A regenerative chit-chat with Michele De Luca

A regenerative chit-chat with Michele De Luca

Marta Paterlini

Published: 25 September 2014

Advances in Regenerative Biology 2014. © 2014 Marta Paterlini. This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 Unported (CC BY 4.0) License (http://creativecommons.org/licenses/by/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material for any purpose, even commercially, provided the original work is properly cited and states its license.

Citation: Advances in Regenerative Biology 2014, 1: 25852 - http://dx.doi.org/10.3402/arb.v1.25852

 

An interview with Professor Michele De Luca, Director of the Centre for Regenerative Medicine ‘Stefano Ferrari’, University of Modena and Reggio Emilia, Modena, Italy.

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Professor Michele De Luca is Full Professor of Biochemistry, University of Modena and Reggio Emilia, and Director of the Centre for Regenerative Medicine of the same university, one of the biggest centers in Europe focused on research on epithelial stem cells and their clinical application in cell and gene therapy. He is also Director of the Interdepartmental Centre for Stem Cells and Regenerative Medicine, University of Modena and Reggio Emilia, and Scientific Director of HolostemTerapie Avanzate. De Luca has been involved in epithelial stem cell biology aimed at clinical application in regenerative medicine for over 20 years.

ARB: From bench to bedside. At which point does regenerative medicine stand?

De Luca: Regenerative medicine is considered as a new frontier of medicine and is strictly related to stem cell biology. But its concept is broad, and we often speak about it out of turn. The drug-stimulation of human cells in situ to trigger their proliferation or their regenerative capability is considered part of regenerative medicine and has been going on for many years. Examples are platelet growth factor extracts and lyophilized cultured epidermal cells to treat skin leg ulcers.

However, if we want to give regenerative medicine a more noble and pure sense, such as the regeneration of a missing or destroyed tissue, we step in the real field of regenerative medicine and, in turn, in the stem cells’ field. In most of the cases, the tissues we want to regenerate are tissues that highly renovate – we change blood every 3 months, skin every month, the cornea every 6 months. Thus, regenerative medicine requires access to stem cells.

ARB: How do stem cells fit into regenerative medicine?

De Luca: There is a big confusion around the definition of stem cells – also among us scientists.

The only pluripotent stem cell in nature, capable to form all tissues of the human body is the embryonic stem cell. The only pluripotent stem cell we can create in the lab is the so-called induced pluripotent stem cell (iPS) of Shinya Yamanaka. Then, there is a plethora of adult stem cells that are usually multipotent and employed to regenerate the tissue where they reside. Nevertheless, to date, the stem cells linked to regenerative medicine for an actual cure of diseases are not many in the clinic.

Indeed, embryonic stem cells and iPS, both very promising, are just in the very early phases of clinical trials. Anders Björklund, at Lund University, and Lorenz Studer, at Memorial Sloan-Kettering Cancer Center in New York, have recently succeeded in making highly efficient dopamine-producing neurons from human embryonic stem cells and have transplanted them into the brains of patients with Parkinson’s disease. The neurons need to be made in sufficient numbers to be effective, and produced in a way that ensures the cells are safe. In Japan, the phase I of a trial just started where iPS cells will be morphed into retinal cells, then given to a few patients with a major cause of blindness: age-related macular degeneration on diseases affecting the retina.

Personally, I am optimistic, but let’s wait for the data, because there is still a need to invest a lot of effort on basic research. The reprogramming mechanism of iPS is still not clear enough, with some black boxes, for example.

The only somatic stem cells that are effectively used in the clinic are the hematopoietic stem cells for the treatment of blood disorders and the epithelial stem cells for skin and ocular burns, probably because blood and squamous epithelia are relatively simple tissues.

ARB: When did you step into the field?

De Luca: I have been in the field for around 28 years. Soon after the degree in medicine, I realized that I could not spend the rest of my life by curing flus and visiting bellies. I was in my mid-20s. I dusted my broom and left to the States to work on the thyroid physiology with Leonard Kohn at NIH, where I forged my scientific skills.

