First in human phase I / II clinical trial of RAFT for aniridia related keratopathy.

The cornea on the front surface of the eye is our window to the world. If transparency is compromised, visual impairment and even blindness can occur. Aniridia is a rare blinding disease (1:100,000 incidence) caused by a mutation in PAX6 which is one of the genes responsible for development and healthy function of the eyes. Aniridia-related keratopathy (ARK) manifests as persistent, chronically painful defects of the outer epithelial layer of the cornea called the epithelium. Blood vessels grow into the cornea and scarring also occurs, both of which obstruct vision. ARK induced light sensitivity can lead to social exclusion. The cause of these symptoms is related to the inability of the mutated limbal epithelial stem cells (LESC), stromal cells and tissue to maintain normal corneal epithelium. Current treatments include whole donor tissue transplantation and cultured LESC therapy which have both shown poor long-term outcomes. Since stem cells require support from neighbouring cells and proteins in their environment, transplanting cultured LESC alone may not be sufficient to preserve / improve patient vision. An optimal ARK treatment would include transplantation of both healthy LESC and a stroma (corneal support tissue) populated with stromal cells. Our proposed solution utilises our patented technology known as RAFT (Real Architecture for 3D Tissues) in which LESC and stromal cells are cultured together in a transplantable collagen matrix (artificial tissue). We are able to make this tissue in compliance with the required regulations which are known as Good manufacturing practise, or GMP for short, in our clinical cell therapy production laboratory. Pre-clinical safety studies supports us moving forward to a first in human study. In this project we will undertake 1) full GMP protocol validation for RAFT in our Cells for Sight licensed manufacturing facility, 2) write and submit all of the documentation required to obtain regulatory approval for a clinical trial and 3) proceed to first in human RAFT transplantation studies in patients with ARK. In this phase I/II clinical trial we will perform RAFT transplantation in one eye of 21 ARK patients to assess RAFT safety and preliminary efficacy. The outcome measures will include restoration of a normal corneal epithelium without any defects, blood vessel ingrowth or scarring. If successful, this therapy could provide a much-needed solution for patients with ARK and also act as a springboard for the development of RAFT for other blinding eye diseases.

Aniridia is an orphan heritable disease (1:100,000 incidence) in which PAX6 gene mutations cause severe blinding developmental eye problems. Aniridia-related keratopathy (ARK) manifests as persistent, chronically painful defects of the outer epithelial layer of the cornea, vascularisation and scarring. This correlates with dysfunction in the ability of limbal epithelial stem cells (LESC), stromal cells and matrix to maintain normal corneal epithelium. ARK induced light sensitivity can lead to social exclusion. Current treatments include whole tissue transplantation and cultured LESC therapy which have both shown poor long-term outcomes. This may in part be due to 1) antigen presenting cell presence in whole tissue transplantation and 2) stromal cell absence in cultured LESC therapy. An optimal ARK treatment would include transplantation of both healthy LESC and a stroma populated with stromal cells. Our proposed solution utilises our patented technology known as RAFT (Real Architecture for 3D Tissues) in which LESC and stromal cells are co-cultured in a transplantable type I collagen-based tissue equivalent. Good manufacturing practise (GMP) protocols have been established in our pre-GMP laboratories and RAFT has undergone pre-clinical safety studies in a rabbit model. Having obtained regulatory advice (MHRA) we now need to undertake 1) GMP protocol validation in our Cells for Sight MHRA/HTA licensed manufacturing facility, 2) finalise IMPD to submit for clinical trial authorisation of a FIH transplantation study and 3) proceed to first in human RAFT transplantation studies in patients with ARK. In this phase I/II clinical trial we will perform RAFT transplantation in one eye of 21 systemically immunosuppressed ARK patients to assess RAFT safety and preliminary efficacy. The outcome measures will include corneal surface normalisation and stability (lack of conjunctivalisation, vascularisation and epithelial defects, and improvement in corneal clarity).

Patients, Academics, clinicians, commercial private sector, policy makers, charities will benefit from this research.

Patients will benefit from this research if it leads to the demonstration that RAFT is a suitable technology for the transfer and survival of stem cells on the ocular surface. If this project is successful, it will provide early safety data and efficacy data for the use of RAFT in the human eye. This will consolidate our drive to develop additional ocular therapies, using RAFT, to treat diseases with much larger indications. These will include replacement of scarred corneal tissue, delivery of corneal endothelial cells, delivery of cells for retinal degeneration. Success of such approaches will improve quality of life, and make a positive contribution to the economy by alleviating the financial burden on the NHS and by generating new jobs. Such advances would strengthen the UK's position in terms of international research leadership that would in turn attract new economic investment.

Academics interested in the research areas of regenerative medicine, corneal biology, stem cell regulation, cell-cell interactions, tissue engineering and reducing the use of animals in experiments will benefit from having a simple, easy to make and reliable model of human tissue to adapt for their own research.

Clinical academics interested in enhancing health span, alleviating the effects of ocular surface failure and corneal disease will have a model in which to test new concepts and therapies.

Existing and any new IP and knowhow generated could be licensed by the commercial private sector to generate future economic return for the University and the companies involved.

Availability of reliable models of human tissue and a demonstration of their therapeutic potential could inform policy makers with regards to the direction of future research investment.

Charities may also benefit by having a tangible cause against which to raise funds.
The researchers working on the project will benefit from engaging with scientists from different backgrounds. This will seed new ideas, forge further new collaborations and secure future research funding.