Corneal Skin: Good Eyesight Ahead!

14. December 2015
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The European Commission recently approved the first stem cell-based medical product. Holoclar uses autologous stem cells in order to enable patients with severe corneal injury to be able to see again. We have here the first step towards new forms of therapy.

Holoclar is one of the so-called “tissue engineered products”, and represents a novel form of therapy. Limbal stem cells are taken from the patient and cultured in the laboratory on a membrane. Together with the cells the membrane is then implanted in the patient’s eye. The product is approved for the treatment of adults with moderate to severe limbal cell deficiency.

With this disease the limbus – the transition zone between dermis and cornea – as a result of burns no longer forms enough stem cells. Damaged cells of the corneal surface epithelium are not able to be replaced. This leads to the event that epithelial cells of the conjunctiva migrate into the cornea in order to protect the injured eye on its outer surface. However, these cells also provoke inflammation, scarring, corneal opacity and eventually blindness and produce severe pain.

The EU says “yes”

The European Commission’s approval decision was based primarily on the results of retrospective observational study HLSTM01. It was able to be shown that 75 of the 104 Holoclar treated patients (72.1%) 12 months after the medical intervention exhibited stable corneal epithelium without significant neovascularisation. The proportion of patients with symptomatic pain, burning or photophobia decreased significantly: whereas before surgery 40 patients (38.5%) had at least one of these symptoms, a year after the transplant only 12 patients (11.5%) did. What’s more, visual acuity improved for 51 patients (49.0%) by at least a full line on the Snellen-Index. In 2010, the New England Journal of Medicine released data showing that the Holoclar-procedure was successful with 76.6% of patients. Meanwhile, there are results from a multicentre prospective study [Paywall], confirming that Holoclar led to success in the majority of treated patients (success: 66.1%, partial success: 19.1%) leading to the formation of stable, transparent corneal epithelium. It should not be left unmentioned that two of the authors are part of the management of Holostem Advanced Therapies, the manufacturer of Holoclar.

Cells to order

Holoclar can only be used on patients who still possess limbal stem cells. Using limbus biopsy a 1-2 mm large piece of tissue is removed from the undamaged eye (or with a two-sided injury from a small healthy limbus area) and sent to the producer in Modena, Italy. The stem cells are made to multiply in a cell culture laboratory using murine feeder cells. The cell suspension is frozen until a transplant date is set. From the thawed cells a confluent cell layer is cultured on a fibrin membrane and the finished Holoclar-product is sent to the hospital where the transplant takes place. There it needs to be surgically implanted immediately in the patient’s eye.

Rare disease – multiple causes

Whereas a primary limbal cell deficiency (LSCD) is characterised by having no identifiable underlying cause, a secondary LSCD is caused by injury to the eye. These may be diseases of the ocular surface (for example, with Stevens-Johnson syndrome) or chemical/thermal burns, damage from UV and ionising radiation, bullous pemphigoid of the eye, severe microbial infections, the wearing of contact lenses, as well as multiple eye surgeries or cryotherapies. Where chemical burns are the cause of LSCD, alkalis tend to play the main role, since basic agents quickly penetrate the eye tissue and lead to extensive necrosis of the epithelial cells and stromal-denaturing.

In Europe, however, few people are affected by this disease: prevalence is estimated at 0.34 per 10,000 inhabitants. For this reason Holoclar has since November 2008 had orphan drug status. To date, the treatment of LSCD has been confined to transplantation of corneas from donors with the aim of restoring the transparency of the ocular surface. However without stem cells corneal grafts cannot survive in the long term. “The only way to restore the integrity of the cornea is via the transplantation of limbal stem cells so as to regenerate a well-functioning limbus”, explains Dr. Paolo Rama [Paywall], ophthalmologist at the San Raffaele Hospital in Milan and co-author of the published Holoclar studies.

The competition is not sleeping

Holoclar is however by no means the only product based on limbal stem cells – for example, a group led by ophthalmologist Dr. Virender Singh Sangwan at the LV Prasad Eye Institute in India has also developed a form of therapy which employs autologous stem cells. Cell cultures derived by this group are even fully free of animal-tissue components, whereas at Holoclar feeder cells from mice are used. Data derived from the successful treatment of the first 200 patients treated have already been published, and even children can be successfully treated using this method. Another medical product called ReliNethra, which is also free of animal components, also comes from India, where it is approved for the treatment of a variety of causes of LSCD whereas Holoclar (so far) has only been permitted for use on burn-related LSCD.

Dr. Sangwan’s group however goes even one step further and recently published a technique in which the stem cells are cultured directly on the surface of the eye. The stage involving multiplication of cells in a special laboratory would in this way be able to be side-stepped, so that the method can be used “anywhere wherever an eye surgery operating room and a corneal surgeon are available”, according to Dr. Sangwan [Paywall]. More than 200 people have been treated using this new method, and the success rate is as good or even better than that of conventional cell culture-based therapy.

Bilateral challenge

All autogenous stem cell therapies have nevertheless one decisive disadvantage: They can only be used if the patient still possesses limbal stem cells. If this is not the case, allogeneic donor stem cells are used; however a life-long therapy with immunosuppressants is then required. Therapies such as Holoclar can therefore only be described as a first step, says Dr. Alex Shortt, ophthalmologist at University College London. “While the launch [of Holoclar] is really encouraging and it’s great to see that cell-based therapies can get this far, this is in my opinion the easiest problem to be solved by us with regard to this patient population”, explains Dr. Shortt [Paywall]. “People with unilateral chemical injuries are the easiest group to get treated, but they are not necessarily the largest group, because if you added up all patients with bilateral disease, there are far, far more patients – and for these people we still have no good treatment”.

For this reason, Holoclar pioneers such as Prof. Grazielle Pellegrini and Prof. Michele De Luca are not only working to improve the existing technology, but they are also looking for new ways to use cell-based therapies. “My main goal for the future of Holostem is gene therapy”, reveals Prof. De Luca, scientific director and co-founder of Holostem and director of the Center for Regenerative Medicine at the University of Modena, Italy. “As soon as you know a stem cell well enough, you know how it works and you can put it into cell therapy; you are then in a position to think about its genetic components and how they could be modified in order to cure genetic diseases”.

The focus of his work is currently Epidermolysis bullosa, a painful condition in which the skin begins to bubble and detach from the body. Prof. De Luca’s follows an approach involving the use of autologous epidermal stem cells on keratinocyte cultures derived from the affected patients. The aim is to change them using retroviral vectors, engineered such that they express a functional variant of the mutated gene. Using these “corrected” stem cells epidermis cultures are raised and transplanted onto the patient. The results of a first clinical phase I / II show that more than six years after the transplant the transgenic epidermis was fully functional and almost indistinguishable from a healthy epidermis. The next step is to test the technique on more patients – Holostem is collaborating for this reason with the Department of Dermatology at the University Hospital Salzburg. “We are trying to go the same way as with Holoclarin in order to make this gene therapy accessible to those affected. This is my dream, one to reach before I retire”, says De Luca. It is quite possible that this dream may actually be realised.

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