- Open Access
Loss-of-function genetic diseases and the concept of pharmaceutical targets
© Ségalat; licensee BioMed Central Ltd. 2007
- Received: 5 March 2007
- Accepted: 2 July 2007
- Published: 2 July 2007
The biomedical world relies heavily on the definition of pharmaceutical targets as anessential step in the drug design process. It is therefore tempting to apply thismodel to genetic diseases as well. However, whereas the model applies well togain-of-function genetic diseases, it is less suited to most loss-of-function geneticdiseases. Most common diseases, as well as gain-of-function genetic diseases, arecharacterized by the activation of specific pathways or the ectopic activity ofproteins, which make well identified targets. By contrast, loss-of-function geneticdiseases are caused by the impairment of one protein, with potentially distributedconsequences. For such diseases, the definition of a pharmaceutical target is lessprecise, and the identification of pharmaceutically-relevant targets may bedifficult. This critical but largely ignored aspect of loss-of-function geneticdiseases should be taken into consideration to avoid the commitment of resources toinappropriate strategies in the search for treatments.
- Genetic Disease
- Familial Mediterranean Fever
- Spinal Muscular Atrophy
This conception of the drug discovery process is commonly accepted beyond the industrialworld and is deeply rooted into the biomedical field, including academia. The sequencingof large genomes is often justified as a way to enlarge the repertoire of targets. The sequencing of the human genome,for instance, was sold as such to the decision-makers. The pharmaceutical industry'sappetite for targets is filled by academic laboratories and by spin-off companiesspecialized in the commercial identification of targets. Although the pharmaceuticalindustry has experienced a decline in bringing new drugs to the market in recent years,the target-based approach remains by far the dominating drug discovery paradigm[3, 4].
Since rare diseases were neglected for decades by both policy-makers and industry, drugdiscovery for rare diseases has a relatively short history, and remains a dwarf in termsof expenditure when compared to drug discovery for common diseases (cardiovasculardiseases, cancer, diabetes, Alzheimer's disease, etc.). It may, therefore,sound like a reasonable endeavor to apply to an emerging field a strategy that is thestandard in another not-so-distant field. For this reason, when it comes to geneticdiseases, a shared view exists within the scientific community that the target-baseddrug development concept should apply to genetic diseases as it does to non-heritablediseases. This one-size-fits-all strategy is conservative but, as we will see, may notbe the optimal strategy, since some genetic diseases are only poorly adapted to it.
Gain-of-function (gof) genetic diseases, as the term indicates, are caused by theectopic or increased activity of the mutated gene product. Proteins mutated in gofdiseases may or may not carry a dominant-negative effect. Ectopic or increasedprotein activity most often turns on cellular processes that normally do not occur ina healthy cell, thereby triggering a pathology. In this respect, gain-of-functiongenetic diseases are comparable to the common diseases that are in the focus of thepharmaceutical industry (cancer, stroke, infectious diseases, Alzheimer's disease)and that may also be defined, in first approximation, as an activation ofpathological cellular processes that do not occur in a healthy cell. Therefore, it isof no surprise that the concept of the target-based drug design applies well to thisclass of diseases. Who could claim to have a better approach against polyglutamineexpansion diseases, for instance, than neutralizing the faulty protein and blockingthe downstream chain of deleterious events?
Another example is provided by metabolic diseases. Metabolic diseases are aphysiologically-damaging alteration in the amount of a key cellular metabolite, andare often caused by loss-of-function mutations in enzyme-encoding genes. Whensupplementation treatments are not possible, metabolic diseases may be treated bypharmacological strategies aimed at restoring an appropriate level of the keymetabolite by playing with adjacent metabolic pathways (Figure 2B). Here again, the relatively simple physiopathology allows for an easyidentification of therapeutic targets.
Duchenne muscular dystrophy (DMD), one of the most studied genetic diseases, is due tothe impairment of dystrophin, a structural protein underlying the muscle membrane. After20 years of research on dystrophin, neither the role of dystrophin in a healthy musclenor the physiopathology of the disease are fully understood yet [6, 7]. It is established that the absence ofa functional dystrophin results in muscle fibre calcium overload, mislocalization ofsignaling proteins, and membrane fragility. Calcium overload may in turn translate intodozens of secondary effects, ranging from increased muscle excitability to impropercaspase activation. Mislocalization of signaling proteins and membrane fragility, thetwo other main traits of DMD, may also be subdivided into numerous items, some of thembeing deleterious and others not. What, then, causes the end-point phenotype ofprogressive muscle necrosis? Is it just one of the many secondary effectors or, morelikely, a combination of several of them? As in many other diseases affecting structuralproteins, the loss-of-function mutation has a pleiotropic effect, distributed amongstvarious cellular functions, pathways and compartments.
Pleiotropy is also a hallmark of diseases affecting genes involved in central cellularprocesses: DNA replication and maintenance, transcription and RNA processing, proteinmaturation, trafficking, etc. Spinal muscular atrophy type I (SMA 1), one ofthe most frequent genetic diseases, is caused by mutations in the SMN gene.Although the genetics of the SMN locus is complex, it can be considered as alof disease, since it results in a reduction of functional SMN protein. The SMN proteinplays a role in spliceosomal snRNP biogenesis, and SMN mutations seem to resultin a shortage of functional spliceosomes [8, 9], thereby globally perturbing mRNA processing. The number ofmisprocessed mRNA species is not yet fully established, but is probably very large. Howmany of them contribute to the progressive death of motorneurons? Probably more thanjust a few.
