Treating DEB itch with stem cells (2022)

This project aims to understand and reduce (using bone marrow cells from people who don’t have EB), the itchiness that has a massive effect on the quality of life of people with EB.

Professor John McGrath

Prof John McGrath and Prof Jemima Mellerio work at King’s College, London, UK on this two-part project to firstly understand itch (PRUMEC) then to see if putting bone marrow cells from people who don’t have EB into the blood of people who do have EB can reduce symptoms of itching (PRUSTEM). The project will compare skin and blood from people with dystrophic EB pruriginosa (a sub type of DEB that causes particularly itchy skin), regular DEB and no EB at all and ask them to complete questionnaires before and after the DEB-pruriginosa group receive the cell therapy. If the cell therapy works, it may be developed into routine clinical care for DEB patients.

About our funding:

Research leader	Prof John McGrath and Prof Jemima Mellerio
Institution	St John’s Institute of Dermatology, Kings College, London, UK
Type of EB	DEB – sub type pruriginosa (DEB-p)
Patient involvement	Yes
Funding amount	£497,360
Project length	2.5 years (extended due to Covid)
Start date	May 2018
DEBRA internal ID	McGrath21

Final progress summary:

Three groups of people were involved in the PRUMEC study: people with DEB-pruriginosa, and two ‘control’ groups: people with DEB (not pruriginosa) and volunteers without EB.

The results of comparing skin and blood samples from the three groups suggested that immune system responses (inflammation) in the skin, rather than in the blood, were responsible for the itch. This inflammation was of two key types, one involved in eczema and the other involved in psoriasis, suggesting that medications for these conditions could be repurposed effectively to treat EB itch.

The researchers plan to carry out clinical trials to provide evidence that these drugs work in EB so that, in the future, they can be licensed and routinely used to improve EB quality of life.

The researchers published a review in the British Association of Dermatology journal in 2021 and some results of the research here: "Transcriptomic profiling of recessive dystrophic epidermolysis bullosa wounded skin highlights drug repurposing opportunities to improve wound healing".

About our researchers:

Research Leaders:
Prof John McGrath MD FRCP FMedSci is Professor of Molecular Dermatology at King’s College London and Head of the Genetic Skin Disease Unit, as well as Head Consultant Dermatologist at St John’s Institute of Dermatology, the Guy’s and St Thomas’ NHS Foundation Trust in London. He was previously a DEBRA-funded junior EB research fellow and has worked on EB research for more than 25 years. He now leads and collaborates on several National and International projects to develop gene, cell, protein and drug therapies that can lead to better treatments for people living with EB.

Prof Jemima Mellerio is a Consultant Dermatologist and professor at St John’s Institute of Dermatology, Guy’s and St Thomas’ NHS Foundation Trust. She has over 20 years working clinically in the field of EB and other genetic skin diseases, as well as a research background looking at the molecular basis of different types of EB, and clinical trials into newer therapies for EB such as fibroblast and mesenchymal stromal cell therapy. She is dedicated to continuing this work to develop more effective treatments for all types of EB.

Why this research is important:

One of the most troubling symptoms in people with EB is itch. At the moment, we know little about what causes the itch and even less about how to treat it. We are delighted to receive DEBRA funding to work on itch. We will be studying people with a very itchy form of EB called EB pruriginosa. We also plan to carry out a clinical trial of intravenous bone marrow cells that we hope will lessen the itch and improve EB skin.

Prof John McGrath

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Researcher’s abstract:

Grant title: Evaluation of the early efficacy of intravenously administered allogeneic mesenchymal stromal cells on itching in adults with epidermolysis bullosa Pruriginosa (PRUMEC - PRUSTEM).

This research grant is divided in to two stages - PRUMEC and PRUSTEM.
Stage 1 - PRUMEC Case-control mechanistic study of pruritus (itch) in adults with dystrophic epidermolysis bullosa pruriginosa.
Stage 2 - PRUSTEM - Evaluation of the early efficacy of intravenously administered allogeneic mesenchymal stromal cells on itching in adults with epidermolysis bullosa Pruriginosa.

