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Novel therapeutic strategies for the treatment of erectile dysfunction
Vol. 1, No. 2 2004
Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Genitourinary diseases
Novel therapeutic strategies for the treatment of erectile dysfunction Jason Hafron1, George J Christ2,* 1
Department of Urology, Montefiore Medical Center, Albert Einstein College of Medicine, 3400 Bainbridge Avenue, Bronx, NY 10467, USA Department of Urology and Physiology and Pharmacology, Wake Forest Institute for Regenerative Medicine, Medical Center Blvd, Wake Forest University Medical School, NRC Building, Room 110, Winston-Salem, NC 27023, USA 2
The success of phosphodiesterase (PDE)5 inhibitors has revolutionized the treatment of erectile dysfunction (ED). Although these drugs cause few side effects, the lack of a spontaneous erection in response to sexual stimulation, the identification of specific patient groups with poor response rates and the presence of medical contraindications to PDE5 inhibitors are all reasons for displeasure with the current therapy. Taken together, these clinical limitations point towards the need to develop novel therapeutic strategies. The thesis of this report is that the new generation of therapeutics will probably involve mechanism-based, patient-specific restoration of erectile function, reducing the necessity for on-demand therapy. Introduction Erectile dysfunction (ED) is defined as the consistent inability to achieve and maintain an erection sufficient for satisfactory sexual intercourse [1]. It is estimated to affect up to 30 million men in the United States [2], with 52% of men between the ages of 40 and 70 reporting difficulty with erectile function [3]. In the year 2025, it is estimated that 322 million men worldwide will suffer from some degree of sexual dysfunction [4]. Briefly, an erection is the result of a neurovascular cascade of integrative pathways that are triggered by peripheral (i.e. tactile) stimulation and/or higher central activation (i.e. auditory, visual, and olfactory cues). Parasympathetic cavernous *Corresponding author: (G.J. Christ) [email protected] 1740-6773/$ ß 2004 Published by Elsevier Ltd.
DOI: 10.1016/j.ddstr.2004.08.023
Section Editor: David P. Brooks – Department of Renal and Urology Research, GlaxoSmithKline, King of Prussia, PA 19406-0939, USA The ‘‘discovery’’ that sildenafil, and subsequently vardenalfil and tadalfil, are effective in erectile dysfunction has revolutionized the therapy for this disorder, which had previously involved the use of surgically implanted prostheses or often painful penile injections of a vasodilator. The PDE5 inhibitors work by inhibiting the breakdown of cyclic GMP, the cellular mediator of nitric oxide. Although extremely effective in a large proportion of patients, there remains a group of patients for whom this class of agents is less effective or contraindicated. Christ and his colleagues in NY have been leaders in investigating novel targets and strategies for this disorder.
(see ‘Glossary’) nerves release nitric oxide (NO), causing relaxation of the sinusoidal arterial and corporal smooth muscle cells (see ‘Glossary’) and thus increased penile blood flow [5,6]. The increased pressure from the expanded penile blood flow leads to compression of the emissary veins draining the corpora and causes penile engorgement and a rigid erection [7]. The pathophysiological basis of erectile dysfunction is clearly diverse. Despite the potentially large numbers of physiologic deficits that can contribute to ED, the etiology of ED in the vast majority of impotent men is probably related to relatively subtle alterations in the effects of endogenous contracting and relaxing pathways on the corporal and arterial smooth muscle cells. In fact, it is thought that ED most frequently results in heightened contractility, impaired relaxation or both [8]. In this scenario, the treatment possibilities are enormous. Phosphodiesterase (PDE)5 inhibitors are excellent therapy for the treatment of ED and represent the current first-line www.drugdiscoverytoday.com
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Glossary Angiogenic: increases new blood vessel formation. Chondrocyte: a cell type found in cartilage. Corporal sinusoids: the trabecular mesh-work structure formed by the corporal smooth muscle cells and collagen matrix. The corporal sinusoids serve as an expandable reservoir for the blood originating from the helicine arterioles within the tissue proper. Corporal smooth muscle cells: specialized vascular smooth muscle cells that regulate blood flow into and out of corporal sinusoids during flaccid and erect states. Corpus cavernousum: the singular term for one of the two parallel tube-like vascular tissues that run the course of the penis. The corpus cavernosum is enclosed in a connective tissue sheath called the tunica albuginea. Hypercholesterolemia: abnormally high levels of cholesterol in the blood. Parasympathetic cavernous nerves: branches of the pelvic plexus that innervate the penis and are responsible for tumescence. Sinusoidal endothelium: a monolayer of endothelial cells lining the corporal smooth muscle cells in the penis. Venous leak: abnormal venous outflow from the corpora cavernosa preventing a rigid erection. In many cases, incomplete relaxation of the corporal smooth muscle cells prevents trapping of blood in the penis (via compression of the veins against the tunica albuginea).
