can be seen as a molecular switch capable of activating or deactivating various signals related to cell growth and tissue development. In a mouse model, inhibition of YAP1 by injecting wounds with a YAP1 inhibitor called Verteporfin prevented the conversion of ENFs into pEPFs and led to complete skin regeneration without any visible scar tissue, either to the naked eye or histologically. What is this drug, verteporfin? Verteporfin is officially used in a treatment called photodynamic therapy to treat certain eye problems. In this therapy, verteporfin is administered to the patient via intravenous injection and acts as a photosensitizer, meaning it makes the patient's cells more sensitive to light. When a light source is applied to the targeted area, it triggers a reaction that leads to the destruction of abnormal cells. Verteporfin has been approved in Switzerland by Swissmedic and in the USA by the Food and Drug Administration (FDA) for more than twenty years. It has undergone numerous tests and has shown an exceptional safety profile. A more recent study has confirmed its safety and efficacy in this indication. Recently, verteporfin has shown promising results even when used outside its official indication of photodynamic therapy. By inhibiting YAP1, studies have shown that verteporfin may have anti-tumor effects even without the need for light activation. This discovery is exciting because it suggests that verteporfin itself may inhibit the harmful behaviors of cancer cells. Returning to the main topic of our study, verteporfin is also being studied for its ability to reduce fibrosis. Studies have demonstrated that YAP1 is generally overexpressed in fibrotic conditions and that inhibition of YAP1 by verteporfin can lead to a reduction in fibrosis. For example, as previously described, experiments conducted on mice have shown that when verteporfin is injected into the skin of injured mice, it allows for complete skin regeneration without leaving a scar. In another study, mice with cardiac fibrosis caused by a heart attack showed a significant reduction in fibrosis after receiving verteporfin. Furthermore, verteporfin has proven promising in reducing fibroblast proliferation, even in human samples. For instance, fibroblasts present in keloids, which are scars undergoing abnormal healing leading to excessive scar tissue formation, were inhibited by verteporfin, resulting in a decrease in fibrosis. Many other fibrotic conditions have been studied from human samples and have shown that verteporfin leads to a reduction in collagen accumulation and an improvement in fibrotic conditions. The discovery of YAP1, its inhibition by verteporfin, and their effects on fibroblasts during tissue repair represent an important step in our understanding of the fibrosis process. This innovative research is very promising, not only for improving wound healing outcomes but also for preventing or treating organs with non-functional fibrotic tissues after an injury. In summary, verteporfin is approved for intravenous injections in the context of photodynamic therapy. Additionally, it has been studied for its anti-cancer and anti-fibrotic properties. The critical role of YAP1 in fibrosis has been established based on irrefutable evidence from animal and human samples. The remarkable reduction of fibrosis observed by inhibiting YAP1 with verteporfin supports the launch of a proof-of-concept study in humans. Verteporfin is approved for intravenous administration without safety issues so far. Experimental studies using it topically have also not revealed significant side effects. Therefore, we propose to use it locally through intradermal injections with a total dosage of < 3% of the approved intravenous dose. The organ of choice is the skin, as dermatological surgeries are numerous and standardized, and the skin repair process can be easily observed both clinically, with the naked eye and by palpation, as well as histologically.

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Sponsor

Jöri Pünchera, Hôpitaux Universitaires de Genève

(BASEC)

Nome del comitato etico approvante (per studi multicentrici solo il comitato principale)

Commissione d'etica Ginevra

(BASEC)

Data di approvazione del comitato etico

28.11.2024

(BASEC)

Risultati dello studio