Abstract
This research is about itch in epidermolysis bullosa (EB). We know that itching is a common and distressing symptom, and that better control of itch is an important research priority for people living with EB. At the moment, it is not understood why the skin is itchy in EB and we know that most current treatments are not particularly effective.
Previous clinical trials of a form of cell therapy took bone marrow cells (mesenchymal stromal cells, MSCs) from unrelated healthy donors and infused them via a vein into children and adults with recessive dystrophic EB; these trials were called EBSTEM and ADSTEM and showed that the cells were safe and that in most people the cell infusions had positive benefits for wound healing, skin pain and itching.

This project will investigate the underlying mechanisms and potential treatment for itch in EB will be divided in to two stages, PRUMEC and PRUSTEM.

Stage 1 - PRUMEC

This is a case control study, (a type of observational study involving 2 or more groups) which aims to determine whether the groups have different outcomes after the study. As this is a mechanistic study, this means the research aims to understand the biological processes behind pruritus (itch) and identify treatment targets for this.
Since this research involves studying the underlying mechanisms of pruritus, there will be 3 distinct groups:

10-30 adults with dystrophic epidermolysis bullosa pruriginosa (DEB-P), which will have skin and blood samples taken and compared to,
10-30 adults with DEB non-pruriginosa subtype (DEB-NP), and
10-30 healthy volunteers as control groups.

Recruited patients will be matched if possible, as closely as what is practical clinically and logistically feasible, based on age, gender, ethnicity, EB severity, time of biopsy and site of biopsy. Questionnaires as well as the blood and skin samples will be taken from each group over a 12 month period. This will allow comparison between groups.

Stage 2 - PRUSTEM (Phase I/II trial)

This stage will follow the completion of PRUMEC, where the sub group of DEB-P patients enrolled will be given a medicinal product depending on the results of the PRUMEC. The blood tests, questionnaires and biopsies will be repeated and carried out as they were in the PRUMEC study and compared with the baseline assessments carried out in the first stage.

The medicinal product will be in the form of cell therapy where up to 10 adults with EB pruriginosa will each receive 3 infusions of MSCs. This work will measure the itch using a detailed scoring system called the Leuven Itch Scale, which has been previously tested in EB. Skin and blood will be examined after the cell therapy has been administered to investigate how the cells might be working in reducing itch and compared with results taken before.

The results will also be compared with the blood of 10 people with DEB - NP and 10 control subjects who do not have EB from the PRUMEC study. Those individuals will not receive MSC cell therapy, but their samples will be helpful in trying to work out what causes the very itchy EB pruriginosa in the first place.

The overall aim of this work is to improve understanding about (a) what causes itch in EB pruriginosa (and potentially other forms of EB), (b) whether intravenous infusions of MSCs offer a helpful treatment for people with EB pruriginosa and, (c) how do the MSCs work in reducing pruritus in EB pruriginosa. It is hoped that the combined results of EBSTEM, ADSTEM and PRUSTEM/PRUMEC will define the potential benefits of this form of cell therapy for people with DEB (and potentially other forms of EB) and provide momentum for the development of MSC cell therapy as part of routine clinical care for DEB.

Researcher’s final progress update:

PRUMEC: A case-control mechanistic study of pruritus in adults with dystrophic epidermolysis bullosa pruriginosa.

Itch is one of the most important problems of people with epidermolysis bullosa (EB). It is particularly common and severe in the dystrophic subtype of EB (DEB). There has been extensive research into mechanisms of itch in commoner skin conditions in the last two decades, which has increased our understanding and therefore ability to develop effective treatments for it. However, itch in DEB has not been studied to the same extent and most importantly, treatments that can reduce or stop it effectively are not available to this group. We therefore organised a research study, aiming to find out what causes itch in the extremely itchy subtybe of DEB, known as pruriginosa. Our ultimate goal was to identify pathways that we can target and block with drugs, to relieve the itch.

