Improved viral delivery of gene therapy to RDEB skin could lead to longer lasting, more effective symptom control with fewer side effects.

 

Dr Ángeles Mencía works at CIEMAT in Madrid, Spain, on this project to improve the options for delivering gene therapy directly to RDEB wounds. Current gene therapy methods involve a standard altered virus applied directly to the wound as a gel. This project aims to use a different virus for delivering working collagen genes, initially into skin cells grown from a person with RDEB. This type of virus has a natural ability to deliver genes specifically into skin cells and is expected to be more effective, cause fewer side effects and be easier to manufacture. Additionally, it will be tested for use in CRISPR/Cas9 gene editing to correct a broken part of the RDEB gene so working collagen protein can be made from a person’s own gene. 

Read more in our researcher's blog.

 

Contents:

• Project summary (top of page)
• About our funding
• Latest progress summary (2024)
• About our researchers
• Why this research is important
• Researcher's abstract
• Researcher's progress update (2024)

 

About our funding:

Research leader	Dr Ángeles Mencía
Institution	CIEMAT, Spain
Type of EB	RDEB
Patient involvement	No
Funding amount	£15,000
Project length	1 year
Start date	01 January 2024
DEBRA internal ID	GR000043

 

Latest progress summary (2024):

Researchers have used cells grown in the laboratory to start making their new gene therapy. 
Their aim is to be able to make gene therapy more efficiently and in larger amounts, and they report that their initial experiments show that this is possible.

 

About our researchers:

Lead researcher:

Dr Ángeles Mencía has more than 20 years of experience in molecular diagnosis of rare diseases, participating in the design, validation and translation of diagnostic tools based on next generation sequencing, including panels for the diagnosis of epidermolysis bullosa. She has extensive experience in the development of molecular tools for gene editing that are being transferred to the clinic.

Co-researchers:

Dr Silvia Gómez-Sebastián is associate professor at the faculty of Medicine, Universidad Autonoma de Madrid. She has more than 20 years of experience in genetic manipulation of viruses, working with herpesviruses during her early years as a researcher. She has worked with HSV-1 amplicon vectors carrying the complete FRDA locus, to restore the frataxin (FA) in Friedreich´s Ataxia patient cells. 

Dr Rodolfo Murillas is a senior scientist at CIEMAT with extensive experience in the field of skin biology, including epidermal transgenesis, the development of viral vectors for gene therapy of the skin, and the development of experimental protocols for the correction of dystrophic epidermolysis bullosa through gene editing. 

Dr Mirentxu Santos is a senior scientist at CIEMAT with extensive experience in cell cultures, primary cultures, molecular and cellular biology, cell cycle and signalling pathways. 

Dr Marta García is Professor of Tissue Engineering in Universidad Carlos III de Madrid UC3M. Dr García has a longstanding interest in the molecular study of genodermatosis and is a recognized expert on the development of models of humanized skin for rare dermatological diseases. 

Diana de Prado is a Graduate Student working on her PhD under the supervision of Drs Mencia and Murillas, beginning in 2023.

 

Why this research is important:

Advances in gene therapies for RDEB in recent years allow us to envisage treatments that are effective and simple to administer topically, but with the potential for significantly improve patients' lives.”

Successful gene editing using these vectors opens up the possibility of treating other types of EB, such as dominant EBS or EBD, with allele-specific CRISPR/Cas tools to eliminate the expression of pathogenic alleles.

Dr Ángeles Mencía

 

Researcher’s abstract:

Grant title: Novel Platform for generation of safer Pseudorabies Herpesvirus-based Vectors for RDEB Therapy.

Gene therapy has emerged as a potential curative treatment for recessive dystrophic EB (RDEB) through different strategies to correct mutations. Viral vectors are lab tools that are used to transport what is necessary to correct mutations or to transport healthy genes that help restore the affected protein. These lab tools usually come from different viruses, such as adenoviruses or the herpes virus. 

Previously, our group demonstrated that adenovirus-derived vectors are useful for reestablishing Collagen VII and restoring adhesion between dermis and epidermis in vivo. In addition, new advances in the design of viral vectors will allow progress towards a more extensive and effective treatment of the RDEB skin. Herpes virus-derived vectors have great potential for EB gene therapy given their natural ability to infect the skin. A recent clinical trial used a herpes simplex virus (HSV-1) vector to deliver a functional version of the COL7A1 gene into wounds of people with RDEB. The results showed a significant improvement in wound healing and increased resistance to blistering. These promising results confirm the potential of herpesvirus-derived vectors for RDEB therapy. 
In this regard, our team is developing a new vector platform based on the porcine pseudorabies virus (Herpesviridae family), which has some advantages over the HSV-1, as it is safer and easier to produce in large amounts. Based on this novel platform, we propose to generate vectors for RDEB, comparable to those currently being tested in clinical trials, with the potential for longer-lasting correction after topical application.

Our team has worked hard to develop effective and easy-to-administer topical treatments that could revolutionize the approach to RDEB treatment. Unlike traditional methods of gene graft therapy that involve invasive and painful surgical procedures, our approach is focused on topical gene therapies aimed at improving the healing of chronic wounds and lesions that cannot be treated with skin grafts. Our lab has pioneered the development of molecular gene editing tools for the correction of RDEB mutations with the potential to achieve lasting improvements. Recently, we have successfully restored Collagen VII and the adhesion between dermis and epidermis in preclinical models.

We are currently developing new types of vectors for this purpose, specifically those derived from herpes-like viruses, which have a strong natural ability to infect the skin and, therefore, could be highly effective in the treatment of chronic wounds in people with RDEB. Promising results from recent clinical trials in the United States based on approaches similar to the one we are proposing give us confidence that we are moving in the right direction. This line of research represents a great opportunity to advance the treatment of RDEB, and we are committed to continuing our work with enthusiasm and rigour.

Our goal is to bring hope to those suffering from this disease and improve their quality of life. Together, we can move toward a brighter and more promising future for those fighting RDEB.

 

Researcher’s progress update (2024):

New vectors derived from herpesvirus hold great promise for treating epidermolysis, offering a potential cure for this debilitating skin condition. For these treatments to be viable for clinical use, it is crucial to produce these vectors in large quantities. Amplicon vectors, a subclass of herpes-derived vectors, present a safer alternative as they lack viral genes. However, their production process is complicated by the need for co-production with helper herpes viruses. 

Our project proposes an innovative production platform designed to enhance the yield of therapeutic vectors, thereby optimizing the quality of the final preparations. In the initial phase, we modified PK15 producer cells to preferentially produce the desired vector by eliminating of helper viruses. This approach successfully shifted the vector/helper ratio in favor of the therapeutic vector, serving as proof of concept for this production strategy and demonstrating the efficacy of our design. Moving forward, we are selecting specific cell clones to further refine and enhance the production platform. A clonal population is anticipated to significantly improve the inactivation of helper vectors, thereby boosting the output of therapeutic vectors. 

This work, made possible by the generous funding from DEBRA UK, is not only a significant advancement in vector production but also a critical step toward developing advanced therapeutic options. It offers hope and a brighter future for patients suffering from epidermolysis, heralding new treatments and improved quality of life. From 2024 progress report.

 

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Image credit: National Human Genome Research Institute