What types of Research are we interested in funding?
At the EI Cure Project, we are all about finding new treatments for the EI Community, both now and in the future. One of the only ways to achieve a true cure, where the genetic code that causes EI can be replaced by a healthy code, is to use gene-editing.
In our About the Project page we provide an overview of the beginnings of gene-editing for EI, where Dr Oliver March and Dr Julia Reichelt used a gene-editing technique called TALENs to correct the EI-causing pathogenic gene mutation. Since this time, the tools available for gene-editing have moved-on, and the widespread availability of CRISPR-based gene-editing tools have changed the face of genomic medicine to one where up to 90% of genetic diseases have the potential to be cured one day.
The short video below, shows Jane Doudna who won the NOBEL prize alongside Emanuelle Charpentier in 2020, talking about CRISPR-Cas9 and it’s ability to change life as we know it.
Like all things in life, there are pros and cons to consider with any tool or medical intervention. CRISPR-Cas9 has its limitations, and one of the concerns is the fact that a ‘Double-Strand Break (DSB)’ is produced by the Cas9 protein during the gene-edit. DSBs can be problematic because if they are not corrected as planned, this can cause new health problems to arise. Fixing one health problem, but creating a new one, is not a desirable outcome for any new treatment when we’re talking about modifying our DNA.
In a very short space of time, new gene-editing tools which don’t induce double-strand breaks have been developed which make gene-editing safer, more precise, and more accessible. These new tools continue to use the technology and principles of gene-editing established through CRISPR, but have names which refer to new types of technology. In our current plans for research, we would like to explore the use of Base Editors and Prime Editors. These are newer gene-editing tools, the benefits of which are explained in much greater detail in this useful blog, The Aggie Transcript and the main differences between them are shown in this helpful diagram taken from a recently published article from EI Cure Project Research Alliance members, Professor John McGrath and Dr Joanna Jacków-Malinowska.
Diagram Credit: British Journal of Dermatology, Volume 190, Issue 5, May 2024, Pages 617–627, https://doi.org/10.1093/bjd/ljad528
The tools to make the gene-edit needed to correct the pathogenic genetic variant which causes EI are available, and have been proven to work on skin cells in a laboratory setting. You can read more about this research from EI Cure Project Research Alliance member, Professor Matthias Schmuth, for the work he presented at the 1st annual world congress of the International Societies for Investigative Dermatology Meeting held in Tokyo, Japan in May 2023.
Whilst we celebrate the work of Professor Schmuth’s team, there remains a lot more research to be done in order to translate these findings from the lab into a clinical treatment for human skin.
Gene-editing for the skin presents a whole new set of challenges to be explored because the skin is designed to keep things OUT.
In order to get our clever gene-editing tools through the natural skin barrier, we need to find a way to keep the tools safe from the natural defences of the body, and to ensure that they can find the target cells for the treatment to be effective.
To penetrate the skin barrier, and to ensure safe passage through charged skin cell membranes, it is necessary to combine our gene-editing tool of choice with a vector. There are many different types of vector, which are typically viral or non-viral, but the EI Cure Project Research Alliance have chosen to focus their efforts on two different delivery approaches: Lipid Nano-Particles (LNPs) and Engineered Virus-like Particles (eVLPs).
Each type of vector or gene-editing delivery system has pros and cons, and you can learn more about these details in these two useful articles: 1) Lipid Nano-Particles (LNPs); 2) Engineered Virus-Like Particles (eVLPs). In very simple terms, both of these vectors have the potential to penetrate the skin barrier and deliver gene-editing tools to the desired target of the skin stem cells.
Skin stem cells are responsible for making new skin cells in the basal layer of the skin before they travel up to the surface to be shed as part of a typical skin cycle. If the DNA of skin stem cells can be edited successfully, the new skin cells which are made will carry the edited DNA. Stem cells also have a living memory, which means that once the DNA gene-edit is successful, it should not need to be repeated, and would therefore provide a permanent cure.
The two diagrams of skin cells in the epithelium demonstrate the location of the skin stem cells immediately above the base membrane, and how these related to the location of Keratinocytes (KRT1, KRT10, etc), found in the layer directly above the stem cells.
What remains to be explored is the mode of delivery of both vector and gene-editing tools through the skin (Will a topical gel or cream be sufficient, or will micro-needles or lasers be needed too), how efficiently they will transfect the skin, and what the therapeutic gains will be (Will it simply reduce symptoms, or can it be considered to be curative).
Currently, there is only one FDA approved gene-therapy for a genetic skin disease, and that is VYJUVEK for Dystrophic Epidermolysis Bullosa (EB). This gel form of gene-therapy is applied to open EB wounds, where the skin barrier is already compromised. The approval of VYJUVEK was a revolutionary breakthrough for genetic skin diseases however, and it offers hope to many families as a treatment to alleviate chronic wounds that are so prevalent in Dystrophic EB.
For the Congenital Ichthyoses, there are currently no approved gene-therapies. However, there have been recent active clinical trial using KB105 gene-therapy for Lamellar Ichthyosis, and another from EI Cure Project Research Alliance member Professor Wei-Li Di using a Lenti-viral vector gene-therapy to grow gene-edited skin grafts for the treatment of Netherton Syndrome. Both KB105 and VYJUVEK use a modified form of the Herpes-Simplex Virus as the vector to penetrate the skin barrier. Whilst there are no other active gene-therapy clinical trials for the congenital ichthyoses, there are increasing numbers of preclinical studies happening at present, as summarised in a recently published literature review by Joosten et al, 2022 in the Orphanet Journal of Rare Diseases. The diagram below provides a useful summary of current research into therapies for the congenital ichthyoses.
