How gene therapy is changing the trajectory of dermatology therapeutics by direct targeting of mutations.

Treatment methods in dermatology have evolved from purely topical medications to include oral treatments, injectables and light and laser therapies. Now, gene therapies offer a new trajectory to address the cause of the disease, rather than simply alleviating symptoms.

Gene therapy is becoming established in oncology and in several inherited disorders, including lipoprotein lipase deficiency, inherited retinal dystrophy, and spinal muscular atrophy. However, expert knowledge in dermatology gene therapy clinical trials can be hard to come by, as the use of gene therapy in dermatology is still a very new concept. The accessibility of the skin, partnered with its regenerative capacity, makes it an attractive target for genetic therapies. In particular, genome editing technologies have the potential to rapidly accelerate the treatment of genodermatoses, a heterogenous group of skin disorders with a variety of phenotypic severity¹.

Until recently, treatments have always aimed to relieve symptoms through wound management, rather than addressing the root cause. An experimental approach in the rare inherited skin disorder, junctional epidermolysis bullosa (JEB), provided a unique opportunity to treat the origin of the disease. In JEB, genetic mutations prevent the layers of the skin from adhering properly, causing the skin and mucous membranes to blister. In 2015, a team in Germany took a patch of skin from a young boy with JEB. They genetically modified the skin with a fully functional form of the defective gene, LAMB3, and grew it into sheets. These were used as skin grafts to cover 80% of his body. Two years on, the skin was functioning well with no signs of blistering².

As advances continue in the field of genome editing, gene therapy also shows potential in several other disease areas, such as Netherton syndrome, xeroderma pigmentosum, and ichthyosis. Many vector delivery techniques are being assessed for their effectiveness and safety. Whilst gene therapy can pose various constraints, including immunogenicity, mutagenicity, and lack of sustainable benefit, dermatology indications are a promising area of focus for future gene therapies³.

Creating effective dermatology gene therapy clinical trials

Because this is still a new area, there are specific considerations when designing dermatology gene therapy clinical trials. It is important to have suitable endpoints for gene therapy studies. The endpoints need to be meaningful to patients and physicians, as well as producing the right data for regulatory and health technology assessment bodies, and for pricing and reimbursement.

As with most clinical trials investigating therapeutics in rare diseases, patient recruitment can be a challenge:

1. Conditions targeted by gene therapy are typically rare, meaning there is a small pool of eligible patients, and there can be intense competition among clinical trial sponsors recruiting from this group.
2. Suitable study sites may be limited, due to the requirement for specific resources, such as laboratories for preparation of the gene therapy, facilities for storing the therapeutic at the right temperature, and staff training on the required administration techniques.
3. Smaller numbers of study sites mean a lower number of eligible patients nearby, depending on how far patients are willing to travel and if they are reimbursed. Patients and caregivers may also be required to stay overnight.
4. Long-term follow-up is a necessity in gene therapy clinical trials, to ensure long-term efficacy and safety. This could further deter patients from enrolling.
5. Studies may have to implement a special safety survey, given the techniques required for administration and the immune reactions that can occur.

Conversely, patients and parents of children with rare diseases are generally well informed and understand the value of clinical trials improving their own, or their child's quality of life. They are supportive of trying therapies potentially more effective than existing ones, or those that can be administered less frequently, causing less disruption to their daily lives.

With the small patient populations available for dermatology gene therapy trials and high unmet need, gene therapies are often on an accelerated development pathway.

In order to build a strong value story for gene therapy in dermatology, researchers will need long-term safety and efficacy data, which will not necessarily be available from the novel endpoints originally accepted as part of an expedited review. This information can be collected from follow-up studies, and from long-term patient surveillance, which may be required as part of the market authorization.

Innovative treatment approaches are often developed by smaller biotech companies, but they may not have the infrastructure to carry out a gene therapy clinical trial. While large pharma may have dermatology experience, medical, regulatory, and operational expertise, as well as access to physicians and markets, they may be lacking in access to the innovations typically generated from the smaller biotechs. Collaborations between pharma and biotech give smaller companies support and routes to the market, while providing larger companies access to innovation.

Building a future in dermatology gene therapy

Although there are key challenges for biotech companies to overcome, the scene is set for gene therapy research to make important progress in treatment of dermatology conditions. Current clinical trials are exploring uses of gene therapy in dermatology, most prominently in the treatment of melanoma and wound healing. The use of genetically modified skin grafts has even made its way into experiments investigating ways to treat diabetes⁴ and drug addictions⁵. What was once a futuristic concept, is now becoming a game-changer in the realm of dermatology. With guidance, expertise and support, these challenges can be overcome with confidence.

Please contact us to discuss how we can help support your gene therapy clinical trial.

References

1. March O, et al. Context-Dependent Strategies for Enhanced Genome Editing of Genodermatoses. Cells. 2020;9(1):112. Available at: https://www.mdpi.com/2073-4409/9/1/112
2. Hirsch T, et al. Regeneration of the entire human epidermis using transgenic stem cells. Nature. 2017 Nov 16;551(7680):327-332. Available at: doi: 10.1038/nature24487. Epub 2017 Nov 8. PMID: 29144448; PMCID: PMC6283270
3. Sarker T, et al. Gene Therapy and its Application in Dermatology. Indian Journal of Dermatology. 2020;65(5):341-350. Available at: https://www.e-ijd.org/article.asp?issn=0019-5154;year=2020;volume=65;issue=5;spage=341;epage=350;aulast=Sarkar
4. Yue J, et al. Engineered Epidermal Progenitor Cells Can Correct Diet-Induced Obesity and Diabetes. Cell Stem Cell. 2017 Aug 3;21(2):256-263.e4. Available at: doi: 10.1016/j.stem.2017.06.016. PMID: 28777946; PMCID: PMC5555372
5. Li Y, et al. Genome-edited skin epidermal stem cells protect mice from cocaine-seeking behaviour and cocaine overdose. Nat Biomed Eng 3, 105–113 (2019). Available at: https://doi.org/10.1038/s41551-018-0293-z