8 minute read
GAMBA
A gene-activated platform for
tissue repair
Growth factors play a central role in the mechanisms behind bone and cartilage regeneration, mechanisms which are disrupted in people suffering from arthritis. We spoke to Professor Christian Plank of the GAMBA project about their work in developing a geneactivated matrix platform for tissue repair and how it could improve treatment of the condition
It is known that growth factors play a central role in many important mechanisms within the body, including bone and cartilage regeneration. This area forms the main research focus of the GAMBA project, which is aiming to develop a gene-activated matrix platform for tissue repair, taking into account the underlying nature of the repair process. “Usually it’s not one growth factor alone that induces tissue repair, but rather several growth factors in concerted action,” says Professor Dr Christian Plank, one of the project’s scientific initiators. The scientific question for the project, the nanotechnology part of their research, was whether a nano/ biotechnology approach could be used to get three growth factors into concerted action. “Is it possible to address the appearance and disappearance of growth factors; can we turn them on and off? And can we do this in different compartments?” continues Professor Plank. “One technical and therapeutic tool to do this is gene therapy – gene vectors. You can construct systems using gene vectors where you can switch gene expression on and off.”
Arthritis
This research could have important implications for the treatment of arthritis. The body maintains a delicate balance between degrading and regenerating processes in our bones, tissue and cartilage, which is disrupted in people suffering from the condition. “In arthritis the natural healthy balance is out of regulation. For example, in bone you have osteoblasts – the bone cells which are important for the formation of bone – and osteoclasts, which eat bone, they degrade it. These two cell types are in balance in healthy bone. In arthritis the
natural healthy balance is out of regulation and the degradation processes overwhelm the regenerative processes” explains Professor Plank. Research groups in GAMBA are working to identify the growth factors involved in arthritis, and to investigate the underlying causes of the condition. “There is still a lot to find out about the molecular causes of arthritis. One of the major questions is whether impaired regenerative potential is the cause of the disease, or whether other factors are also involved,” says Professor Plank. “It is known that inflammatory reactions are important causes for overwhelming degradation.”
This type of research is an important element of the GAMBA project, yet the focus for Professor Plank and his colleagues is on basic research and developing a gene-activated matrix. The matrix is designed to carry gene vectors to damaged tissue and stimulate the regeneration process. “The other important role of the matrix is that it’s a
substrate for cells to grow in the matrix, while it’s also biodegradeable,” outlines Professor Plank. The matrix introduces one gene vector to regenerate bone, one to regenerate cartilage, and one to fight inflammation. “They are the three different targets that we have. They act in three different compartments within the joint,” says Professor Plank. “If you consider the knee joint, the lowest compartment would be the bone, which naturally is covered by cartilage. The cartilage faces the synovium, which is
The GAMBA team
the fluid in the knee joint, where you have these inflammatory factors in the diseased joint. The situation in the diseased joint can be modelled with so-called osteochondral defect models, so defects where cartilage is missing, and also bone is degenerating. Such models can be established with pieces of bone from the slaughterhouse or in animal experiments.” These defects will be filled with a matrix platform carrying three gene vectors. First there will be a vector to induce bone regeneration, followed by a compartment with a vector to support cartilage regeneration, and an upper compartment facing the joint fluid. “This upper compartment will have a vector which will produce an anti-inflammatory effect in response to inflammation in the joint,” explains Profesor Plank. The project’s Dutch partners have been working with bone from cows to look at the effects of these different growth factors. “They drill a 1cm diameter hole into the surface of the tibia - they drill through the cartilage, into the bone, and eventually into the bone marrow space. And then they keep this piece of bone in culture, and we examine what happens in the drill hole when you add different growth factors,” continues Professor Plank. “Our idea was to use exactly such a model to reproduce these three compartments that I’ve talked about. This work is still ongoing – the idea was to look at these idealised, standardised defects for research purposes.”
The project’s French partners have produced a bone replacement material, which has been approved for clinical use, while researchers are also working on methods to promote cartilage regeneration. The gene vector promoting cartilage regeneration has been embedded in a hydrogel. “The hydrogel would also support cell growth, but it would be a gel as opposed to a bone replacement material, which is a solid body. The third thing would be mesenchymal stem cells, which have the potential to differentiate into not only bone cells, but also into cartilage cells,” outlines Professor Plank. This would stimulate cells to form the desired tissue and generate bone morphogenetic protein, which would induce bone regeneration; however, Professor Plank says it is difficult to control the level of bone formation. “We have found, along
Full Project Title
Gene activated matrices for bone and cartilage regeneration in arthritis (GAMBA)
Project Objectives
The GAMBA Consortium is developing a novel gene-activated matrix platform for bone and cartilage repair with a focus on osteoarthritis-related tissue damage. The scientifi c and technological objectives of this project are complemented with an innovative program of public outreach, actively linking patients and society to the evolvement of this project.
Project Funding
Total budget €3,526,178, total requested EU contribution €2,644,630.
Contact Details
Project Coordinator, Dr Martina Anton Institute of Experimental Oncology and Therapy Research The ISAR TUM hospital Ismaninger Str. 22 81675 München Germany T: +49 89 4140 4453 E: m.anton@lrz.tum.de W: http://www.gamba-project.eu/
Plank et al.: Gene activated matrices for bone and cartilage regeneration in arthritis. Eur. J. Nanomed. 2012;4(1):17–32 © 2012 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/ejnm-2012-0001
Professor Christian Plank
Group Leader
Christian Plank is a professor at the Institute of Experimental Oncology and Therapy Research of the Technische Universität München. In 2003 he cofounded OZ Biosciences, a company that develops and markets reagents and technologies for the delivery of active substances to living cells. In 2009 he cofounded ethris GmbH, a company which develops novel nucleic acid therapeutics. with many others, that using the bone morphogenetic protein encoding vector alone leads to the healing of bone defects that otherwise would not heal, because the defect is too large. However, we don’t yet have a tool to control the level of bone formation,” he explains.
This is a challenge that the GAMBA project is working to address. The main focus is on switching genes on and off, to control for example the production of the growth factor that promotes bone generation, while researchers are also looking at the anti-inflammatory response. “The idea for the antiinflammatory response was to have a
feedback loop. So in the upper layer facing the synovium you would have a gene vector whose therapeutic gene is turned on in response to inflammatory signals from the synovium. Then the cells facing the synovium would start to produce an anti-inflammatory protein, which would turn off the inflammation in the synovium. It would be like an oscillator,” says Professor Plank. Many research questions remain before this type of system can be produced, but Professor Plank believes they can and will be solved. “The goal is to have this type of oscillator system in the joint. These systems will respond to a biological signal, and they will be turned off as soon as the biological signal isn’t present any more. This is a really interesting scientific and basic research challenge,” he outlines.
Basic research
Resolving these questions around oscillator systems could have great implications for the treatment of arthritis. While GAMBA is focused on basic nanotechnology research, the project has also run outreach panels to understand how arthritis affects people individually. “We had two types of panels – patient panels and citizen panels. This was one of the highlights of the whole project, and was well appreciated by scientists, patients
and citizens,” says Professor Plank. The panels gave scientists important insights into how arthritis affects people, and the matrix platform could in future be the basis for more personalised treatment, taking into account the specific nature of each individual case. “You can modify the dosing of the vector to suit the needs of the patient. One patient may have a tissue defect for example, and you could give a higher dose of the anti-inflammatory vector, whereas a different patient would get more of the bone-generating vector,” continues Professor Plank. “This would be the kind of fine-tuning that could be done. The matrix is flexible enough to really adapt it to the patient’s particular situation.”
Dr Martina Anton and Professor Christian Plank