As with the mRNA processing genes, so too with the transcription factor genes. How manymisregulated genes are responsible for the numerous symptoms observed in Cleidocranialdysplasia (CCD) and Waardenburg syndrome, to mention only these two diseases among themany affecting transcription factors?
What are the pharmaceutical targets for Emery-Dreifuss dystrophy (mutation in a nuclearenvelope protein), for Schwartz-Jampel disease (mutation in the basement membraneprotein perlecan), for Centronuclear congenital myopathy (mutation in dynamin, atransport vesicle protein)?
These few examples demonstrate that the concept of a pharmaceutical target – abiochemical entity which can be levered by a drug – is unsuitable to manyloss-of-function genetic diseases.
Risks and difficulties of applying the «target-first» strategy tophysiologically complex genetic diseases
Twenty years ago, in the early days of human molecular genetics, the scientificcommunity propagated the erroneous idea that, once a disease gene was identified, thetreatment would be around the corner. The following years have been sobering anddisillusioning. We should be careful not to repeat that mistake by spreading anotheridea, which might be as over-optimistic as the previous one: that genetic diseases willbe modeled around «targets», and that targets will be the key to treatments.In this view, targets identified by biologists will be passed on to medicinal chemistswho will design target-based treatments. This scheme is in line with the contemporaryapproach of drug discovery. Unfortunately, when it comes to genetic diseases, twofactors greatly reduce the feasibility of this strategy: i) the definition ofpharmaceutical targets is, at best, vague, for the majority of lof genetic diseases; ii)to have some chance of success, a target-designed treatment against the above-mentioneddiseases should be directed against not one but several targets simultaneously –an almost impossible challenge.
There is another contextual element which is rarely mentionned, but which should also belooked at with open eyes. The contemporary drug discovery strategy has scored somespectacular successes on certain fronts. However, other less successful stories remindus that it is by no means a trivial matter to battle diseases, even when the targets areclearly identified and the picture looks simple. In the fight against infectiousdiseases, for instance, in which the pathological process starts by a sequential andalmost linear chain of well-characterized events, we are still a long way from totalvictory. The same is true for cancer. Some forms of cancer are far from contained,despite well-known targets and big spending. What then, are the chances of findingtreatments against genetic diseases on a large scale, by applying the same and, in thiscase, a less appropriate strategy with much less money?
1. Invest in the understanding of the physiopathology, but not for the reasonusually put forward
This dark picture does not mean that money invested in trying to dissect out themechanisms underlying physiologically complex lof genetic diseases is useless. It isimportant to carry on investing in the understanding of the physiopathology of thesediseases, but the main reason to do it might not be the one usually put forward(finding targets that pharmacologists and chemists will turn into treatments).Otherwise, the scientific community may once again promise more that it candeliver.
The first reason for investing in the understanding of genetic diseasephysiopathology is that even though the efficiency of the «target first»strategy as a global approach has been overestimated, its fallout on specificdiseases must not be neglected. There will be instances when findings involving thephysiopathology will shed light on mechanisms rapidly amenable to drug therapies,such as idebenone against Friedreich ataxia . However, such situations are rare and there is no reason tothink that their proportion will increase.
2. Consider alternative strategies
It is probably time to reevaluate the choice of the «target first» strategyas the main option in the search of pharmaceutical treatments against physiologicallycomplex lof genetic diseases. For these diseases, success may well come from a lessambitious but more pragmatic strategy: the «screen first, understand later»strategy. This alternative strategy, also referred to as physiology-based, is ofinterest in all indications where no obvious target is available . In the search for treatments against rarediseases, the bonanza of existing drugs has been surprisingly underexploited up tonow. Yet, anecdotal evidence demonstrates that old drugs can have an unpredictedbeneficial effect on some genetic diseases: colchicine was serendipitously found tocure Familial mediterranean fever (FMF), and acetazolamide is active against Episodicataxia despite any rationale underlyings. Since these discoveries are the result ofsheer luck (co-occurrence of diseases in one case and diagnostic error in the other),one can extrapolate that the pharmacopea contains many more unraveled gems.Furthermore, beyond approved drugs, chemical libraries constitute another vastreservoir of potentially useful molecules against genetic diseases. These chemicalresources should be taken advantage of more thoroughly. Currently, the limitingfactor for molecule identification is the shortage of high-throughput screening (HTS)systems. For most genetic diseases, in vitro models either do not exist orare not suitable for HTS screening. This bottleneck is less a technological one thanthe result of insufficient development. Committing financial resources to overcomethis limitation and running high-throughput molecule screens might at the end of theday be one of the most cost-efficient investments in rare disease research.
After being ignored by governments for decades, rare diseases are now a biomedicalresearch priority in most developed countries. However, the fundamental difference thatexists between loss-of-function genetic diseases (the most numerous ones) and most otherhuman disorders has been largely overlooked. As a consequence, confusion exists in thedefinition of what the optimal drug-discovery strategy against the majority ofloss-of-function diseases is. In-depth reflection is necessary to resolve this issue andto avoid the commitment of energy and money to inappropriate research strategies.
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