What is Apoptosis?
Apoptosis is a natural, highly controlled process in the body changing the physiology of a cell resulting in its rapid death, followed by the inconspicuous removal of its corpse. The process has several functions in the body:- it occurs during embryonic development of organisms, e. g. to shape the extremities and to dispose of superfluous cells,
- it is initiated if a cell is damaged beyond repair by stress, radiation, chemical agents, or viruses, and
- it is part of the body’s regulatory processes that keep the number of cells relatively constant.
In human beings, several billion cells die apoptotically every day just to counter the cells newly arising from mitotic divisions.
Apoptosis also plays a central role in the pathogenesis of many human diseases. As an example, reduced sensitivity to apoptosis induction may cause uncontrolled cell proliferation and thus lead to malignant diseases like cancer, while excessive apoptosis may lead to cellular attrition observed in many degenerative conditions, e.g. spinal cord injuries.
Understanding and modulating apoptosis therefore has great potential for the treatment of human diseases: down-regulating apoptotic death may mitigate the severity of degenerative disorders or prevent cell death and subsequent neurological deficits after stroke and spinal cord injuries. However, targeted enhancement of apoptosis is regarded beneficial for the treatment of conditions, in which aberrant cellular proliferation is observed, such as cancer.
Approaches to modulate Apoptosis
Apoptosis is a carefully orchestrated process within the cell involving multiple proteins and various pathways. The process of programmed cell death can be stopped at several points by intracellular anti-apoptotic proteins.Apoptosis can be initiated by extrinsic as well as intrinsic pathways. The “extrinsic“ pathway is controlled by so-called death ligand systems like the CD95 system. CD95 (also known as Fas or Apo-1) is located on the cell surface and is activated through binding to its cognate ligand, CD95L (also known as FasL). Activation of death receptors very rapidly triggers the so-called caspase cascade, an intracellular cascade of cysteine proteases that ultimately results in shrinkage, fragmentation and death of the cell.
The “intrinsic” apoptosis pathway is induced by stress stimuli, which result in the perturbation of mitochondria influencing a complex system of proteins promoting and inhibiting the release of proteins into the cell. As a result, the mitochondria react to the stress by releasing, e. g. cytochrome C, into the cell. Once released, these proteins also trigger the caspase cascade, which eventually leads to cell death.
Apogenix reckons that preventing the initiation of the apoptotic process as early as possible, i.e. outside the cell, is more effective than interfering with it once it has started inside the cell. Therefore, Apogenix is pursuing different approaches all aimed at either apoptosis modulators or apoptosis receptor ligands to modulate apoptosis for therapeutic purposes:
- Blocking apoptosis by neutralizing apoptosis-inducing ligands, e.g. for the prevention of acute “Graft-versus-Host Disease”
- Re-establishing apoptosis by sensitizing cells to apoptotic signals, e. g. for the treatment of cancer, or
- Stimulating apoptosis by apoptosis receptor ligands that induce targeted cell death in specific cells, e. g. tumor cells.