The Road to Curing Recessive Dystrophic Epidermolysis Bullosa
Butterflies. Perhaps what’s most remarkable about them is their journey through metamorphosis: the four stages spanning from egg to caterpillar to pupa to adult. Once at the adult stage, they are what we know them as: beautiful creatures with striking patterns and bright colors spanning across their wings. What many don’t know is that their wings are incredibly fragile. They have dust-like scales that rub off easily when touched, and can be torn if not handled gently. Think about this: What if our skin was as fragile as the wings of a butterfly? Hugging a friend, holding a pencil, feeding oneself with a spoon would all be difficult to do. This is the reality for many patients who have Epidermolysis Bullosa or the “butterfly disease”.
What is Epidermolysis Bullosa?
Epidermolysis Bullosa (EB) is a rare skin disease that affects 1 in every 50,000 children born, and has been called “the worst disease you’ve never heard of”. Children affected by EB have extremely fragile skin, which may tear and blister at light touches and slight trauma. Heat, friction, rubbing, and scratching must be avoided to prevent blisters from forming. Infants born with EB experience blistering everywhere and may have missing patches of skin due to trauma during birth. Once the blisters heal, they leave scars, which may affect the mouth and esophagus, making swallowing food difficult and leading to malnutrition. The scars can also lead to fusing of skin on hands and feet, deformities that prevent motion in joints, and vision loss due to eye inflammation. EB patients are also susceptible to squamous cell carcinoma, a form of skin cancer.
There are more than 30 EB subtypes with 21 distinct genes being the culprits for these mutations. Depending on the type of EB a patient has, they will have varying symptoms from minor to severe.
To understand how EB works, we must first understand the structure of our skin, shown above. Skin has two layers, with the outer layer called the epidermis and the inner layer called the dermis. The area between the dermis and the epidermis is called the basement membrane or the dermal-epidermal junction. This is where anchoring fibrils are, which are the glue that hold the epidermis and the dermis together. Patients with EB don’t have the proteins required to hold the epidermis and dermis together. While normal skin has these specific proteins, EB skin is missing them since the patient has a mutation in the gene that disrupts the production of these proteins. Thus, any friction upon EB skin can cause the layers of skin to separate and cause blistering, which is said to be comparable to third-degree burns.
There are four main types of EB, which are Epidermolysis Bullosa Simplex, Dystrophic Epidermolysis Bullosa, Junctional Epidermolysis Bullosa, and Kindler Syndrome. Each is defined by which area of skin the blistering forms in. Some of these are autosomal dominant disorders, while others are autosomal recessive disorders. Autosomal dominant means that if one parent is a carrier of a mutated gene, the child can develop the disease. Autosomal recessive means that both parents must be carriers for the mutated gene for the child to develop the disease.
Epidermolysis Bullosa Simplex
Epidermolysis Bullosa Simplex is characterized by blister formation in the epidermis. Patients with EBS lack keratin proteins to form strong connections in the epidermis. This is an autosomal dominant disease.
Dystrophic Epidermolysis Bullosa
Dystrophic Epidermolysis Bullosa (DEB) is characterized by blister formation in the dermis. They have extremely fragile connections between the layers of skin. DEB is caused by a deficiency in type VII collagen, which is a helical protein that connects the skin together. *More on this later!* This disorder can be inherited in a either recessive or dominant way. Recessive Dystrophic Epidermolysis Bullosa specifically is a recessive disorder.
Junctional Epidermolysis Bullosa
Junctional Epidermolysis Bullosa is characterized by blister formation between the dermis and the epidermis, which is called the basement membrane. This is autosomal recessive disease.
Kindler Syndrome
Kindler Syndrome is characterized by blister formation in any area of the skin. There have only been 250 cases reported worldwide. It is caused by mutations in the FERMT1 gene and is an autosomal recessive disease.
We will focus on the type of EB, Recessive Dystrophic Epidermolysis Bullosa (RDEB) for the rest of the article. In a nutshell, RDEB patients are missing the COL7A1 gene which produces type VII collagen. This deficiency of type VII collagen production is the cause of the disease.
Deep-dive:
RDEB is caused by mutations in the COL7A1 gene. COL7A1 provides the instructions for making the pro-α1(VII) chain which is a crucial component of the protein type VII collagen. Collagens are proteins that protect and support connective tissues such as bones, muscles and skin. Type VII collagen specifically is essential for providing stability and strengthening skin. Type VII collagen is an important component of anchoring fibrils, which is a structure in the skin between the epidermis and the dermis that acts as a glue, holding them together. The COL7A1 gene mutation is often caused by nonsense mutations — an insertion or deletion that causes a frameshift in the gene.
How is Recessive Dystrophic Epidermolysis Bullosa Currently Treated?