treatment option. Nonetheless the success of PDE5 inhibitors, and their popularity has focused attention on an increasing group of patients who are dissatisfied with current therapies. Sources of dissatisfaction include the irreversibility of surgical treatments (i.e. penile prosthesis), the general aversion to penile injection (with alprostadil), the medical contraindications of PDE5 inhibitors and the lack of spontaneity associated with virtually all of these treatment options (i.e. the need to plan for intimacy). To improve efficacy and to make treatment options more ‘user friendly’, we envision
three main areas in which novel therapeutic strategies will be developed: (1) improved pharmacotherapy, (2) tissue regeneration or tissue engineering, and (3) cell and gene transfer (Table 1).
Pharmacotherapy The enhancement of the extant physiologic pathways that mediate the erectile response is the most frequent strategy employed for the treatment of ED. Current FDA-approved therapies are largely targeted to the end organ (the penis), but more targets in the central nervous system (CNS) (the brain) are anticipated in the future (Fig. 1). Three PDE5 inhibitors (sildenafil, vardenafil and tadalafil), and prostaglandin E1 (alaprastodil) have been approved by the FDA to date [9].
End-organ pharmacotherapy PDE5 inhibitors
During sexual activity, nitric oxide is released from the cavernous nerves and activates soluble guanylyl cyclase, which in turn raises intracellular cGMP levels [10]. Activation of cGMP-dependant protein kinase (PKG) results in multiple intracellular changes, with a primary end result being a lowering of free intra-cytosolic calcium levels that starts smooth muscle relaxation. PDE5 inhibitors block the degradation of cGMP within the corpora cavernous tissue, thereby promoting smooth muscle relaxation in both the corpus cavernousum (see ‘Glossary’) and the surrounding vessels [11]. Increased dilation of the corporal sinusoids (see ‘Glossary’) increases blood flow to the penis, creating a more rigid erection. The efficacy and safety of oral phosphodiesterase inhibitors have made them an excellent first-line therapy for the treatment of ED.
Table 1. Comparison of the different therapeutic strategies to treat erectile dysfunction Pharmacotherapy
Regenerative medicine
Gene transfer
Pros
Oral, topical, intra-urethral and intra-nasal therapy
Options for medical therapy failures, congenital and traumatic defects
Restoration of erectile function, spontaneous erections
Cons
On-demand only
Lack of clinical studies
Lack of clinical studies
Latest developments
CNS directed therapeutics: apomorphine, PT-141a
Formation of corporal tissue in vivo using human cavernosal muscle and endothelial cells seeded on collagen matrices Recombinant VEGFb protein
Gene transfer: hSLOc, Ad/VEGFd, Ad/EC-SODe, Ad/PnNOSf, Ad/eNOSg, Ad/iNOSh, Ad/CGRPi, Ad/BDNFj, Ad/Rhok Cell-based therapy: endothelial cells with eNOS and myoblasts with iNOS
[24,25,27,28,30–33]
[34–50]
Penis directed therapeutics: alprostadil/topiglan (topical) References
[11,13,14,16–22]
a
Cyclic heptapeptide melanocortin analog. b Vascular endothelial growth factor. c Plasmid-derived (‘‘naked’’) DNA. d Adenoviral-mediated vascular endothelial growth factor. e Adenoviral-mediated extracellular superoxide dismutase. f Adenoviral-mediated penile nitric oxide synthase. g Adenoviral-mediated endothelial nitric oxide synthase. h Adenoviral-mediated inducible nitric oxide synthase. i Adenoviral-mediated calcitonin gene related peptide. j Adenoviral-mediated brain derived neurotrophic factor. k Adenoviral-mediated mutant RhoA kinase.
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Figure 1. Current and future strategies using pharmacotherapy.
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Prostaglandin E1 (PGE1)
PGE1 modulates cAMP systems; specifically, it activates the EP2/4 receptor on the corporal smooth muscle to increase the activity of adenylate cyclase and the accumulation of cAMP [12]. An increase in cAMP leads to a cascade of intracellular changes that culminate in decreased intracellular calcium, and in turn, in the relaxation of the corporal smooth muscle cells and an erection [13]. Delivery of PGE1 is limited to intracavernosal and transurethral mechanisms, which are successful but have high discontinuation rates because of discomfort, the pain of local injection or local fibrosis. Current research is directed at improving the delivery system, specifically on topical applications that represent a potentially exciting non-invasive method for the treatment of ED. Recently, a topical PGE1 with a transdermal penetration enhancer produced an adequate erectile response in an animal model [14].
