Gene silence to set to quieten neuropathic pain - Novartis research expands the potential of siRNA

DailyUpdates 16th April: RNA interference is emerging as a major tool to help researchers identify new therapeutic targets.  Novartis researchers have recently used this technology to underline the role that the ligand activated cation-channel, P2X3 plays in neuropathic pain.  This study also demonstrates the therapeutic potential of P2X3 gene silencing in the treatment of this major unmet area of analgesia.

RNAi or gene silencing involves the use of double stranded RNA (dsRNA). Once inside the cell, dsRNA is processed into short 21-26 nucleotide RNAs termed siRNAs that are used in a sequence-specific manner to recognize and destroy complementary RNA. Already a major tool in the process of target selection, the ability to block intracellular proteins at will means that siRNAs has the potential to revolutionize the treatment of multiple diseases.

The market for RNAi reagents for use in research and drug development is already estimated to be $500-800 million and is set to increase to as much as $1.8 billion by 2010. Although the entry of RNAi-based drugs onto market is still some way off some analysts predict the value of such drugs will be as much as $3.5 billion by 2010 (for a full analysis of RNAi R&D click here). 

In their recent Nucleic Acids Research journal article Novartis researchers demonstrate the potential of harnessing siRNA technology to treat neuropathic pain.

Approximately 26 million patients worldwide (10 million in the US) suffer from some form of neuropathic pain, spending an estimated $2-3 billion annually on treatments. This condition is associated with a variety of etiologies including trauma, infection, diabetes, immune deficiencies, ischemic disorders, and toxic neuropathies and precipitates other serious pathologies such as depression. The lifestyle of patients can be severely impeded, a problem compounded by the lack of efficacy and frequent incidence of side effects associated with current treatment options (click here for an insight into neuropathic pain or here for a full analysis of the neuropathic pain market).

In their study Dorn et al focused their attentions on the role that the ligand activated cation-channel, P2X3 plays in neuropathic pain. 

ATP has long been known to induce pain in humans and animals. At first it was thought that ATP was most likely to play a role in acute pain, following its release from damaged or stressed cells and a wide variety of experimental techniques and approaches have been used to study this possibility. Whilst it is clear that exogenous and endogenous ATP can indeed acutely stimulate sensory neurones, more recent reports indicate that ATP is more likely to be involved in chronic pain conditions, particularly chronic inflammatory and neuropathic pain. 

The P2X3 receptor was identified in 1995 and was shown to be a hetero-oligomeric protein that functions as a membrane ion channel sensitive to extracellular ATP gating. This and the expression of the P2X3 channels on a subset of sensory neurons involved in pain signaling suggests that this protein may be a useful target for the development of pain therapeutics. This has been substantiated by the recent development by Abbott Laboratories of A-317491, a small molecule that selectively blocks P2X3 receptors, and which is effective in a range of animal models of neuropathic and chronic inflammatory pain.

Dorn et al now report that rats, intrathecally infused with a 21nt siRNA complementary to the pain-related cation-channel P2X3, showed diminished pain responses compared to missense siRNA-treated and untreated controls in models of both agonist-evoked pain and chronic neuropathic pain. This form of delivery caused no adverse effects in any of the animals studied. Molecular analysis of tissues revealed that P2X3 mRNA expressed in dorsal root ganglia, and P2X3 protein translocated into the dorsal horn of the spinal cord, were significantly diminished.

These important studies once again underline the value of siRNA technology as a tool for target evaluation in proof of concept studies and in particular demonstrate the role that P2X3 plays in pain mechanisms.  Furthermore, this study confirms that the silencing of P2X3 expression may offer a useful approach to the treatment of neuropathic pain.  The involvement of P2X3 receptors has also been demonstrated in the etiology of visceral pain (eg interstitial cystitis; IBS etc) and this may extend the potential of siRNA that silence P2X3 still further.

Source DailyUpdates 16th April; for a full abstract of the original papers see  Nucleic Acids Res. 2004 Mar 16;32(5):e49.

Recommended further reading:

• RNAi - technologies, markets and companies
• Neuropathic Pain - Comparative Overview of Treatment Preferences Across the Seven Major Markets
• Neuropathic Pain Insight - Life Beyond Gabapentin