CommentaryRecent clinical failures in Parkinson's disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases
Introduction
By the mid 20th century, the process of physiological cell death had been known for over a century, being an active research area for developmental biologists and histologists [1] but with a limited interest in cell death mechanisms from a therapeutic perspective. Studies of the breakdown of silkmoth abdomen intersegmental muscles that occurred at the end of metamorphosis however, triggered the concept of an active, regulated process termed ‘programmed cell death (PCD)’[2] that could be modulated by pharmaceutical agents [3].
In 1972, Kerr et al. [4] described a type of active cell death characterized by chromatin condensation, cell shrinking, membrane blebbing and, finally phagocytosis of the remaining cell by neighboring cells, and coined the term, ‘apoptosis’ that is now widely used as a synonym for PCD.
Until recently, cell death was generally considered to be either necrotic or apoptotic despite concerns that the process might not be so simple [5]. Cell death can be divided into several distinct phenotypes, from caspase- dependent or-independent apoptosis, to autophagy, to programmed and passive necrosis. Elements of the different types of active cell death can also coexist in the same dying cell, with pathways partially overlapping and with one form of cell death transitioning to another depending on as yet poorly understood factors [5], [6].
It was not until the early 1990s that the concept of a directed, well-regulated process of cell death was accepted. This was driven by discoveries that included: the identification of bcl2 as an anti-apoptotic gene; the pro-apoptotic functions of p53 and c-Myc; the death-mediating cellular receptor, Fas/Apo-1; the caspases [1] and the role of mitochondria in cell death [7]. It soon became apparent that apoptosis, in addition to being a programmed process for the controlled demise of single cells in response to developmental needs or cellular damage, could also represent a novel therapeutic target for a variety of human disease states. While the initial focus was on cancer, it was soon hypothesized that neurodegenerative processes could also be of interest [8], [9], [10], since these could result either from erroneously induced apoptosis (“death by mistake”), in response to serious tissue damage or as part of an over acceleration of the intrinsic aging process. In these latter instances, inhibition of apoptosis might allow the time for tissue self-repair thus providing an effective treatment for neurodegenerative diseases [11] including Alzheimer's disease (AD), Parkinson's Disease (PD) and amyotrophic lateral sclerosis (ALS) [12].
Section snippets
Anti-apoptotic drugs
By the mid-1990s, knowledge related to apoptotic mechanisms and signaling pathways had progressed to a level [9], [12], [13], [14], [15], [16], [17], [18], [19], [20] where strategic intervention points to interfere with apoptosis could be defined. NCEs directed against targets like the pro-apoptotic caspases [21], p53 [22] and the JNK pathway [23] were sought and their anti-neurodegenerative potential extensively evaluated in various cellular and animal models [11], [24]. Alternatively, e.g.,
Anti-apoptotic agents and Parkinson's disease
In the research landscape described above, CEP-1347 and TCH346 entered clinical trials for the treatment of PD as their primary indication. Although historical reasons influenced this choice in the case of TCH346 (the original concept was to develop an NCE that shared the neuron rescuing/anti-apoptotic properties of the novel MAO (monoamine oxidase)-B inhibitor, deprenyl, but did not inhibit MAO and was also not metabolized to amphetamine-like compounds [36]), the principal reason was the
Possible reasons for the lack of effect of CEP-1347 and TCH346 in PD
At the time that the decisions were made to develop CEP-1347 and TCH346, a number of issues were already recognized as possible hurdles to NCE advancement and these remained of concern during development. However, in the absence of reliable information to judge their importance, and the lack of an already established clinical path forward for disease modifying as opposed to palliative agents, an awareness that risk is inherent to advancing novel approaches in drug discovery and confidence in
Conclusions
The lack of clinical efficacy of two NCEs targeting different elements of the apoptotic pathway function that is thought to be involved in the death of DA neurons in PD, raises serious concerns as to the suitability of currently available models, e.g., the classical 6-OHDA and MPTP models of PD as a basis for the preclinical evaluation and prioritization of NCEs designed to slow or halt progression of PD based on novel cellular mechanisms and in vitro cellular activity. These concerns obviously
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