ARB: Who and what inspired you scientifically?

De Luca: From NIH, I moved to Harvard where I found my mentor and scientific guru, Howard Green, a pioneer in regenerative medicine. In 1984, Green had developed the first therapeutic use of epithelial cultured stem cells with cells grown in his laboratory for a life-saving treatment of massive burns, at Harvard. Simply, I fell in love with this system.

ARB: Your work fuses medical practice and basic research. Which were your most important contributions to the field?

De Luca: After my American parenthesis, I moved to the lab of Ranieri Cancedda, at the National Cancer Research Institute, in Genoa. Here, I introduced the system mastered at Harvard as well as embraced the opportunity to set up my line of research. On one side, I was absorbed with the treatment of hundreds of burn patients. On the other side, I also invested in basic research extensively. You can’t do regenerative medicine and transfer knowledge to the clinic without understanding the bases of it.

I started with a few proof of principles by establishing human urethral epithelia stem cell cultures aimed at urethra regeneration in posterior hypospadias (1). But the most important studies of ours are on the cornea. In 1997, we published a long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium (2). Together with Graziella Pellegrini, my lifelong precious collaborator, we built on Green’s technique for cultured epidermis, developed, first in the world, methods of stem cell identification and culture for the regeneration of corneal epithelium. Paolo Rama, ophthalmologist at the Hospital San Raffaele in Milan, participated in the development of the translational side to treat lesions in dozens of patients. Therefore, in 2010, our research culminated with a paper showing long-term restoration of severely damaged corneas and recovery of visual acuity by transplantation of cultivated epithelial sheets prepared from autologous limbal cells. This therapy allows treating massive corneal burns that cannot be resolved by donor corneal transplants. Most importantly, it can restore severe bilateral ocular burns provided that a small limbal area has been spared and used for stem cell cultivation (3). Importantly, clinical results have been correlated to the expression level of ΔNp63α, a specific stem cell transcription factor. Since then, we treated over 300 patients with many ophthalmology departments throughout the country (4).

We are developing epidermal stem-cell-based ex vivo gene therapy to treat epidermolysis bullosa (EB), a devastating disease caused by mutations in genes encoding for proteins forming the skin adhesion machinery. We are currently coordinating the first ex vivo gene therapy clinical trial for junctional EB (JEB), which is caused by mutations of the basement membrane component laminin 332 (LAM332). In 2006, we described the transplantation of a JEB patient with genetically modified stem cells. In particular, the patient’s epidermal stem cells affected by LAM332-beta3-deficient JEB were transduced with a retroviral vector expressing LAMB3 cDNA (encoding LAM5-beta3), and used to prepare genetically corrected cultured epidermal grafts. Nine grafts were transplanted onto surgically prepared regions of the patient’s legs (5). The follow-up after seven years showed his legs had recovered (6).

ARB: Despite these amazing results, your research had to face a slowdown due to the EU regulation (1394/2007) on Advanced Therapy Medicinal Products (ATMPs). What happened?

De Luca: In 2007, the European Community established that advanced therapy products based on cultured cells are classified as medicinal products; hence, they are regulated by the European Medicines Agency (EMA) and need to be produced under the same Good Manufacturing Practices (GMPs) adopted by the pharmaceutical industry for the production of medicines. As in many other labs throughout Europe, this caused a block of all our activities for a while until we set everything up suitable for the GMPs standards.

ARB: Were these rules necessary?

De Luca: Our work was heavily disrupted and my first reaction was of rebellion. Before the directive, the rhythm was 4–5 papers every year and hundreds of patients to treat; after the legislation in 2007, my lab published two papers in total and had zero patients. Upon the directive, we spent a lot of time to build up the center in order to certify it with GMPs standards.

