Author: Robyn Bell, Imperial College London, 19 May 2021
Chronic pain has a high prevalence globally, with estimates of 20-30% of the population in Europe and the United States suffering from recurrent or persistent pain¹ ². Yet treatment options for chronic pain are limited with opioids prescribed widely despite their unfavourable and often severe side-effects. Most notably is the highly addictive nature of opioids and their common misuse which has become a major crisis particularly in the United States³. Treatment of chronic pain in an effective yet safe manner thus represents an unmet clinical need that requires urgent novel strategies. One such approach investigated by Ana Moreno and colleagues from the University of California, San Diego involves the use of gene therapy to dampen a specific component of the pain signalling pathway. Although the target of the therapy itself is not new, the strategy employed by Moreno and colleagues may be an innovative strategy for chronic pain treatment moving forward.
Historically there have been many attempts to target various components of the pain signalling pathway. The identification of mutations within the NaV1.7 (voltage-gated sodium channel isotype 1.7) gene of individuals who suffer from extreme pain and those with congenital insensitivity to pain incited the investigation of this channel as a therapeutic target⁴. NaV1.7 channels are involved in the transmission of signal following a pain inducing stimuli, thus small-molecule drugs and antibodies inhibiting their action, in theory, should alleviate pain⁵. However cross-reactivity with other sodium channels and poor bioavailability hindered the success of these strategies. Published recently in Science Translational Medicine, Moreno et al. instead focused on regulating the NaV1.7 gene (SCN9A) using tools widely available in the gene and cell therapy field. Their aim was to deliver a repressor specifically targeted to the SCN9A gene and to measure the efficacy and duration of these therapies in various rodent models of pain⁶.
Adapted from Moreno et al.⁶
Two methods were investigated, each consisting of a DNA targeting component fused to a commonly used transcriptional repressor, Krupel-associated box (KRAB). One method utilised zinc-finger proteins (ZFP-KRAB) to selectively target SCN9A. The other approach tested in parallel was a modified or ‘dead’ Cas9 (dCas9-KRAB) lacking the ability to cleave and thus ‘knock-out’ the gene yet retaining selective DNA targeting via guide RNA. The system was coined ‘long-lasting analgesia via targeted in vivo epigenetic repression of NaV1.7’ or LATER for short. To target the desired neuronal cells harbouring NaV1.7 channels in mice, Moreno et al. directly injected adeno-associated virus 9 (AAV9) encoding the dCas9-KRAB or ZFP-KRAB systems into the spine. Intrathecal delivery of AAV9-repressor systems significantly reduced hypersensitivity in three pain models: inflammatory pain, chemotherapy-induced neuropathic pain and ATP analog (BzATP) tactile pain. Repression of NaV1.7 expression in vivo showed evidence of long-term duration (44-week efficacy in the inflammatory model) without evidence of negative side-effects and off-target repression of other sodium channels.
Here, Moreno and colleagues have demonstrated proof-of-concept that dCas9 and ZFP-repression of NaV1.7 can ameliorate hypersensitivity in murine models of pain. In these early experiments, LATER is efficacious with evidence of long-term duration without off-target effects. However it is important to consider how these experimental therapies can translate into the clinic. Can AAV9 vectors be repeat administered when the repression wears off or will it be a one-off treatment? How will the extremely high cost of gene therapy compare against the socioeconomic cost of opioid misuse? Other groups targeting NaV1.7 by utilising antisense oligonucleotides, short-hairpin RNA and microRNAs have also demonstrated success in multiple rodent models of pain⁷ ⁸. Moreno is now chief executive of spin-out company, Navega Therapeutics, in which they aim to develop LATER further towards human trials. Overall, reducing the transmission of pain signalling through targeted gene regulation may hold great promise for the future, especially with current treatments unsuccessfully managing the global health issue of chronic pain.
Breivik, H., Collett, B., Ventafridda, V., Cohen, R. & Gallacher, D. Survey of chronic pain in Europe: Prevalence, impact on daily life, and treatment. Eur. J. Pain 10, 287–333 (2006).
Nahin, R. L. Estimates of pain prevalence and severity in adults: United States, 2012. J. Pain 16, 769–780 (2015).
Vowles, K. E. et al. Rates of opioid misuse, abuse, and addiction in chronic pain: a systematic review and data synthesis. Pain 156, (2015).
Drenth, J. P. H. & Waxman, S. G. Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders. J. Clin. Invest.117, 3603–3609 (2007).
Mulcahy, J. V et al. Challenges and Opportunities for Therapeutics Targeting the Voltage-Gated Sodium Channel Isoform NaV1.7. J. Med. Chem.62, 8695–8710 (2019).
Moreno, A. M. et al. Long-lasting analgesia via targeted in situ repression of Na V 1.7 in mice. Sci. Transl. Med. 13, eaay9056 (2021).
Mohan, A. et al. Antisense oligonucleotides selectively suppress target RNA in nociceptive neurons of the pain system and can ameliorate mechanical pain. Pain 159, (2018).
Cai, W. et al. shRNA mediated knockdown of Nav1.7 in rat dorsal root ganglion attenuates pain following burn injury. BMC Anesthesiol. 16, 59 (2016).