Novel tissue implantable slow release tablet therapy to prevent scarring
Lead Research Organisation:
University College London
Department Name: Institute of Ophthalmology
Abstract
There are no licensed treatments to prevent scarring in the human body. Scarring plays a part in most of the major blinding conditions in the world today. It is also important in many lung, heart, kidney, intestinal, brain and skin conditions.
The group of eye diseases called glaucoma are the commonest cause of irreversible blindness worldwide and the commonest reason for an eye outpatient appointment. In glaucoma the nerve carrying vision to the brain gradually collapses. We treat glaucoma by lowering the eye pressure. We can create a new eye drainage channel. Unfortunately this fails due to scarring. In our recent long term surgery study, in patients who had minimal scarring with low pressures not one patient got worse over nearly a decade. In contrast if scarring was bad 24% got worse. The problem is we can only achieve this in 30% of people using an anticancer agent called 5-fluorouracil.
We have discovered that inhibiting enzymes called matrix metalloproteinases dramatically reduces scarring. When we inject this after glaucoma surgery we greatly reduce scarring, more than any anticancer agent we currently use. The problem is we have to inject the eye many times. We have now invented a way to make it into a tiny tablet which is painlessly placed into the operation area. This releases the drug at just the right level. A pilot study has shown this tablet is better than anything we currently have. The aim of this project is to scientifically develop the best shape and concentration of the tablet and then scale this up for human use and benefit.
This is being carried out by research groups at UCL Ophthalmology and the London School of Pharmacy, two groups with a world-class track record for developing new treatments. They are part of the new National Institute for Health Research Biomedical Research Centre which has been established to ?fast track? developments like this rapidly though to patient benefit and include the new NHS Pharmaceutical production facility at Moorfields Eye Hospital.
If successful, this new single tablet has the potential to considerably improve the treatment of glaucoma all over the world with fewer visits to clinic and prevention of blindness. There is great potential to improve the treatment of other diseases of the eye including macular degeneration, diabetic retinopathy, retinal detachment, blinding retinopathy of premature children and other scarring problems in the human body.
The group of eye diseases called glaucoma are the commonest cause of irreversible blindness worldwide and the commonest reason for an eye outpatient appointment. In glaucoma the nerve carrying vision to the brain gradually collapses. We treat glaucoma by lowering the eye pressure. We can create a new eye drainage channel. Unfortunately this fails due to scarring. In our recent long term surgery study, in patients who had minimal scarring with low pressures not one patient got worse over nearly a decade. In contrast if scarring was bad 24% got worse. The problem is we can only achieve this in 30% of people using an anticancer agent called 5-fluorouracil.
We have discovered that inhibiting enzymes called matrix metalloproteinases dramatically reduces scarring. When we inject this after glaucoma surgery we greatly reduce scarring, more than any anticancer agent we currently use. The problem is we have to inject the eye many times. We have now invented a way to make it into a tiny tablet which is painlessly placed into the operation area. This releases the drug at just the right level. A pilot study has shown this tablet is better than anything we currently have. The aim of this project is to scientifically develop the best shape and concentration of the tablet and then scale this up for human use and benefit.
This is being carried out by research groups at UCL Ophthalmology and the London School of Pharmacy, two groups with a world-class track record for developing new treatments. They are part of the new National Institute for Health Research Biomedical Research Centre which has been established to ?fast track? developments like this rapidly though to patient benefit and include the new NHS Pharmaceutical production facility at Moorfields Eye Hospital.
If successful, this new single tablet has the potential to considerably improve the treatment of glaucoma all over the world with fewer visits to clinic and prevention of blindness. There is great potential to improve the treatment of other diseases of the eye including macular degeneration, diabetic retinopathy, retinal detachment, blinding retinopathy of premature children and other scarring problems in the human body.
Technical Summary
The causes of fibrosis are complex and contribute to many human diseases, including every major blinding disease. There is a large unmet need for anti-scarring therapies; with at least 42 million procedures in 2004 which could have benefited from anti-scarring products. Administration of cytotoxic agents directly into the eye after surgery to control fibrosis to manage healing is currently the best clinical treatment available. There are many side effects because repeat injections of high doses that rapidly clear are toxic locally and systemically. There is a need to control fibrosis both generally and in the eye after surgery as there are no licensed treatments.
We have solved two major problems of current anti-fibrotic treatments: (1) To address toxicity, we have discovered that repeat injections of a metalloprotease (MMP) inhibitor have a markedly beneficial effect on scarring reduction without the toxicity of cytotoxic agents. (2) To address tissue specific pharmacokinetics, we developed a novel, small, resorbable tissue-tablet to release the MMP inhibitor locally at the fibrotic site. Using a clinically validated in vivo model, prolonged release profiles are achieved with a 100% surgical success rate to date. Preliminary results support a clear pathway to develop the MMP tablet to treat post-surgical fibrosis.
We have solved two major problems of current anti-fibrotic treatments: (1) To address toxicity, we have discovered that repeat injections of a metalloprotease (MMP) inhibitor have a markedly beneficial effect on scarring reduction without the toxicity of cytotoxic agents. (2) To address tissue specific pharmacokinetics, we developed a novel, small, resorbable tissue-tablet to release the MMP inhibitor locally at the fibrotic site. Using a clinically validated in vivo model, prolonged release profiles are achieved with a 100% surgical success rate to date. Preliminary results support a clear pathway to develop the MMP tablet to treat post-surgical fibrosis.