Indeed, do you know what I think? I think that the directive was necessary. Should we not have it on track, all the fake stem-cell-based treatments would have blossomed wildly. Without rules, the regenerative medicine would have been in jeopardy. To accomplish new rules, we built up the Centre for Regenerative Medicine, which contains a large GMP facility, and created the university spin-off Holostem Terapie Avanzate, the first Italian biotechnological company devoted to the development, manufacture, registration, and distribution of products based on cultures of epithelial stem cells both for cell therapy and gene therapy.

After my initial annoyance and the following diligent embracement of the EU regulation, I must add that the equivalence between a stem cell culture and a drug is still not correct, from my point of view. The former is a living cell; the latter is a chemical compound. For the autologous therapy, in particular, there is need of a better set of GMPs standards tailored to the cell culture specificity. And for this matter, I would like to see even stricter rules on the rationale behind a stem cell therapy because the rationale for an antibody against the Ebola virus and for a hypoglycemic agent for diabetes are clear. On the contrary, the rationale behind the use of a stem cell can be very blurry. A mesenchymal stem cell for the regeneration of a bone makes sense, but a mesenchymal stem cell for the regeneration of a neuron is a total nonsense, even if you move within the most perfect GMPs’ framework.

ARB: You are recipient of the 2014 ISSCR Award together with other two Italian stem cell biologists Paolo Bianco and Elena Cattaneo, for your common effort in favor of evidence-based medicine. Indeed, despite the EU regulation, an unproven stem cell therapy proposed by Stamina Foundation has stirred a huge controversy in Italy.

De Luca: With a bit of pride, our intervention helped in saving the country from a disaster. A fake stem cell therapy such as the one by the obscure Stamina Foundation is not a novelty in the scientific scenario. However, the Stamina case, which we have been fighting since 2012, mirrors two peculiar Italian problems: the political weakness and the scientific ignorance of the institutions and media Italy is facing right now.

In other parts of the world, similar situations were halted thanks to the EU directive. Stem cell biologists have been working on stem cells for 20 years in total tranquility. Then the stem cells have become a cult object of interest for all and sundry and the regenerative medicine exploded. The commercialization of stem cells must follow the scientific method that must be at the base of any translational treatment in order to guarantee two aspects: safety and efficiency.

Professor Michele De Luca, thank you for the interview.

Marta Paterlini
Email: martapaterlini@nasw.org

References

  1. Romagnoli G, De Luca M, Faranda F, Bandelloni R, Franzi AT, Cataliotti F, et al. Treatment of posterior hypospadias by the autologous graft of cultured urethral epithelium. N Engl J Med. 1990; 323: 527–30. PubMed Abstract | Publisher Full Text
  2. Pellegrini G, Traverso CE, Franzi AT, Zingirian M, Cancedda R, De Luca M. Long-term restoration of damaged corneal surfaces with autologous cultivated corneal epithelium. Lancet. 1997; 349: 990–3. PubMed Abstract | Publisher Full Text
  3. Rama P, Matuska S, Paganoni G, Spinelli A, De Luca M, Pellegrini G. Limbal stem-cell therapy and long-term corneal regeneration. N Engl J Med. 2010; 363: 147–55. PubMed Abstract | Publisher Full Text
  4. Pellegrini G, Rama P, Matuska S, Lambiase A, Bonini S, Pocobelli A, et al. Biological parameters determining the clinical outcome of autologous cultures of limbal stem cells. Regen Med. 2013; 8: 553–67. PubMed Abstract | Publisher Full Text
  5. Mavilio F, Pellegrini G, Ferrari S, Di Nunzio F, Di Iorio E, Recchia A, et al. Correction of junctional epidermolysis bullosa by transplantation of genetically modified epidermal stem cells. Nat Med. 2006; 12: 1397–402. PubMed Abstract | Publisher Full Text
  6. De Rosa L, Carulli S, Cocchiarella F, Quaglino D, Enzo E, Franchini E, et al. Long-term stability and safety of transgenic cultured epidermal stem cells in gene therapy of junctional epidermolysis bullosa. Stem Cell Rep. 2014; 2: 1–8. Publisher Full Text
About The Author

Marta Paterlini

Sweden