14 February 2020
An Australian-developed regenerative therapy is exploring the possibility of a treatment for Erectile dysfunction (ED) through stimulating the regenerative and healing capacities of the body. Exopharm Limited (ASX: EX1) has been testing its exosomes – natural cellular particles secreted by stem cells, and purified through Exopharm’s proprietary technology –to test their ability to reverse post-operative tissue damage, and thus, to restore erectile function.
ED is a common but highly problematic condition among men aged in their 50s and older; and is a condition that often brings psychological and emotional damage to compound the physical.
ED first burst out from behind the wall of shamed whisper in 1998, when Pfizer’s drug Viagra (sildenafil) won US Food and Drug Administration (FDA) approval – and entered the popular consciousness in a manner rare for a drug. Viagra grew into one of the world’s best-selling medications, with global sales of more than US$2 billion ($2.1 billion) at their peak in 2012. Along the way, it – and similar drugs – lifted the lid on the strong demand for treatments for the condition.
“Animal studies show that exosomes have great potential for reversing a variety of conditions that affect the human “health span,” which is defined as the number of healthy, functional years that a person lives,” says Dr Ian Dixon, founder and CEO of Exopharm.
“ED, with all of its connotations of loss of – or impact on – men’s sexual function, is a perfect example of a ‘health span’ condition. While ED may be considered to be non-medical, ED is linked to higher suicide rates, reduced life expectancy and clinical depression,2,3,4” he adds. Other examples of health span-related conditions include dry age-related macular degeneration (AMD) and osteoarthritis.
ED is common among middle-aged and older men, and increases in prevalence with age. The condition affects approximately 50% of men at 50 years old, 60% of men at 60 and 70% of men at 70.1 But ED can also be the result of prostatectomy (partial or complete removal of the prostate gland) and rectal surgery – both of which are usually linked to cancer.
While Viagra and a variety of competitor drugs address ED, Dixon says they are usually ineffective on damaged tissue.
“Sildenafil and other phosphodiesterase type 5 inhibitor (PDE5-i) drugs are effective where there is generally healthy physiological structure of penile tissue, and where the nitric oxide signalling pathway that triggers erection remains intact.5”
“Damage or degeneration to one or more of the system of nerves, blood vessels and muscle cells required for erection can render PDE5-i drugs ineffective. For example, damage to the cavernous nerve during pelvic surgery (that is, for prostate or colorectal cancer) are common causes of ED, affecting up to 85% of men following radical prostatectomy. PDE5-i drugs typically have little effect in these cases.6”
But regenerative medicine based on stem cells has shown great potential for reversing hard-to-treat ED in animal models, Dr Dixon says. “Preliminary work has shown that, in animal models, stem cells can promote the regeneration of muscle and nerve cells in and around the penis, initiating recovery of erectile function. However, researchers have found that a major limitation of stem-cell injections for ED is that blood flow rapidly washes the cells away from the site of damage, limiting their therapeutic effects.5”
To address this problem, Exopharm has developed therapeutic exosome products as an alternative to stem-cell therapies. “As with essentially all stem-cell therapies, the main way in which stem cells act on the body is by releasing tiny regenerative packets of lipids, proteins and genetic material in the form of ribonucleic acid (RNA), called exosomes.”
Exosomes are produced by virtually all cell types in the body, and are an essential component of cell-to-cell signalling. “Exosomes released by regenerative cells, such as stem cells, can have a powerful rejuvenating effect on the cells that take them up. They are also considered to be an inherently safer and less expensive therapy compared to injections of live cells.7 Increasingly, ED researchers are turning to exosomes as the most promising next generation treatment for ED, and we see our planned clinical trial as a major step in fostering this line of thinking.”
How it works: Hitting a Nerve
Achieving erection is a multi-step process involving several tissue types. In a healthy male, erection is initiated by the cavernous nerve, which activates the nitric oxide (NO) signalling pathway. NO release by the cavernous nerve and by endothelium cells in the penis causes corporal smooth muscle relaxation, which increases blood penile flow leading to erection.2
Damage to the cavernous nerve – a common side effect of prostate or colorectal surgery – has downstream effects on penis physiology. The lack of nerve signalling leads to the deterioration and decline of corporal smooth muscle cells, which PDE5-i treatment fails to prevent. Smooth muscle cell death via apoptosis, and chronic inflammation can set in, leading to the gradual conversion of remaining smooth muscle cells into fibroblasts.8
Exosomes derived from stem cells have shown the potential to reverse this damage and rescue erectile function.8,9 Exosomes can protect smooth muscle cells from apoptosis, and prevent fibrosis, while the corporeal nerve regenerates following surgery, avoiding ED, researchers showed.
