Acid-sensing ion channels: identifying pain mechanisms leads to development of potential treatments

UCL research led by Professor John Wood has examined the importance of acid-sensing ion channels (ASICs) in pain regulation. ASIC-related therapies for a wide variety of conditions are now in clinical trials. UCL research has allowed new therapeutic applications to be conceived for already existing prescribed compounds, and for naturally occurring compounds, that act on ASICs.

Acid-sensing ion channels (ASICs) have a number of functions and are primary sensors in the human body that generate pain. Unrelieved pain associated with ischaemia, arthritis, gastroesophageal reflux, tissue inflammation and injury is a major medical issue. In these conditions and many others, the associated pain often results from tissue acidosis (an increase in tissue acidity), which activates ion channels such as ASICs.

There has been a lack of clinical breakthroughs in recent years, and current therapies are often inadequate, have side effects, or are under-prescribed due to the dangers of addiction. Theralpha aims to develop its pipeline to address unmet medical need in pain, a significant economic burden where more than 300 million people worldwide suffer. - Theralpha

Research in the Wood lab identified and delineated the involvement of two new ASIC isoforms - ASIC1b and ASIC4 - that may play a role in the pain resulting from tissue acidosis. These findings funded by the Medical Research Council, The Wellcome Trust and the BBSRC have increased the potential targets for research in patient populations across a range of conditions, and this is reflected by the recent increase in clinical studies focused on these channels. In the last three years, six clinical studies have been initiated to look at the involvement of ASICs in - and the effects of ASIC-targeted drugs on - conditions such as inflammatory pain, optic neuritis and gastroesophageal reflux. These studies involve over 400 participants, including patients and healthy volunteers. A major challenge in the pain drug market is to reduce the side-effects associated with treatment. UCL's discovery of the roles of ASIC1b and ASIC4 in the pain caused by tissue acidosis - which accompanies a variety of conditions - has provided the pharmaceutical industry with potential targets for the development of more specific painkillers which may have widespread applications.

The discovery that ASIC1b is only expressed in the peripheral nervous system, and has a sensory neuron-specific distribution and more selective ion permeability than other members of the ASIC family, makes it arguably the most promising of the ASIC targets for drug development. Indeed, more than 40 patents on treatments and compounds targeting ASIC1b are now held worldwide. These patents cover painkillers as well as ASIC-focused treatments of conditions such as ischaemic brain injury, epilepsy, and demyelinating diseases such as multiple sclerosis.

Theralpha, an ASIC-focused pharmaceutical company, was established in 2008. Theralpha's work is based on the pioneering studies of Michel Lazdunski in France and of Professor John Wood (UCL Wolfson Institute for Biomedical Research). The company focuses on the development and commercialisation of innovative therapies for the treatment of pain.

Theralpha are "advancing next generation pain drugs based on scientifically validated Acid Sensing Ion Channel (ASIC) pathways", and so far have developed compounds targeting ASIC1a, ASIC3 and ASIC1b. Theralpha's lead products act on the ASIC1b-containing channels that the Wood Group discovered. They describe their programme as follows:

The Wood lab's identification of a new member of the ASIC family has also allowed the mechanisms of existing compounds to be explored . This has increased the clinical understanding and potential therapeutic application of commonly prescribed medication (such as amiloride), and highlighted a therapeutic role for naturally occurring painkillers (such as peptides in black mamba venom).

In one example, a new class of three-finger peptides from black mamba venom has been shown to abolish pain through inhibition of ASICs. These peptides, termed mambalgins, are not toxic in mice but show a potent effect upon central and peripheral injection that can be as strong as morphine. Inhibition of ASIC1a and ASIC2a sub-units in central neurons and of ASIC1b-containing channels in nociceptors is thought to be involved in the pain relieving effect of mambalgins. Thus the Wood lab's cloning of ASIC1b has led to the identification of a mechanism (a key step for regulatory approval) by which natural peptides that block this target can produce a potent painkiller.