Apoptosis inhibitors for treating neurodegenerative diseases

Details Apoptosis inhibitors for treating neurodegenerative diseases Apoptosis inhibitors for treating neurodegenerative diseases

1998-08-14

2001-01-09

Jordan, Kimberly (Department: 1617)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

C514S181000, C514S258100, C514S261100, C514S263370, C514S275000, C514S309000, C514S334000, C514S415000, C514S474000, C514S646000

Reexamination Certificate

active

06172055

ABSTRACT:

This invention relates to the prevention or at least delay of death of cells, particularly non-dividing cells.
Controlling cell death is useful in the treatment of neurodegenerative diseases in general, including stroke, Alzheimer's disease, Parkinson's disease and motor-neuron disease in particular.
Neurons are examples of cells which have terminally differentiated and therefore are non-dividing. There are two general types of neuronal cell death: necrotic and apoptotic. The two differ in terms of initiating factors, morphological changes, time course and mechanism. Necrotic cell death is often seen in situations in which there is excess calcium ion influx caused, for example, by application of the excitatory neurotransmitter glutamate. Apoptotic cell death is sometimes referred to as programmed cell death and is seen as a normal developmental event in the nervous system and in other tissues. Fully differentiated neurons are normally dependent on a trophic factor for their survival and apoptotic death can be triggered by trophic factor withdrawal.
The role of apoptotic death in neurodegenerative disease has not been fully established. However, there are a variety of diseases of the nervous system in which neurons destined to die can be rescued by application of appropriate growth factors. While the cause of a cell's fate may vary from disease to disease, it seems likely that the final death pathway is apoptosis in each case.
The observation that the application of appropriate growth factors can rescue neurons destined to die has given rise to proposals for treatment for certain neurodegenerative diseases in the past. However, because the treatment is based on the use of peptide growth factors, which are unable to cross the blood-brain barrier, most current clinical trials for neurodegenerative disease are for diseases of the peripheral, rather than central, nervous system. Furthermore, such individual treatments as have been proposed are rather disease-specific; there has not hitherto existed the basis for developing a more generally applicable therapeutic or prophylactic regime for the management of neurodegenerative disease and other diseases involving the cell death of non-dividing cells.
It has now been discovered that cell death in a fully differentiated, non-dividing cell such as a neuron appears to be the result of an abortive attempt of the cell to re-enter or pass through the mitotic cycle. Therefore, agents which prevent entry into or passage through the mitotic cycle should be effective in preventing, or at least delaying, apoptotic cell death.
According to a first aspect of the present invention, there is provided a method of treating or preventing a disease involving apoptotic cell death, the method comprising administering to a subject, or to cells of a subject, an effective amount of an agent which prevents cell entry into or passage through the mitotic cycle; provided that the agent is not bFGF, IGF-I, IGF-II, potassium ions or a cAMP-elevating agent.
The mitotic cell cycle has four distinct phases, G
1
, S, G
2
and M. The beginning event in the cell cycle, called start, takes place in the G
1
phase and has a unique function. The decision or commitment to undergo another cell cycle is made at start. Once a cell has passed through start, it passes through the remainder of the G
1
phase, which is the pre-DNA synthesis phase. The second stage, the S phase, is when DNA synthesis takes place. This is followed by the G
2
phase, which is the period between DNA synthesis and mitosis. Mitosis itself occurs at the M phase. Fully differentiated cells such as neurons are generally regarded as not being in any of these four phases of the cycle; they are usually described as being in a G
0
state, so as to indicate that they would not normally progress through the cycle.
Preferred agents useful in the invention may totally prevent entry into the cycle. Other agents may allow passage through the cycle to a certain extend but not completely. In some cases it well be preferred to block passage through the cycle relatively early on; in other cases, blocking later may be more appropriate. Generally, agents may block the cycle at G
1
, G
1
/S, S or S/G
2
.
Agents which may totally prevent entry into the cycle may include FK-506.
Agents which block the cell cycle at the G
1
phase include agents which interfere with early gene expression or which interfere with the proper functioning of the products of early expressed genes. Examples of early expressed genes include c-fos, c-jun and c-myc. Agents which prevent the phosphorylation state of the retinoblastoma (Rb) protein may also block the cycle at this early stage.
The cell cycle may be stopped at the late G
1
stage by agents which interfere with the expression or proper functioning of cyclin D or E. (Interference, in this and other cases, may be direct or indirect). Correspondingly, the cell cycle may be stopped at the G
1
/S stage by agents which interfere with the expression or proper functioning of cyclin A and/or D. Other agents which block the cell cycle at G
1
/S include those which interfere (directly or indirectly) with the activation of the enzymes cdc2, cdk2 and/or cdk4; the activated form of cdk2 has been shown to be necessary for normal passage through the S phase.
The principal way of preventing passage through the S phase is of course to block DNA synthesis. Many agents useful for this purpose, including the use of nucleotide analogues such as dideoxynucleotides and the use of inhibitors of DNA polymerase, are known in the art.
Among agents useful in blocking the cell cycle at the G
2
phase are those which inhibit, directly or indirectly, inactivation of the enzymes cdc2 and cdk2.
The cell cycle may be stopped at G
2
/M stage by agents which interfere with the expression or proper functioning of cyclin G and/or those which inhibit the reactivation of the enzyme cdc2.
Finally, the cycle may be stopped at the M phase by interfering with the proper processing and organisation of tubulin.
Generally speaking, it is possible to monitor the stage in the mitotic cycle at which the passage of cells have been stopped by looking for the expression, proper functioning, activation or inhibition, as the case may be, of the various genes and enzymes discussed above. In addition, in the S phase, the extent of DNA synthesis taking place can be assessed by any suitable method such as might be used for assessing DNA synthesis in other situations. Examples include measuring the incorporation of a detectable nucleotide, such as bromodeoxyuridine (BrdU), and fluorescence-activated cell sorting (FACS) analysis based on the intercalation of a suitable fluorescent dye, such as propidium iodide. In fact, not only does the extent of DNA synthesis serve as a marker of whether cells are in the S or subsequent phases of the mitotic cell cycle (in which case the cells have a double DNA complement), it also serves as a marker of whether cells are undergoing cell death (in which case the DNA complement of the cells is less than the normal, single level). An additional marker of cells being in the M phase is provided by the gross morphological changes (including chromosome condensation and nuclear envelope breakdown) which are taking place then.
To summarise, there are a number of different ways in which agents useful in the invention may prevent entry into the mitotic cell cycle. First, DNA synthesis could be inhibited. Secondly, cell division cycle-associated enzymes could be inhibited. Many of these enzymes are encoded by the cdc series of genes; additionally, many of the enzymes involved are kinases or phosphatases. Either the enzyme itself may be inhibited, or its activation, from a precursor, could be inhibited. Equally, entry into the mitotic cycle can be measured in a number of different ways. Markers of DNA synthesis can be used; or other cell cycle markers can be examined. Such cell cycle markers include cyclin synthesis, cdc2 or cdk2 activation, early gene expression and redistribution or modification of certain tran

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