In this interview, Michele De Luca (University of Modena and Reggio Emilia) discusses the development of a gene therapy for epidermolysis bullosa, pediatrics sufferers of which are known as butterfly children.
Could you introduce yourself and your institution?
I am the Director of the Centre for Regenerative Medicine “Stefano Ferrari” at the University of Modena and Reggio Emilia (Modena, Italy), which was created 10 years ago. I joined the University almost 15 years ago, but I have been working in the field of regenerative medicine for over 30 years now.
What was it that first interested you in the field of regenerative medicine?
During the 1980s, I was in the laboratory of Howard Green at the Harvard Medical School (MA, USA) where he was growing keratinocytes from the epidermis and he was starting the clinical treatment of burns. Now, young post-docs and people are used to tissues and cells, even pieces of cartilage and bone or neurons and muscle, that are grown in the lab; in those years to see human tissue coming out of a dish was something spectacular, it was amazing, it was sort of a dream coming true.
I just fell in love with keratinocytes and when I was back in Italy, I started working on human epithelial cells starting with the skin, starting with full thickness burns patients. During the subsequent years, we developed new clinical applications with different epithelial stem cells, such as the cornea, and, in the last decade or so, we have developed genetic modification of those cells. We are now addressing genetic diseases of the skin such as epidermolysis bullosa (EB), so has been a long journey.
What prompted this new work on genetic modification and the genetic cause of disease?
There was a certain natural evolution. When you know the basic biology of certain stem cells, in our case the epithelial stem cells, you know how to grow the cells and how to apply them in the clinical setting. Once we can do this, it is obvious that the next step to do is to modify those cells.
We tried to address issues which are related to genetic disease because in this case you could potentially cure not only accidents or the injuries, but also genetic disease. In the field of dermatology, we have EB which is a tremendous, devastating skin disease and causes “butterfly children”; it was an obvious target for us.
You recently were awarded the Innovators in Science Award. Can you share some moments from your career that you feel were particularly innovative?
I was happy and honored about this award because it came from prestigious institutions such as the New York Academy of Sciences (NY, USA) together with Takeda (Tokyo, Japan); obviously it is not the only award we have received but was particularly important to me. It recognized the three decades of work that we have done using stem cells, specifically epithelial stem cells, in trying to translate the basic biology of the stem cells into a lifesaving clinical setting.
The research Graziella Pellegrini, University of Modena and Reggio Emilia, and I conducted in corneal regeneration using limbal stem cells for severe ocular burns led to the approval of the first stem cell-based advanced product in Europe, called Holoclar. We have also shown the possibility of developing an ex-vivo gene therapy for EB in two or three key papers. Specifically, the end of 2017, we published a paper in Nature where we regenerated the entire epidermis of a child with junctional EB.
Why was this award so important to you?
I think it was one of the most important. Beside the Black Pearl Award from EURORDIS, a rare disease patients’ organization, I want to mention another award that we received with Graziella Pellegrini: the Innovation Award from the International Society of Stem Cell Research (ISSCR). Now both awards, the ISSCR award and the New York Foundation award are quite important because they come from our colleagues and peers. It is the recognition of a stem cell society and the stem cell scientists working in the same field that makes these awards to me particularly important.
How did the EB gene therapy come to be developed?
What we are trying to do is to address a specific aspect of the disease and the most important for the patients, which are the devastating skin lesions they have. We are trying to isolate stem cells from the skin, genetically modifying them then preparing cultures of transgenic epidermis that we can transplant on those patients. There are three main types of EB, of which junctional and dystrophic are the most severe. Up to now, we have treated 3 patients with the junctional form of the disease and have had very good results: in these patients, the transgenic epidermis is very stable. It does not blister anymore and it is being restored.
In the future, we want to pursue the junctional EB patients and try to make this a real therapy, but we are also working on the other types of EB, such as dystrophic EB, which is the most frequently occurring severe form of EB and is caused by a different gene.
You previously worked on developing a stem cell therapy, Holoclar. How do the challenges in developing a gene therapy compare to those of a stem cell therapy?
The challenges are actually similar. Regenerative medicine and advanced therapies by means of genetically modified cells is a new branch of medicine. However, the type of regulations that we are complying with are very similar to the ones that are applied to regular drugs. Often, it is not easy to adapt the rules that are made for classical pharmaceutical drugs to something that is a live tissue.
Many of the regulatory bodies understand this now and they are adapting the rules but it is still quite challenging and very expensive to navigate the complex regulatory network. We managed to do it because we took advantage of the collaboration between the academics of the university, and companies. Holostem Terapie Avanzate is a biotech stemming from this cooperation.
In the classical pharmaceutical world, you have a compound that you make available to the pharmaceutical industry to bring it to patients. In advanced therapies, you are dealing not with the real product but a process. It is the process which is personalized medicine because we are working with autologous cells and we have to follow the process to turn it into skin or the cornea, which needs very stringent scientific control.
Therefore, we have to combine basic science, control of the scientific process together with the rules of the manufacturing and the pharmaceuticals. We worked together with scientists, biotechnologists, regulators and the experts in GMP and pharmaceuticals. By bringing this expertise together, we were able to develop properly a product/process that is safe, efficient and shows efficacy.
The only difference between the Holoclar-type therapy and a gene therapy is that we have to introduce an additional step, which is regenerative modification of the cells; beside this they are very similar.
You have been in this industry for a little while now. What questions do we still need to answer?
This is an interesting question. We are dealing with regenerative medicine by epithelial stem cells, but the field of regenerative medicine is exploding right now with many, many, many types of cells and therapies being developed. I think that it will be extremely important to understand that you need a lot of basic science before you can start the translation. Sometimes, it is not that easy; the epithelium is a superficial tissue and has a simple structure. Other types of tissue such as the heart, kidney or the liver are much more difficult.
The other thing that I think is going to be very interesting in the next few years would be the possibility of using pluripotent stem cells such as embryonic stem cells or induced pluripotent stem cells (iPSCs) to try to cure disease where we cannot use somatic cells. There are already interesting data coming out in the literature on the possibility of utilizing embryonic stem cells for the regeneration of the retina in age-related macular degeneration or the generation of dopaminergic neurons for Parkinson’s disease. People have already started clinical trials for both. In the case of iPSCs, in the next few years I think we will witness development of similar clinical trials.
I gave you just two examples but they are not exhaustive: I am looking forward to see the next step in the field of regenerative medicine.