Researchers have recently demonstrated that exosomes can also promote repair to damaged nerves. Exosomes derived from stem cells can reduce inflammation, scarring and apoptotic cell death of nerve cells, promoting nerve regeneration and recovery following trauma.10,11
Age-related ED and exosomes
Exosomes can also be a regenerative tonic to treat non-surgical causes of ED. Although the condition is increasingly prevalent with age, several age-related diseases are associated with high levels of ED. For example, the incidence of ED in men with diabetes is two- to three-fold higher than the general population.5 Key factors contributing to ED include the impaired blood circulation and nerve damage associated with diabetes.
Injections with exosomes can ameliorate diabetes-related ED, animal research has recently shown.12 Exosomes promote penile neural regeneration, smooth muscle regeneration and reduced collagen deposits, enhancing erectile function, the study showed. Proangiogenic RNAs in the exosomes, promoting new blood vessel formation, is the potential mechanism behind the effect, the researchers conclude.
Conclusion
Exosomes hold much promise in the treatment of age-related disease: treating the underlying causes that leave humans susceptible to conditions from cancer to Alzheimer’s disease.7,13
Exosomes can reactivate the natural regenerative processes that rapidly repair damage when we are young, but which become less effective with age.14,15 A growing list of animal studies has already shown exosomes can directly initiate tissue regeneration to restore erectile function in models of ED, but so far no human trials with exosomes have commenced.
Exopharm, a leader in the exosome medicine field, will soon report on studies that may support a clinical trial to treat post-operative ED with exosomes.
References:
1. Mobley, D.F., et al. Recent advances in the treatment of erectile dysfunction. Postgraduate Medical Journal 93, 679 (2017). https:doi.org/10.1136/postgradmedj-2016-134073
2. Chou, P.-S., et al. Newly Diagnosed Erectile Dysfunction and Risk of Depression:A Population-Based 5-year Follow-Up Study in Taiwan. The Journal of Sexual Medicine 12, 804–812 (2015) https://doi.org/10.1111/jsm.12792
3. Araujo, A B., et al. Erectile Dysfunction and Mortality. The Journal of Sexual Medicine 6, 2445-2454 (2009) https://doi.org/10.1111/j.1743-6109.2009.01354.x
4. Rajkumar, R. P. and Kumaran, A. K. Depression and anxiety in men with sexual dysfunction: a retrospective study. Comprehensive Psychiatry 60, 114-118 (2015) https://doi.org/10.1016/j.comppsych.2015.03.001
5. Yan, H., et al. Current Status and Prospects in the Treatment of Erectile Dysfunction by Adipose-Derived Stem Cells in the Diabetic Animal Model. Sexual Medicine Reviews (2020), https://doi.org/10.1016/j.sxmr.2019.09.006
6. Emanu, J. C., et al. Erectile Dysfunction after Radical Prostatectomy: Prevalence, Medical Treatments, and Psychosocial Interventions. Current Opinion in Supportive and Palliative Care 10, 102 (2016) https://doi.org/10.1097/SPC.0000000000000195
7. Wiklander, O. B. P., et al. Science Translational Medicine 11, eaav8521 (2019) https://doi.org.10.1126/scitranslmed.aav8521
8. Ouyang, X., et al. MSC-derived exosomes ameliorate erectile dysfunction by alleviation of corpus cavernosum smooth muscle apoptosis in a rat model of cavernous nerve injury. Stem Cell Research & Therapy 9, 246 (2018) https:doi.org/10.1186/s13287-018-1003-1
9. Li, M., et al. Exosomes derived from mesenchymal stem cells exert therapeutic effect in a rat model of cavernous nerves injury. Andrology 6, 927 (2018) https://doi.org/10.1111/andr.12519
10. Rong, Y. et al. Neural stem cell-derived small extracellular vesicles attenuate apoptosis and neuroinflammation after traumatic spinal cord injury by activating autophagy. Cell Death & Disease 10, 340 (2019) https://doi.org/10.1038/s41419-019-1571-8
11. Chen, J., et al. Exosomes from human adipose‐derived stem cells promote sciatic nerve regeneration via optimizing Schwann cell function. Journal of Cellular Physiology 234, 23097 (2019). https://doi.org/10.1002/jcp.28873
12. Ouyang, B., et al. Extracellular Vesicles From Human Urine-Derived Stem Cells Ameliorate Erectile Dysfunction in a Diabetic Rat Model by Delivering Proangiogenic MicroRNA. Sexual Medicine 7, 241-250 (2019) https://doi.org/10.1016/j.esxm.2019.02.001
13. Bellantuono, I. Find drugs that delay many diseases of old age. Nature 554, 293 (2018) https://doi.org/10.1038/d41586-018-01668-0
14. https://exopharm.com/the-new-science-of-aging-winding-back-the-body-clock/
15. Fafián-Labora, J., et al. Influence of mesenchymal stem cell- derived extracellular vesicles in vitro and their role in ageing. Stem Cell Research & Therapy 11, 13 (2020) https://doi.org/10.1186/s13287-019-1534-0
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