Comparative Technology Evaluation
RNAi is proving itself a logical progression, or replacement, of antisense and ribozyme mechanisms
The timely discovery of siRNA to address target validation issues in 2001 coincided with the stagnation of antisense and ribozyme technologies, as the latter two processes were enveloped in a pattern of delivering disappointing results that cast doubt on the effectiveness of the technologies as valid drug discovery mechanisms.
RNAi, antisense and ribozymes are similarly oligonucleotides that identify target mRNAs and disturb the function of proteins, but their similitude starts to differentiate after that.
RNAi entered the market's consciousness with an agenda that either conquered or presented a compelling premise for many of the problematic issues associated with antisense and ribozyme platforms for years, including stability, specificity, toxicity and design.
After more than 25 years of research, it is estimated that only approximately 10 percent of identified antisense oligonucleotides (ODNs) are effectively functional, while RNAi, in fewer than five years, has produced operative libraries that encompass entire genomes of mammalian and plant cell lines.
RNAi already exceeds the stability of its two would-be gene silencing predecessors, enduring for as much as six generations in applicable cell lines and affording researchers the opportunity for phenotypic observation in a sustained environment.
What success antisense has achieved has been tempered with unacceptable risk, given that its efficacy depends on extremely high dosages, and such high toxicity attributed to ODNs has been a challenge that has persevered throughout its research cycle; however, RNAi has summarily eradicated that concern even before the technology enters the clinic, inasmuch as it is triggered at very doses that minimize opportunity for side effects.
Ribozymes are afflicted with issues of low potency, high dosage and brief in vivo duration, and have yet to overcome those obstacles. There are no ribozyme products that have been approved by the United States Food and Drug Administration.
ODNs, ribozymes and RNAi often use liposomes and polymers for delivery, but RNAi provides a faster and more effective way to turn off genes because it relies on a natural cellular procedure.
RNAi is discernible from antisense and ribozymes through its attribute to operate by way of a natural cellular mechanism to manage protein production, thus making it more potent than comparative ribozyme and antisense mechanisms combined.
The RNAi process relies on a double-stranded RNA, which gives it improved stability over the single-stranded antisense and ribozyme approaches. Upon delivery to its target, RNAi stabilizes even further when forming a natural amalgamation with numerous defensive proteins, rendering an RNA Induced Silencing Complex (RISC).
That additional stability of RNAi precludes the need for the type of artificial chemical alterations which are an essential component in the stabilization of antisense and ribozyme drug candidates. These toxicity-inducing, efficacy-reducing stabilizing chemical modifications contribute immensely to the fallibility of the two tottering strategies.
A principal dilemma correlated to ribozyme research is the issue of specificity, given that cells construct a large number of RNAs from an even larger number of genes; as a result, ribozymes are inherently undisciplined enough to run amok, cutting all RNA messengers with which they have contact, resulting in unreliable evaluations, since an excessive number of non-disease-specific genes will be indiscriminately turned off.
RNAi has shown success with specificity in almost all of its laboratory applications, particu- larly with Caenorhabditis elegans (C.elegans), and indications that RNAi will be able to degrade only disease-specific genes in clinical trials without affecting the function of untargeted ones is promising, offering another advantage over the random, or uncontrol- lable, dispatch of antisense ODNs and ribozymes.
While antisense and ribozyme mechanisms have shown an ability to temporarily, or inter- mittently, prevent targeted gene function, RNAi-based drugs may be able to degrade the target RNA and indefinitely stop the related undesirable protein production required for dis- ease proliferation.
After decades pursuing antisense and ribozyme without big results, companies face serious decisions.
A quarter-century quest to develop drugs has resulted in the approval of one antisense product (Isis Pharmaceuticals Inc.'s Vitravene for cytomegalovirus (CMV)-induced retinitis in 1998); consequently, the antisense market is regarded as disappointing, given that it has not delivered on its potential and is in danger of being displaced by a newer, stronger technology.
Such dour acknowledgement is attributable to the fact that the sector's lone success has relatively few applications, rendering it a niche drug that cannot support an entire market that is in need of a blockbuster therapeutic for validation and investor/partner recognition.
Many antisense and ribozyme therapeutics companies are contemplating, or implementing, incorporation of RNAi into struggling R&D programs, while at least one of the major players in the RNAi market, Sirna Therapeutics Inc., restructured its entire strategy in abandoning ribozyme drug development to concentrate on RNAi therapeutics.
Sirna Therapeutics Inc. COO and Sr. VP. Nassim Usman, Ph.D., when asked for his thoughts on the future of ribozyme product development, said, "We pursued this technology with dedication and determination for almost a decade, and if there were something to get out of it, I have to think we would have found it, because we really wanted it to succeed."
"I believe we got all we could out of it, and it's likely that the market for ribozyme drugs will be replaced by RNAi drug discovery and is all but over," Usman added.
It would seem that movement has begun in the shift from antisense and ribozyme agendas to RNAi, as evidenced by recent developments such as Isis Pharmaceuticals Inc.'s decision to open a branch in Singapore that will conduct mRNA research that includes RNAi as a trigger mechanism.
Isis also announced in October 2004 that it had entered into a significant license and research and development agreement with RNAi players Max Planck Society, Garching Innovation GmbH, of Munich, Germany and Alnylam Pharmaceuticals Inc. of Cambridge, MA to develop relative therapeutics and to exploit the pioneering work of Thomas Tuschl, Ph.D., who is credited with discovering the structure of mammalian RNAi and is a co-founder of Alnylam.
In a released statement that sounded like verification of intentions to integrate RNAi into its agenda, Isis' Executive Vice President and Chief Financial Officer B. Lynne Parshall said, "Our business strategy has been to participate in all areas of RNA-based drug discovery directly and through collaborations with outstanding companies like Alnylam. Through this alliance, we benefit from Alnylam's high-quality focused research efforts on the RNAi mechanism and participate fully in the potential upside of this particular RNA-based mechanism."
Isis had the resources to attract industry stalwarts Amgen Inc, Novartis and Merck & Co. in the past for deals, so forging alliances based on a more promising, and advanced, technology could be just as likely and would be an incentive to entice other antisense and ribozyme companies to expand R&D programs with RNAi.
The eruption of RNAi over the past few years has significantly hastened research in many disciplines and allowed it to outpace its counterpart platforms in applications ranging from basic gene function recognition to target validation
With research tools that address a broad range of target models and offer improved reliability, RNAi's ascending chart growth for reagents is intersecting in juxtaposition with the horizontal movement of the antisense and ribozyme sectors.
In the laboratory, RNAi has perceptibly become the method of choice for a wide range of biomedical applications and has emerged as the most effective and preferred new functional genomics screening tool for identification and validation of new therapeutic drug targets.
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