Stimulating bioelectronic medicine discovery for urological disorders
AJP - Renal Physiology
WILL THIS ERA of disruptive technologies bring new opportunities for treating urological and kidney-related disorders? This seems likely if recent major government and private investments in bioelectronic medicines are any indicator. Interest in bioelectronic medicine has grown rapidly following a series of public-private initiatives which signaled the intention of GlaxoSmithKline to develop "electroceuticals" that could transform the use of biological stimulation devices as therapeutics (2) .
... therapeutics (2) . Further significant investments in this emerging field were then made by US government agencies (13). One source has been the Defense Advanced Research Projects Agency (DARPA), but possibly more relevant to urological and kidney-related disorders is the National Institutes of Health (NIH) Common Fund program Stimulating Peripheral Activity to Relieve Conditions (SPARC), which is specifically targeting bioelectronic medicine research to organ dysfunction. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is one of four Institutes working in partnership with the NIH Office of the Director on this program (https://commonfund.nih.gov/sparc). Is bioelectronic medicine new technology, or old technology with a new name? Electrical stimulation of the nervous system had been used in urology since the 1970s (3), when pioneering work produced the first experimental "neuroprostheses" designed to recover voiding and storage function in patients with spinal cord injuries. Neuromodulation or neurostimulation techniques are now well established as an effective therapeutic technology for treating urological dysfunction, and devices approved by FDA are available (5). However, given the rapid evolution of consumer technologies and strategic positioning of technology companies to disrupt the health sector, it is easy to see how electrical stimulation therapeutics could also be rapidly transformed-for example, by introducing more selective modes of stimulation, miniaturization, closed-loop control, and more effective programming (5, 7). It is also expected that bioelectronic medicines will not be confined to electrical stimulation as technology will also advance magnetic, optical, and other modes of stimulation. For this reason, the therapeutic targets of bioelectronics medicines will be far more extensive and diverse than those previously targeted by electrical neurostimulation techniques (8). A major perceived benefit of bioelectronic medicine is the possibility of treating disorders where small-molecule drugs and economic model of pharmaceutical companies have provided few solutions. Detrusor underactivity (DU) and underactive bladder (UAB) are related urological disorders that are representative examples of clinical conditions of this type where effective pharmacotherapy is unavailable. A working definition of DU is provided by the International Continence Society (ICS) as "a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or failure to achieve complete bladder emptying within a normal time span," but it has limitations and a complex relationship with the broader symptom complex of UAB that have been repeatedly discussed and reviewed by experts in the literature (4). As is typical of many urological, kidney-related, and other organbased disorders, DUA and UAB have complex multimodel pathophysiology that is difficult to diagnose and mostly poorly understood, which also frequently involves direct or indirect contributions from other diverse disorders. This includes other urological disorders such as bladder outflow obstruction (BOO) as well as neurogenic disorders, diabetes, and other metabolic conditions and aging (1). A challenge to the development of bioelectronics medicines will be the availability of clinically relevant animal models that predict efficacy in humans. Animal models have traditionally been a foundation but also a limitation for drug discovery, and it is possible that this will also be true for electroceuticals as well. In this context, it is significant that Gonzalez and Grill in their article of the American Journal of Physiology-Renal Physiology (11) have added a new model based on obese-prone rats to the pool of animal models of DU/OAB available for research on electrostimulation techniques (3). Obese-prone/ obese-resistant rats have been used extensively to study dietinduced obesity (10) but not urological disorders. In this new study, obese-prone rats developed urinary retention and impaired detrusor contractility as shown by urodynamic evidence of increased volume threshold, decreased peak micturition pressure, and decreased voiding. The urological parameters affected in different animal models of obesity and type 1 and 2 diabetes has been recently reviewed (6). The urological dysfunction in obese-prones was similar to detrusor underactivity-like symptoms reported in Zucker diabetic fatty rats (a type 2 diabetes model). In GK rats (a type 2 diabetes model in nonobese rats), however, there are conflicting reports of both bladder overactivity and underactivity that could be explained by an underlying relationship with age and duration of the chronic condition (6). This complexity of urological outcomes extends to other animal models of obesity and type 1 and 2 diabetes, and is consistent with DU/OAB comprising only a fraction of the urological complications of obesity and diabetes (UCOD) that have been identified in humans (6). The obeseprone rat model requires more extensive characterization to determine if the underlying pathophysiology contributing to symptoms of DUA are in any way homologous to human DU/OAB, but in the meantime, this first report demonstrates