Sadly, none of the preclinical studies listed in the Joosten et al, 2022 review include EI, and yet at the time of writing (May 2024) Dr Julia Reichelt of the EI Cure Project Research Alliance has commenced new preclinical research exploring gene-editing for EI with a PhD student, funded by the Qatar Foundation.
In addition to the KB105 clinical trial on gene-therapy for Lamellar Ichthyosis, Professor Sarah Hedtrich of the EI Cure Project Research Alliance is currently conducting preclinical gene-editing feasibility experiments with skin samples from patients affected with Lamellar Ichthyosis. She is using a Base-Editor gene-editing tool with a Lipid-Nanoparticle vector which is helped through the skin barrier with the use of micro-needles or laser therapy. The hope is that the eventual treatment would prove to be curative, provided it is possible to effectively treat enough skin stem cells which would then produce skin cells with modified DNA. She plans to include EI skin samples in her feasibility experiments in the coming months, and hopes to move to human clinical trials within the next few years. The most recent publication for this work can be found here.
Finding a true CURE with gene-editing for EI is the ultimate dream for many in the EI community. However, we appreciate that achieving this will take many more years of preclinical and clinical research.
For the more immediate future, the EI Cure Project would like to gain a better understanding of the inflammatory pathways and biological mechanisms at play in the condition. If we can understand these aspects of EI better, then we may be able to utilise existing FDA approved therapies such as drugs and biologics that were created for other, more prevalent conditions such as psoriasis, eczema, or EB Simplex for example. This is a concept known as ‘Drug Repurposing’ or ‘Drug Repositioning’ and the benefits can be significant in terms of time and cost when compared with trying to develop a brand new therapy.
As shown in the diagram above, the potential for developing a new drug solely for a rare disease seems highly unobtainable. However, if we can learn more about EI and gather enough data for a ‘Biological Knowledge Graph’, we may be able to find existing drugs that could help improve the symptoms and therefore the quality of life of those in the EI community in the immediate future, and without the hefty price-tag.
Some studies on gene expression, disease associations, and molecular interactions have already been done for EI. Paller et al, 2017 found similarities in IL-17 and IL-23 expression between EI and Atopic dermatitis and Psoriasis. Later, Malik et al, 2019 performed molecular fingerprinting studies and found profound TH-17 skewing, which could indicate that IL-17/IL-36 targetted therapeutics designed for psoriasis may work well for the ichthyosis, with particular emphasis on EI sharing many similarities with the inflammatory markers demonstrated in psoriasis. Has et al, 2020 reclassified EI alongside Pachyonychia Congenita (PC) and Epidermolysis Bullosa Simplex (EBS), these are all keratinisation disorders caused by mutations on the Keratin genes and are associated with skin fragility and/or hyperkeratosis. Much more recently, Frommherz et al, 2024 conducted the largest population study of the German EI population study, documenting genotypes and phenotypes for 45 patients with EI alongside clinical severity scores and economic evaluation data.
These important studies have helped scientists to understand EI better, and were used to justify a clinical trial, which included adult patients with EI, for the use of a biologic therapeutic agent called Secukinumab. The findings published by Lefferdink et al, 2023 indicated that Secukinumab was a safe therapeutic option for those with EI because patients did not suffer any significant adverse reactions. However, it was found that Secukinumab did not achieve a statistically significant improvement in symptoms and therefore could not be recommended as a new therapeutic option for EI. The investigators did also state however, that whilst there was no statistical significance, some EI patients reported good improvements in their symptoms, but perhaps the tools used to measure some outcomes did not demonstrate the benefits that the participants described.
Clinical trials continue to test biologic agents for other types of Ichthyosis, but at present, there are no further studies available to patients with EI. EI is often excluded from congenital ichthyosis trials because the measurement of outcomes is more complex when the condition includes both non-uniform hyperkeratosis alongside skin fragility and blistering.
The inconclusive findings of the Secukinumab trial and the fact that EI is often excluded from clinical trials for congenital ichthyosis confirms that there is a need to better document the natural history of EI. If we are to prove without any doubt that there is or isn’t a therapeutic benefit from a new treatment, we need to know exactly what EI looks and feels like over time, and how it affects both quality of life and the cost of care during childhood and adulthood. If we cannot prove therapeutic benefit, we will never be able to justify the cost of new treatments, nor will we ever gain approval for new treatments.
This type of prospective, longitudinal study of the natural history of EB, which includes economic evaluation of the cost of care, has been active of over 10 years now. Known by the acronym ‘PEBLES’, and led by EI Cure Project Research Alliance Member, Professor Jemima Mellerio, this study has provided a mass of data which has already been used to inform clinical care, but has also been used to justify the continued need to fund research to find new treatments.
In summary, there is a lot of work that needs to be done in order to research and develop new treatments for EI.
Below, you will find a brief summary of the Research Aims for the EI Cure Project, which are all explained in further detail in the paragraphs above. It is already an honour to be able to help and support the members of our EI Community with the day-to-day challenges that come with a severe condition like EI. It is truly our DREAM to be able to offer new treatments as a result of our research. So please help us, and get involved in fundraising for the EI Cure Project TODAY!
We are actively seeking industry partners, sponsors, and collaborators to get involved in this research.
If you are interested in adding Epidermolytic Ichthyosis to your rare disease research portfolio, please do not hesitate to contact:
Helen Lill (Founder and Head of Research) helenlill.eicureproject@gmail.com