A rare disease is one that affects fewer than 200,000 people in the U.S. Despite that number, there are still more than 25 million Americans and 30 million Europeans afflicted with a rare disease, and there are nearly 7,000 rare diseases which involve chronic illness, disability, and often, premature death. While these diseases can affect any age group, about half of the individuals impacted by them are children.
Abeona Therapeutics has potential gene therapy approaches for Sanfilippo Syndrome under investigation in clinical trials, and recently conducted a Phase 1/2 clinical trial for individuals with Recessive Dystrophic Epidermolysis Bullosa (RDEB). RDEB is an often fatal connective tissue disorder marked by skin blistering and caused by a lack of a collagen protein responsible for anchoring the dermal and epidermal layers together. The condition makes the skin incredibly fragile, leading to blistering or skin loss at the slightest friction or bump. Abeona is now preparing for a Phase 3 trial investigating EB-101.
Creating New Skin From Cells
The Phase 3 trial Abeona will soon have underway for EB-101 involves gene transfer into keratinocytes, which are the majority of cells in the outer layer of skin. Abeona will biopsy a patient’s skin, grow his/her keratinocyte cells in cell culture, and then deliver to those cells a modified virus to insert a correct form of the COL7A1 gene. After cells receive the gene transfer, they will be grown into thin sheets of cells and Quality Control tested. The sheets will then be grafted to cover an open and chronic or recurring wound of the very same patient from whom those cells came.
“For this study we are continuing our partnership with Stanford University,” says Michelle Berg, VP of Patient Affairs and Community Engagement for Abeona. “They initiated the Phase1/2 study and developed the original manufacturing approach though we will eventually transition production to our commercial facility in Cleveland, The Elisa Linton Center for Rare Disease Therapies. Stanford has an amazing clinical team that is deeply invested in the patients, their families, and the greater Epidermolysis Bullosa community. That made for a very helpful transition for us because they already had so much established before we came onboard.”
Abeona already has two therapies for Sanfilippo Syndrome in clinical trials, but this study for RDEB is quite different. It is also an autosomal recessive inherited disease, however it has immediate onset, as opposed to Sanfilippo which shows up after the first few years of a child’s life, and is typically diagnosed when they stop developing as expected. With individuals impacted by RDEB, their cognitive functions are fully intact, which is not the case with children diagnosed with Sanfilippo as they progressively lose these capabilities.
For caregivers, RDEB also presents different challenges. The blistering and loss of skin presents a situation that parents and family members must always address. Berg notes care givers must bathe and tend to these wounds on a daily basis. Patients must have clean, specialized bandages to prevent further harm or infection. The patients also typically lack the independence to care for these wounds on their own. “These wounds also create a high level of pain and itching along with other significant challenges caused by the disease such as malnutrition, trauma to the mouth, esophagus, and a phenomenon called pseudosyndactyly,” says Berg. “Pseudosyndactyly is the fusion of fingers and toes, also called mittening. For these patients, the pain never really goes away. That is their normal.”
Driving Toward Relief For Patients
Abeona is still working on the clinical plan for the upcoming Phase 3 trial for RDEB, and details on it could not yet be released. However, Berg notes that as with the original Phase 1/2 study, Abeona will take cells from a patient and use them to create the thin sheet of cells noted earlier. The sheets are approximately the size of a smart phone. Eight of these sheets will be produced; two that will be used for quality control release testing and up to six of the remaining will be grafted onto recurring or chronic wounds of the patient. The retrieval of the original skin cells and subsequent grafting will be performed at Stanford and will be done while the patient is under anesthesia.
“Not all six have to be used, but they are available and will be used at the discretion of the physician and clinical site based on the size and location of the wound to be studied,” says Berg. “The new skin cells must be used on the very same patient for whom they were created. These personalized sheets of gene-corrected skin result in immediate closure of the open wounds and will be monitored over time for healing and expression of type VII collagen.”
The new skin cells will be very fragile and care must be taken so as not to tear or damage the sheets. The recovery phase will require patients to remain still and restrict movement to allow for engraftment. Care is also taken to avoid placing the cells in areas of the body where bending will occur, as that may also cause the new sheets to tear. Asking any child to stay still for a period of time is a challenge, as any parent will tell you. Berg is considering whether there are ways (games and movies, for example) that might help patients restrict their movements.
There certainly is a quality of life issue involved in understanding what EB-101 can do to reduce the level of pain for patients in the engrafted areas. Itching is also a concern, and it is believed the new cells could reduce that as well. Since the treatment may reduce the need for bandaging, it could also save patients and their caregivers time and money. Once EB-101 is engrafted onto a patient, researchers will monitor whether they are staying in place and can compare them to other untreated wounds over time.
“Right now our Patient Affairs team is focused on meeting the RDEB community where they are and providing as much appropriate education as possible,” adds Berg. “These patients are in a lot of continuous pain and they and their caregivers want to avoid or reduce that. Another hospital visit can be a very scary thing for them, especially younger children. It’s very important that they and their families understand what a clinical trial is and what this approach entails. People learn differently so we are coming up with different ways to convey information. As we learn more from patients and families on what they prioritize and want us to know, we ensure that colleagues in other areas hear it too and understand just what the impact and needs are.”