Currently, there is no cure for RDEB, but researchers have made tremendous strides and are putting all of their best efforts into finding one. There are a few treatments to cope with having Epidermolysis Bullosa, which focus on alleviating its symptoms and preventing blister formation. These include bandaging wounds to prevent infections and encourage healing, maintaining a healthy diet that is high in calories and protein, doing physical therapy to ensure physical function remains optimal, and surgery of placement of a feeding tube since swallowing may be difficult.
Quick Article Recap
- Epidermolysis Bullosa (EB) is a rare skin disease that results in blisters forming at light touches.
- People with EB lack the proteins that hold layers of skin together.
- There are 4 main types of EB which are EBS, DEB, JEB, KS, which each vary in terms of where blistering forms in the skin (epidermis, dermis, basement membrane zone).
- Specifically focusing on RDEB, this disorder is caused by a mutation in the COL7A1, restricting those who are affected to not be able to produce a key component of a collagen protein.
- There are ways to cope with the disease, but no definite cure yet.
- Many rare diseases like EB are often not known even by clinicians, making it difficult for rare disease patients to seek treatment for it. 95% of rare diseases don’t have an effective cure/treatment. This highlights the need for increased awareness of rare diseases.
What Research is Happening in the EB World?
Personalized medicine is revolutionizing the health world, and has been particularly important for the treatment of rare diseases. Targeting the genome of a patient with RDEB opens the door to treating the underlying cause of the disease, and not just the symptoms of it. By fixing or transporting the COL7A1 gene, researchers hope to induce collagen production, which will produce the anchoring fibrils RDEB patients are missing. There are many exciting methods that researchers have employed, and I’ll discuss three that have been particularly fascinating.
There has been a CRISPR/Cas 9-based genome editing strategy reported to restore production of the type VII collagen protein in the keratinocytes of a patient with severe DEB. This study called “Predictable CRISPR/Cas9-Mediated COL7A1 Reframing for Dystrophic Epidermolysis Bullosa”, demonstrates the potential for CRISPR to revert the complications of the DEB disease. CRISPR allows us to cut and paste sections of genes, taking out, adding or altering DNA.
First, researchers isolated a cell line from a patient with RDEB. This patient had a homozygous mutation, so in both copies of genes, there was an absence of the section that enables type VII collagen production. Researchers pinpointed an exact target site in exon 73 (exons are the component of genes that carry the instructions to make proteins), which was the cause of the patient’s inability to produce type VII collagen. Next, they inserted a small piece of DNA which had adenine, a building block of DNA, into the target site and reading frame of the COL7A1 gene. The patient’s cells then had the tools required to produce functional type VII collagen. Over 70% of their cells analyzed produced type VII collagen. This demonstrates that CRISPR is an efficient and possible strategy to cure RDEB.
Krystal Biotech developed a patented gene therapy strategy called KB103 that uses STAR-D, a Skin TARgeted Delivery Platform (shown above). It uses a HSV-1 virus that has been genetically modified to produce no immune reaction, to deliver a healthy copy of the COL7A1 gene to a patient’s keratinocytes (skin cells). This virus doesn’t integrate with the patient’s DNA, so it wouldn’t be a once and for all procedure. But the therapy comes in the form of a gel that can easily be applied to the patient’s wounds. The delivery of the healthy copy of COL7A1 gene enables the patients’ skin cells to produce the type VII collagen protein, allowing wounds to heal and preventing blister formation.
Results from the Phase 3 clinical trial in 31 participants demonstrated that 67% of treated wounds achieved complete healing, compared to the 22% that were treated with placebo medication, following weekly applications of the gel medication.
Abeona Therapeutics has pioneered a therapy called EB-101 which uses “LEAES”, which stands for LZRSE-Col7A1 Engineered Autologous Epidermal Sheets, which is essentially a skin graft made to express the essential type VII collagen protein (shown above). They do this by taking a small biopsy of skin tissue from the patient, and isolating the patient’s skin cells. Then the cells are put into cell culture (growth media) to help the cells grow and multiply. Next, the cells are infected with a virus (retrovirus) which has been genetically engineered to transport the COL7A1 gene into the cells. These “corrected” cells are now capable of producing the type VII collagen proteins which will produce anchoring fibrils. After gene transfer, the cells are grown into a larger sheet that resembles a plastic film, which is then transplanted onto the patient’s skin to promote wound healing.
This study has been promising, as the Phase 1/2a clinical trial in 7 participants showed that wound healing of over 50% was present in 95% of wounds treated with LEAES, while 0% of wounds were healed in untreated skin.
The bottom line for all three of these studies is that the research for treatments for EB is taking off, and the findings have hope for a definitive cure.
For Further Reading:
Thank you so much for reading this article! I write to raise awareness for rare diseases like EB and their potential cures! If you’re interested in reading more about EB, here are a few articles I found interesting:
