RegenVOX: phase I/II clinical trial of stem cell based tissue engineered laryngeal implants

The larynx protects the airway during swallowing, regulates breathing, and permits voice: all fundamental human functions. Over 2000 UK patients lose laryngeal function due to trauma or cancer annually and need to spend a lot of time at or in hospitals. 1300 NHS patients a year have their larynx removed entirely. Conventional treatments for these patients leave many with substantial problems talking, swallowing and breathing. For example, the use of combined chemotherapy and radiotherapy for laryngeal cancer results in hoarseness and painful swallowing and can even render the larynx completely disabled. However, if we could accurately replace the normal contours and structure of the larynx, for example by using a living tissue-engineered replacement, the quality of life (and in some cases survival) of these patients would be transformed. In this project we build on some well-publicised successes in replacing the windpipes of adults and children to deliver a laryngeal reconstruction product made from the patient's own stem cells and a laryngeal scaffold prepared, with appropriate permissions, from transplant donors. Our goal is thereby to produce a safe, effective and reasonably therapy suitable for routine NHS use, resulting in improved quality of life for patients and carers.

The product will be a partial laryngeal replacement construct, composed of a a human donor scaffold from which all donor cells have been chemically stripped. This means that the implant will not get rejected, like normal transplants, and so patients do not need immunosuppressant medication, with all the side effects that would entail. Based on extensive laboratory work, we are able to turn the patient's stem cells into cartilage-producing cells to give natural strength to the product, and also produce a replacement mucous membrane to line the inside, just like a normal larynx. Similar technology worked well for our adult and child windpipe recipients treated for life-saving reasons. To perform this work, we need a further years' preparation for a clinical trial, which will then follow ten implanted patients for two years in order to demonstrate to the regulatory authorities that the product is both safe and effective. This will, in turn, allow us to apply to use the technology routinely in the NHS and to market it to bring in much needed funds to our hospitals. Since this is the first stem-cell based organ replacement to enter clinical trials to our knowledge, this project has far-reaching 'path-finding' implications for other related organ replacements such as those for oesophagus and lung. Even more value will be obtained from this work by developing ways of studying cells and tissues in man in trials like this so that we can learn as much about the underlying science of stem cells and tissue repair as possible. Finally, we will study the detailed economics of moving treatments like this into routine healthcare, and determine the most cost-effective ways this can be managed, as well as making sure that any new inventions bring in as much finance as possible to the UK.

There are no satisfactory conventional solutions for patients with end-stage laryngeal stenosis, which can result from trauma or after cancer resection. This has profound impacts on quality of life, especially swallowing, breathing and talking. Based on our 'first-in-human' successes with tracheal implants1,2, we developed an autologous stem cell and biologic scaffold based partial laryngeal implant to correct severe structural disorders. In preclinical studies, this was biocompatible in rats, and safe and effective in pigs (human cells in immunosuppressed animals). We have developed robust processes for production of cells, scaffold, bioreactor and implant within our fully Good Manufacturing Practice (GMP) licensed cell therapy facility. UCLH hosts the national airway service, which has the largest pool of potential recipients in Europe, and skilled clinical staff.
We propose a 50 months' project to encompass a phase I/IIa clinical trial of customized stem cell based laryngeal implants in ten patients with severe laryngeal stenosis who have exhausted conventional therapeutic options, and with two years' follow-up.
Milestones will be:
1. Obtain necessary authorisations, and perform first implant
2. Complete recruitment and submit processes for IP assessment
3. First two patients attain 6- and 12-month efficacy targets; cost-reduction achieved
4. Completion of follow-up, reporting to MRC and MHRA and publication in high impact journal

Who benefits?

2000 UK patients p.a. lose laryngeal function due to trauma or cancer. The main immediate non-academic beneficiaries will be UK patients, their carers and relatives.

In the immediate term, other beneficiaries are both academic and commercial: clinicians, scientists and engineers working in the multidisciplinary environment of regenerative medicine and its robust application to the clinic, life scientists in the field of stem cells and tissue engineering who want to obtain new ways of studying the human organism, and those working at the biotech interface. In the immediate term, benefit will also accrue to the employed researchers, and then the wider UK and international academic communities, public and private education and healthcare sectors, and industry, in which they will be employed.
In the medium- to long-term, beneficiaries include the wider pool of patients with airway disorders, clinicians, the NHS and industry, and ultimately the international healthcare market and needy patients worldwide. Finally, through public engagement, the UK public will also benefit. Also in the longer-term, and if the technology sees it through to commercialisation, University College, London, our host hospital Trusts and the UK economy will benefit. Persons trained in this programme form an invaluable, multidisciplinary reservoir of human resource to help drive and guide the growing RegenMed industry in the UK.

How will they benefit?

The research will have a direct impact on UK health and wealth. The health benefits will come from facilitating UK regenerative medicine by developing the next generation of technologies for the 3d Scaffold and cells growth, characterisation, monitoring and tracking stem cells for clinical applications but also by providing the necessary translational skills to enable the research to directly impact upon the clinic. The outputs will be disseminated widely to all the stakeholder. The ultimate benefit of the research will be a step-change in the production of 3D cell-based scaffold including going from the existing 'open systems' with their reliance on the skill of the operator and a very large manual component towards a closed automatable system. Furthermore, success in this single application will substantially de-risk the field of 3-D tissue-engineered product development by other academic groups and commercial partners.

Whilst the research will concentrate on exploring safety and efficacy of laryngeal replacement implants with immediate outputs at clinical and technology levels, the overall benefits will be far wider and will ultimately impact upon patients with a wide range of organ and tissue replacement needs, such as adults and children with oesophageal and bowel disorders (related hollow organs).

As the research is at the interface between the physical, biological and clinical and management sciences, it offers unique opportunities for training in multidisciplinary research to employed researchers, which will equip them with new skills and give them essential experience for research or related jobs in academia, education, healthcare, and the emerging advanced therapies industry.

What will be done to ensure that they benefit?

We will deliver our Impact Plan through robust, milestone driven and quality controlled management systems, tested by both application to other trials by our highly experienced trials team, and in first-in-human compassionate patients where we demonstrated proof-of-principle of our technology.

We will provide high-quality, tailored and mentored, training to the post-doctoral researchers at the interface between the physical, biological and medical sciences. We have a very strong track record in this arena.

We work seamlessly with UCL Business to explore the potential market for a RegenVOX technology and any potential spin-offs. We embed herein a highly important stream to map out pathways to commercialisation of complex ATMPs.