Business


Figure 3


‘Pseudo-N-of-1’ disease states: Diseases have historically been categorised, and thus


researched and treatments designed, along blunt clinical characteristics. Advances in our understanding of the genetic origins of disease and the slow but positive


progression of personalised medicine (pharmacogenetics) are helping redefine how diseases may be better approached. Unfortunately,


pure ‘n of 1’ research, defined as the deep analysis of a single individual and their disease, does not necessarily equate to an overall advancement in understanding diseases of populations more broadly. Protocols that link an individual and their disease with the myriad of other people and their own, but


slightly different, diseases (ie, ‘pseudo-N-of-1’) will help expand our understanding and power to treat all disease variants


CLINICALLY DEFINED Disease State


PSEUDO N OF 1 Disease State


● Protein kinase inhibition prevents the phospho- rylation of cognate targets which can lead to simple


changes in phosphoprotein levels, but alterations in phosphorylation/dephosphorylation levels induce massive changes in multicomponent complexes that ultimately underlie their efficacy; moreover, data in certain systems have shown phosphatases may con- trol rates and duration of signaling while signal amplifications are controlled primarily by kinases (thus, simple ‘on/off’ phosphoprotein switching does not normally happen)43.


● Ligands acting at GPCRs can activate their cognate G-proteins in a monomeric form, but they can also assemble into dimers or larger oligomers; moreover, ‘asymmetric’ organisation of some dimers may lead to activation of certain signalling cascades while ‘symmetric’ organisation may acti- vate other cascades44.


● ‘Conformational ensembles’ of GPCRs exist and various conformations in the ensemble can produce functional selectivity for signalling path- ways45.


● Genetic buffering (ie the activation or deactiva- tion of certain gene products following physiologi- cal stimuli) can mask phenotypic consequences, and at least three completely different relationships (mixed epistasis, complete redundancy and quanti- tative redundancy) underlie the functional overlap and regulatory links between signalling pathways46.


The pharmaceutical industry’s pursuit to find ‘magic bullet ligands’ – agonists or antagonists with ultra-selective qualities – has, by and large, failed. This is not to say that selective agents are not without merit in that they can produce much more limited changes in biological systems that can minimise secondary pharmacological actions and


14


produce unwanted side-effects. Multiple lines of evidence, however, suggest that single-point phar- macological agents either do not exist, or that there are very few biological targets that are involved in single and self-limiting processes within the human body. And even when there are genetic defects in single biological systems (eg -hexosaminidase in Sandhoff disease, -galactosidase A in Fabry’s dis- ease, glucocerebrosidase enzyme mutations in Gaucher’s disease), recombinant human enzyme replacement (rhEnzyme replacement) can offset many of the disease symptoms, but not all of them and not without, for example, enzyme production at ‘non-native’ sites and at levels beyond normal physiological levels47. Moreover, rhEnzyme replacement can result in non-native enzyme-pro- tein or enzyme-lipid complexes, as well as the dis- ruption of native enzyme complexes, and may well be subjected to pharmacogenetic differences in the target and signalling cascades similar to those of small molecule approaches48,49, all of which can produce unwanted effects. Finally, a recent review has shown that only 885 of the 1,204 approved non-biological drugs satisfy the widely adopted ‘rule-of-5’ drug-likeness criteria, with only 619 of the 885 being available in oral formulations36. It appears, then, that only half of the successful mar- keted products match the desired attributes that govern drug discovery and development para- digms, prompting some to propose novel para- digms in drug discovery5.


The degree which pharmacological agents mimic the actions of endogenous substances can also dramatically affect their overall actions in the body. For example, while not corroborated by decades-worth of clinical data, some have suggest- ed that compounds synthesised from endogenite


Drug Discovery World Winter 2011/12


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