For this study, we recruited participants into three groups: people with DEB pruriginosa (DEB-P), along with two ‘control’ groups of people with DEB without itchy skin and people without any skin or other medical conditions (healthy volunteers, HV). Participants in the control groups were matched to the DEB-P participants as closely as possible for age, gender and ethnicity, for us to be sure that differences seen between the groups during experiments could not have been caused by differences in any of these parameters between the groups. Each participant completed 2-3 research visits with us. During these, we assessed EB severity and extent in the two DEB groups using a score known as EBDASI and asked DEB participants to complete a questionnaire on the impact of EB on their quality of life (QoL). DEB-P participants also completed two validated scales assessing aspects of itch, such as severity, frequency and duration, known as Leuven Itch Scale (LIS) and 5D scale. We took blood samples from all participants and skin biopsies from participants who were happy for us to do so. Screening tests were done in bloods to measure markers of inflammation and to ensure that the participants did not have other problems that could cause itching, such as atopy, liver or kidney function abnormalities. Skin samples from DEB-P and DEB-NP participants were taken from both affected (lesional) and unaffected (non-lesional) areas of skin.

We subsequently did a series of experiments on both blood and skin to determine the expression levels of genes and proteins. These levels were then compared between DEB-P and the two control groups.

Several conclusions were made based on the results.

Notably, it became clear during the study that for people with DEB-P the itching is limited to affected (red, blistered or wounded) areas of skin. This is a fundamental observation which suggests that there is not a systemic cause for the itching, but rather that the processes driving it are limited to the skin, and specifically to skin lesions.

Inflammatory markers in the blood suggested that there is more severe inflammation in DEB-P skin compared with non-itchy DEB, as we can also appreciate when looking at the skin with the naked eye or under a microscope.

Disease severity and impact on QoL are both increased in DEB-P. The severe itching is likely the cause for these findings, as it greatly affects people’s sleep, social life and daily activities, whereas scratching the skin causes new blisters and wounds.

Interestingly, the intensity of the itching was proportionate to the levels of inflammation markers in the bloodstream of DEB-P individuals, suggesting a tight relationship between itch and skin inflammation. This implies that if we focus on studying the inflammation in the skin of people with DEB, that’s likely to help us understand, and therefore treat itch successfully.

Moving to more specific findings at cellular and molecular level, our studies in blood showed that many mediators of inflammation are not raised in the bloodstream of DEB-P compared to controls. This means that either our equipment is not yet sensitive enough to detect differences that are there, or that the inflammation is limited to the skin and does not overspill into circulation to a significant extent. In line with this, there were not significant differences in gene expression levels in blood between the groups. However, our overall measurements of various proteins in blood suggested that blood cells known as platelets, which are involved in the formation of blood clots are activated in DEB-P compared with both controls. This phenomenon however is not specific to DEB-P and has been described in other conditions where the skin is inflamed and itchy.

The most important findings of this study were derived from comparing affected skin of DEB-P individuals with unaffected skin taken from nearby areas in these same individuals, as well as biopsies from the same site taken from DEB-NP and HV. Firstly, gene and protein expression in unaffected, non-itchy skin of DEB-P people were both very similar to those in healthy skin from DEB-NP and HV. It was when we compared DEB-P skin lesions with normal-looking skin from DEB-P, DEB-NP and HV, that differences were seen. In particular, several immune-related pathways were found to be overactive in DEB-P lesions. Two distinct pathways seemed to dominate the immune system response in their skin,. Several molecules are involved in these pathways (or so-called ‘inflammatory cascades’), some of which we can block with newer generation, highly targeted medications known as biologics. These drugs are already used for eczema and psoriasis in clinical practice and are considered reasonably safe. Biologics have not been part of EB treatment traditionally, however the results of this study give us good reason to believe that they might be useful in reducing inflammation, and therefore itch, in the skin of people with dystrophic EB. In the next stage of our research, we are planning clinical trials where we will test some of these agents in DEB. We hope to produce evidence that will allow us to make these drugs routinely available to people with DEB in the clinical setting. (From 2022 final progress report.)