Holostem Terapie Avanzate
Holostem Terapie Avanzate is the first biotechnological company devoted to the development, manufacture, registration and distribution of Advanced Therapy products based on cultures of epithelial stem cells, both for cell and gene therapy.
Holostem Terapie Avanzate is a university spin-off, founded in 2008 through the profitable union among the scientific know-how of internationally renowned researchers such as Michele De Luca and Graziella Pellegrini, the innovative spirit of the University of Modena and Reggio Emilia and the industrial know-how of Chiesi Farmaceutici S.p.A, a leading bio-pharmaceutical company in Italy.
Holostem Terapie Avanzate has a highly experienced management team, with a sound know-how derived from a long tenure both in business administration and in academic research, successfully applied since many years in translational medicine.
Holostem Terapie Avanzate runs a 2.000 sq meters GMP facility (AIFA decree n. aM – 169/2014) containing 17 independent Class BL2 rooms, located into the Centre for Regenerative Medicine “Stefano Ferrari” of the University of Modena and Reggio Emilia, one of the biggest research centres in the world entirely dedicated to epithelial stem cells cultures.
The main aim of Holostem Terapie Avanzate is to promote epithelial stem cell-based Regenerative Medicine for patients with no alternative therapeutic solutions.
Regenerative Medicine refers to innovative therapies aimed at the permanent restoration of diseased tissues and organs. Tissue integrity and regeneration depend on a population of self-renewing somatic stem cells, above all in constantly renewing tissues. Thus, Regenerative Medicine requires a deep knowledge of the biology of tissue-specific stem cells and the development of technologies allowing their maintenance in culture and their clinical application (cell therapy). In case of genetic diseases, stem cells need to be genetically modified before their delivery onto patients (gene therapy).
Michele De Luca and Graziella Pellegrini are internationally recognized as leading scientists in the field of epithelial stem cell biology aimed at clinical application in Regenerative Medicine and played a pivotal role in epithelial stem cell-mediated cell therapy and gene therapy. Beside their pioneering work on the use of human epidermal stem cell cultures in life-saving treatment of massive full-thickness burns (hundreds of patients treated in collaboration with several burn units) and in repigmentation of stable vitiligo and piebaldism (approximately one hundred of patients treated in Italy), they were first in permanently regenerating a functional urethral epithelium – by means of cultured urethral stem cells – in patients suffering from posterior hypospadia.
Michele De Luca and Graziella Pellegrini were first in establishing human limbal stem cell culture aimed at corneal regeneration in patients with severe limbal stem cell deficiency due to massive thermic and chemical burn-dependent destruction of the cornea.
The R&D activity of Holostem Terapie Avanzate S.r.l. is aimed at new protocols for cell and gene therapy based on different epithelial stem cells (epidermis, cornea, conjunctiva, urethra and oral mucosa)
Holoclar®: the first stem-cell therapy approved in Europe
A clear cornea is essential to visual acuity and depends on stromal avascularity and epithelial integrity. Corneal renewal and repair are mediated by stem cells of the limbus, the narrow zone between the cornea and the bulbar conjunctiva.
Ocular burns may destroy the limbus, causing limbal stem-cell deficiency. In such cases, the cornea acquires an epithelium through the invasion of bulbar conjunctival cells. This process leads to neovascularization, chronic inflammation and stromal scarring, with corneal opacity and loss of vision. In this clinical setting, allogeneic corneal transplantation (keratoplasty) is unsuccessful.
Holoclar® is a product of tissue engineering for advanced therapies consisting of an ex vivo reconstructed autologous human corneal epithelium containing stem cells, indicated for the reconstruction of the corneal surface in patients with limbal stem cell deficiency due to ocular burns. The active substance of Holoclar® is represented by the epithelial stem cells contained therein, that engraft and permanently regenerate a functional corneal epithelium allowing recovery of visual acuity.
In August 2008, the European Medicines Agency (EMA) designated this limbal stem cell therapy as an Orphan Medicinal Product and in December 2014 recommended Holoclar® for approval (recommendation included by EMA in the list of the major milestone 1995-2015 in the timeline of 20th anniversary of the agency – see fig. 1). In February 2015 Holoclar ® has been the first stem-cell based ATMP approved by European Commission (conditional approval).
In 2006 and 2014, Michele De Luca and Graziella Pellegrini published a proof of principle of the feasibility of ex-vivo gene therapy for laminin 5-dependent Junctional Epidermolysis Bullosa (JEB) by means of transplantation of autologous epidermal sheets prepared from genetically corrected epidemal stem cells. This trial showed that ex vivo gene therapy of JEB is feasible and leads to full functional correction of the disease.
Holostem Terapie Avanzate is collaborating with the Centre for Regenerative Medicine on the implementation of two Phase I/II clinical trials for ex-vivo gene therapy of Junctional and Dystrophic Epidermolysis Bullosa and on the development of new generation of Self-Inactivating-Gamma Retroviral vectors carrying LAMB3, COL17 and COL7A1 – genes involved in different forms of Epidermolysis Bullosa – under the control of the K14 promoter.
Ex-vivo-expanded autologous human keratinocytes containing epidermal stem cells transduced respectively with a COL7A1-, COL17A1- and LAMB3-encoding retroviral vector for the treatment of epidermolysis bullosa obtained orphan designation in March 2015.