Exemplars molecules in action

Exemplars: molecules in action

Healing skin without scarring All tissues in the body , when damaged, are subject to a conserved process by which cells are recruited to the wound to remove damaged tissue fragments and then deposit and subsequently remodel the tissue (see Chapter 3 ). In the case of the skin, the initial damage results in bleeding into the wound followed by haemostasis and, when the platelets within the clot degranulate, the secretion of proinflammatory factors. The tumour necrosis factor alpha (TNF α ), interleukin (IL) 1 and IL-6, platelet- derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) recruit monocytes and endothelial cells into the wound bed to begin the wound-healing process. These cells release further cytokines, such as transforming growth factor beta 1 (TGF β 1), that mediate the formation of new extracellular matrix (normally initially collagen III in skin). Over time, the collagen III is remodelled and replaced with collagen I, which is normally deposited in a basket weave pattern. This process very e ffi ciently closes wounds and, when not too severe, healing can be with minimal scar formation. In the case of severe damage or infection, the inflammatory response can ‘overshoot’, resulting in the overproduction of cytokines such as TGF β 1, which drive the recruitment of excess myofibroblasts to the wound site. This leads to the deposition and subsequent overcontraction of collagen matrix, which can result in the classic appearance of a scar. A number of interventions have targeted this process with the aim of preventing the formation of a scar on the skin. Of note was the identification and isolation of TGF β 3, which plays a role in regulating extracellular matrix formation. This molecule was shown to regulate wound healing by blocking the TGF β 1 and -2 receptors on the cell surface and by modulating the penetration of cells in a newly forming tissue. TGF subsequently developed as a therapeutic agent for use within the skin, with the aim of preventing scar formation. As TGF is a large, protein-based drug it was challenging to manufacture and purify and so was expensive in comparison with small- molecule drugs. Although this molecule had significant poten tial as an antiscarring agent in phase I and II trials, ultimately it was not adopted. This is an exemplar of a translational approach, working from a proposed mechanism through to stepwise clinical trials to test e ff ectiveness. Molecular delivery to prevent ocular fibrosis Another example of the function of a tissue being significantly impaired by fibrosis is the eye. When the cornea is damaged, as long as the wound is kept clean, re-epithelialisation of the surface can occur relatively quickly with full restoration of the corneal surface within 7 days or so. However, if there is an infection on the surface of the eye there can be a potent inflammatory response that results in the rapid and disordered deposition of collagenous tissue across the ocular surface. patient can become blind. Recent work to create a therapeutic - agent to prevent ocular scarring has focused on the localised delivery of a TGF β 1 antagonist called decorin. Decorin is a proteoglycan with a high a ffi nity for collagen I, which it decorates the surface of in normal extracellular matrix. When free in solution, decorin also has an a ffi nity to seven di ff erent cytokine molecules, one of which is TGF β 1, and has been shown to modulate fibrosis. A decorin-containing eye drop is able to deliver a sustained dose of decorin to the surface of the cornea following damage and subsequent infection. The drop has been shown to be e ff ective in preclinical models of ocular fibrosis, facilitating the restoration of a transparent ocular surface with a significant reduction in markers that are usually indicative of scar formation ( Figure 4.10 ). Challenges to the delivery of molecules Despite the opportunities a ff orded by molecules in tissue regeneration, major challenges remain that relate to getting the therapeutic agent to the right part of the body at the right time. Small molecules tend to di ff use rapidly through excipient (delivery) materials and so are rapidly released into the tissue environment, meaning that a strategy for sustained delivery is a necessity if repeat administration of the drug molecule is to be avoided. A number of implantable materials exist that allow for the slow localised release of molecules at the desired site of application. The majority of these are dense, degrad - able polymers that can be implanted locally and allowed to degrade, thus enabling sustained release of the therapeutic agent. The issues are potentially even more significant for large biomolecules such as proteins, which tend to be v ery sensitive to local environmental changes, with associated reductions in bioactivity . They can also have extremely high activities at very low concentrations and can be extremely expensive. In addi - tion, excipients for these therapeutic products must be chosen very carefully so that potency is maintained and storage time maximised. Exemplars: molecules in action

