Immunophilins: A Promising Treatment for ED after Radical Prostatectomy
Erectile dysfunction is a common complication of radical prostatectomy and other types of pelvic surgery. A study by JD Campbell and AL Burnett shows that cavernous nerve injury (CNI) during surgery leads to ED in more than 50% of the patients. New nerve-sparing surgery techniques have reduced the incidence of ED in men after radical prostatectomy to around 25% but the risks still remain high. Even if the cavernous nerve is not damaged directly during surgery, indirect ischemic, thermal or another form of injury is possible, which also leads to ED.
What makes the treatment of CNI-induced erectile dysfunction especially challenging is the fact that the patients suffering from it show very poor response to first- and second-line therapies. It takes post-prostatectomy patients 3-23 months to restore erectile function using PDE5 inhibitors and vacuum erection devices and even longer with other rehabilitation strategies. Therefore, alternative treatments are in high demand. One of the most promising treatments being researched currently is therapy with immunophilins.
Immunophilins are naturally occurring proteins that were initially researched due to their binding abilities to immunosuppressive drugs. A 2001 study by Sezen et al looked at the neuroprotective function of immunophilin ligands in penile innervation. Immunophilins not only protect neurons but also help grow new ones, which explains their potential therapeutic effect in different kinds of nerve injury.
Sezen et al studied the outcomes of cavernous nerve injury in rats. When treated with immunosuppressant FK506, also known as fujimycin or tacrolimus, subcutaneously, rats’ erectile response returned to 90% of the original pre-injury values. In control group, the erectile response did not exceed 50%.
Treatment of CNI-induced erectile dysfunction with FK506 has its disadvantages too. It causes serious adverse reactions including immunosuppression and nephrotoxicity. To avoid this, new immunophilin ligands that do not affect the immune system in a negative way were developed. Examples of these include products like GPI-1046, FK1706 and GPI-1485. The neuroprotective effect of the former two has been proven in a more recent 2009 animal model study by Sezen et al. GPI-1485 is the only non-immunosuppressive immunophilin ligand that has been tested in humans so far but the clinical trials have failed to prove its effectiveness in restoring erectile function. YB Kandemir and L Sarikcioglu suppose it is due to the varying therapeutic time window in clinical trials and animal model studies. Lab animals are treated with immunophilins immediately after nerve injury while in most human patients the injury and attempted nerve reconstruction are at least several days apart.
Current studies by scientists like K Ghatak, for example, focus on developing combination therapies including the use of immunophilins together with medications for angiogenesis. This approach is more likely to work as it addresses both the neural and the vascular causes of post-CNI erectile dysfunction simultaneously.
- JD Campbell, AL Burnett, Incidence of ED in patients with CN injury after pelvic surgery - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578182/
- AL Burnett, Incidence and causes of ED in patients after radical prostatectomy - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1578536/
- S Basal et al, Penile rehabilitation after radical prostatectomy - https://www.ncbi.nlm.nih.gov/pubmed/23186312
- SF Sezen et al, Neuroprotective function of immunophilin ligand FK506 - http://go.galegroup.com/ps/anonymous?id=GALE%7CA193469353&sid=googleScholar&v=2.1&it=r&linkaccess=abs&issn=10788956&p=AONE&sw=w
- SF Sezen et al, Immunophilins in recovery of erectile function after CN injury - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3361063/#S10title
- AL Burnett et al, Clinical trials of GPI-1485 to treat erectile dysfunction after radical prostatectomy - https://www.researchgate.net/publication/324085870_1162_Neuromodulation_to_Preserve_Erectile_Function_After_Radical_Prostatectomy_Results_from_the_GPI1485_Neuroimmunophilin_Ligand_Clinical_Trial
- YB Kandemir, L Sarikcioglu, Therapeutic time window in administration of FK506 - https://journals.viamedica.pl/folia_morphologica/article/download/FM.2015.0100/30362
- K Ghatak et al, Neurovascular regeneration after cavernous nerve injury - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736639/