Healing skin without scarring All tissues in the body , when damaged, are subject to a conserved process by which cells are recruited to the wound to remove damaged tissue fragments and then deposit and subsequently remodel the tissue (see Chapter 3 ). In the case of the skin, the initial damage results in bleeding into the wound followed by haemostasis and, when the platelets within the clot degranulate, the secretion of proinflammatory factors. The tumour necrosis factor alpha (TNF α ), interleukin (IL) 1 and IL-6, platelet- derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) recruit monocytes and endothelial cells into the wound bed to begin the wound-healing process. These cells release further cytokines, such as transforming growth factor beta 1 (TGF β 1), that mediate the formation of new extracellular matrix (normally initially collagen III in skin). Over time, the collagen III is remodelled and replaced with collagen I, which is normally deposited in a basket weave pattern. This process very e ffi ciently closes wounds and, when not too severe, healing can be with minimal scar formation. In the case of severe damage or infection, the inflammatory response can ‘overshoot’, resulting in the overproduction of cytokines such as TGF β 1, which drive the recruitment of excess myofibroblasts to the wound site. This leads to the deposition and subsequent overcontraction of collagen matrix, which can result in the classic appearance of a scar. A number of interventions have targeted this process with the aim of preventing the formation of a scar on the skin. Of note was the identification and isolation of TGF β 3, which plays a role in regulating extracellular matrix formation. This molecule was shown to regulate wound healing by blocking the TGF β 1 and -2 receptors on the cell surface and by modulating the penetration of cells in a newly forming tissue. TGF subsequently developed as a therapeutic agent for use within the skin, with the aim of preventing scar formation. As TGF is a large, protein-based drug it was challenging to manufacture and purify and so was expensive in comparison with small- molecule drugs. Although this molecule had significant poten tial as an antiscarring agent in phase I and II trials, ultimately it was not adopted. This is an exemplar of a translational approach, working from a proposed mechanism through to stepwise clinical trials to test e ff ectiveness. Molecular delivery to prevent ocular fibrosis Another example of the function of a tissue being significantly impaired by fibrosis is the eye. When the cornea is damaged, as long as the wound is kept clean, re-epithelialisation of the surface can occur relatively quickly with full restoration of the corneal surface within 7 days or so. However, if there is an infection on the surface of the eye there can be a potent inflammatory response that results in the rapid and disordered deposition of collagenous tissue across the ocular surface. patient can become blind. Recent work to create a therapeutic - agent to prevent ocular scarring has focused on the localised delivery of a TGF β 1 antagonist called decorin. Decorin is a proteoglycan with a high a ffi nity for collagen I, which it decorates the surface of in normal extracellular matrix. When free in solution, decorin also has an a ffi nity to seven di ff erent cytokine molecules, one of which is TGF β 1, and has been shown to modulate fibrosis. A decorin-containing eye drop is able to deliver a sustained dose of decorin to the surface of the cornea following damage and subsequent infection. The drop has been shown to be e ff ective in preclinical models of ocular fibrosis, facilitating the restoration of a transparent ocular surface with a significant reduction in markers that are usually indicative of scar formation ( Figure 4.10 ). Challenges to the delivery of molecules Despite the opportunities a ff orded by molecules in tissue regeneration, major challenges remain that relate to getting the therapeutic agent to the right part of the body at the right time. Small molecules tend to di ff use rapidly through excipient (delivery) materials and so are rapidly released into the tissue environment, meaning that a strategy for sustained delivery is a necessity if repeat administration of the drug molecule is to be avoided. A number of implantable materials exist that allow for the slow localised release of molecules at the desired site of application. The majority of these are dense, degrad - able polymers that can be implanted locally and allowed to degrade, thus enabling sustained release of the therapeutic agent. The issues are potentially even more significant for large biomolecules such as proteins, which tend to be v ery sensitive to local environmental changes, with associated reductions in bioactivity . They can also have extremely high activities at very low concentrations and can be extremely expensive. In addi - tion, excipients for these therapeutic products must be chosen very carefully so that potency is maintained and storage time maximised. Exemplars: molecules in action

Healing skin without scarring All tissues in the body , when damaged, are subject to a conserved process by which cells are recruited to the wound to remove damaged tissue fragments and then deposit and subsequently remodel the tissue (see Chapter 3 ). In the case of the skin, the initial damage results in bleeding into the wound followed by haemostasis and, when the platelets within the clot degranulate, the secretion of proinflammatory factors. The tumour necrosis factor alpha (TNF α ), interleukin (IL) 1 and IL-6, platelet- derived growth factor (PDGF), fibroblast growth factor (FGF), insulin-like growth factor 1 (IGF-1) and vascular endothelial growth factor (VEGF) recruit monocytes and endothelial cells into the wound bed to begin the wound-healing process. These cells release further cytokines, such as transforming growth factor beta 1 (TGF β 1), that mediate the formation of new extracellular matrix (normally initially collagen III in skin). Over time, the collagen III is remodelled and replaced with collagen I, which is normally deposited in a basket weave pattern. This process very e ffi ciently closes wounds and, when not too severe, healing can be with minimal scar formation. In the case of severe damage or infection, the inflammatory response can ‘overshoot’, resulting in the overproduction of cytokines such as TGF β 1, which drive the recruitment of excess myofibroblasts to the wound site. This leads to the deposition and subsequent overcontraction of collagen matrix, which can result in the classic appearance of a scar. A number of interventions have targeted this process with the aim of preventing the formation of a scar on the skin. Of note was the identification and isolation of TGF β 3, which plays a role in regulating extracellular matrix formation. This molecule was shown to regulate wound healing by blocking the TGF β 1 and -2 receptors on the cell surface and by modulating the penetration of cells in a newly forming tissue. TGF subsequently developed as a therapeutic agent for use within the skin, with the aim of preventing scar formation. As TGF is a large, protein-based drug it was challenging to manufacture and purify and so was expensive in comparison with small- molecule drugs. Although this molecule had significant poten tial as an antiscarring agent in phase I and II trials, ultimately it was not adopted. This is an exemplar of a translational approach, working from a proposed mechanism through to stepwise clinical trials to test e ff ectiveness. Molecular delivery to prevent ocular fibrosis Another example of the function of a tissue being significantly impaired by fibrosis is the eye. When the cornea is damaged, as long as the wound is kept clean, re-epithelialisation of the surface can occur relatively quickly with full restoration of the corneal surface within 7 days or so. However, if there is an infection on the surface of the eye there can be a potent inflammatory response that results in the rapid and disordered deposition of collagenous tissue across the ocular surface. patient can become blind. Recent work to create a therapeutic - agent to prevent ocular scarring has focused on the localised delivery of a TGF β 1 antagonist called decorin. Decorin is a proteoglycan with a high a ffi nity for collagen I, which it decorates the surface of in normal extracellular matrix. When free in solution, decorin also has an a ffi nity to seven di ff erent cytokine molecules, one of which is TGF β 1, and has been shown to modulate fibrosis. A decorin-containing eye drop is able to deliver a sustained dose of decorin to the surface of the cornea following damage and subsequent infection. The drop has been shown to be e ff ective in preclinical models of ocular fibrosis, facilitating the restoration of a transparent ocular surface with a significant reduction in markers that are usually indicative of scar formation ( Figure 4.10 ). Challenges to the delivery of molecules Despite the opportunities a ff orded by molecules in tissue regeneration, major challenges remain that relate to getting the therapeutic agent to the right part of the body at the right time. Small molecules tend to di ff use rapidly through excipient (delivery) materials and so are rapidly released into the tissue environment, meaning that a strategy for sustained delivery is a necessity if repeat administration of the drug molecule is to be avoided. A number of implantable materials exist that allow for the slow localised release of molecules at the desired site of application. The majority of these are dense, degrad - able polymers that can be implanted locally and allowed to degrade, thus enabling sustained release of the therapeutic agent. The issues are potentially even more significant for large biomolecules such as proteins, which tend to be v ery sensitive to local environmental changes, with associated reductions in bioactivity . They can also have extremely high activities at very low concentrations and can be extremely expensive. In addi - tion, excipients for these therapeutic products must be chosen very carefully so that potency is maintained and storage time maximised.