CNS pharmacotherapy
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ing in the US. Although the clinical efficacy of apomorphine has been somewhat disappointing, this drug has clearly pointed to the tremendous potential of using CNS targets to moderate erectile function. Melanocortin pathway
Another potential target in erectile physiology/dysfunction being critically evaluated in the CNS are the melanocortins. Two agents that induce penile erection by CNS mechanisms are a-melanocyte-stimulating hormone (a-MSH) and oxytocin. Injection of these agents in the CNS of rat models indicates that supraspinal MSH and oxytocin receptors, as well as spinal oxytocin receptors, are involved in erectile function [8]. This concept has been further developed with an intra-nasal a-MSH agonist, PT-141, which in early trials appears to be a promising candidate for further evaluation as a treatment for ED [22]. Clearly, the melanocortin pathway promises to be a fruitful area of future investigation.
Dopaminergic pathway
The complexities of the modulation of erectile function by the CNS are beyond the scope of this report, but several excellent reviews are available (see [15]). Pertinent to this article is the fact that various areas of the cortex send impulses, depending on the source of stimulation, to the paraventricular nucleus and/or the medial preoptic area (MPOA) of the hypothalamus [16–18]. In fact, in both animals and humans, centrally mediated dopamine-induced penile erection involves the D1- and D2-like receptors [19]. Manipulation of the MPOA has not yet advanced past the preclinical research stage, but already, numerous clinical trials have examined apomorphine hydrochloride, a non-selective dopaminergic receptor agonist that activates D2-like receptors [20,21]. Apomorphine hydrochloride has been approved in Europe and Japan for the treatment of ED and has been withdrawn pending a new-drug application and further test-
Tissue regeneration or tissue engineering If damage to the cavernous nerves or corporal tissue has been caused – for example, by trauma, pelvic surgery, pelvic irradiation or congenital defects – then the response to any current ED treatment might be incomplete. The technologies of regenerative medicine, that is the repair or replacement of damaged tissues, cells or organs, have been applied to ameliorate these conditions and hence to treat ED (Fig. 2).
Tissue regeneration Neural auto transplantation
Injury to the cavernous nerves resulting from radical pelvic surgery, irradiation or perineal trauma is a common cause of erectile dysfunction [23]. In the rat, a large single ganglion, the major pelvic ganglion, represents the pelvic plexus, which innervates the penis, prostate and rectum [24]. When
Figure 2. Strategies using regenerative medicine to treat erectile dysfunction.
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the major pelvic ganglion was auto-transplanted into the corpus cavernousum of the penis, it survived for up to 90 days and showed good expression of nitric oxide synthase, protein gene product 9.5 and growth-associated protein 43 [25]. Even though electrostimulation of the transplanted ganglion was unable to produce a full erection, it appears that the sinusoidal structure of the corpus cavernousum with its extensive blood supply might be a suitable host for transplanted neural tissue. Furthermore, the syncytial corporal smooth muscle cell network, which is provided for by intercellular communications through gap junctions, might require only modest innervation density [26]. On the basis of these promising results, the potential ability of fetal neuron transplantation to repair injured nerves warrants further studies. Cavernous muscle cell auto transplantation
Autologous endothelial cells transplanted into the corpus cavernousum of a rat model were shown to adhere to the sinusoidal endothelium (see ‘Glossary’) for up to two weeks [27]. The ability to auto-transplant endothelial cells further opens the possibility of cell-based gene transfer. In theory, one could expose cells to genetic therapy ex vivo, and then reimplant these cells for treatment of ED. In preliminary studies, the penis appears to be a suitable host for auto-transplantation of neurons as well as of corpus cavernousum endothelial cells [25,27].
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would be a functional, non-imunogenic, biocompatible material. Autologous tissue engineering with human cavernosal smooth muscle and endothelial cells seeded on acellular matrices can form tissue structures (in vivo, ex situ) that mimic corporal tissue [31]. Recently, Falke et al. [32] were also able to demonstrate that engineered corporal cavernosal tissue was able to maintain erectile function in a rabbit model. The use of autologous-engineered functional tissue replacement for the reconstruction of penile defects seems promising. Autologous tissue engineered penile prosthesis
Penile prostheses are mechanical devices developed in the 1970s that permit excellent penile rigidity and are usually reserved for patients who fail medical therapy. However, biocompatibility has been a problem for several patients and autologous tissue engineering has been investigated as a possible route to eliminating this problem. Kim et al. [33] demonstrated that a natural penile prosthesis could be created from chondrocytes (see ‘Glossary’) isolated from the human ear. The chrondrocyte cells are expanded in culture on a rod-shaped polymer scaffold. Transplantation of the chondrocytes resulted in well-formed, milk-white cartilaginous rods. After approximately two months, the rods displayed comparable mechanical properties to the silicone prostheses used today. The preliminary results have significant potential in treating some of the most difficult cases of ED.
Intra-corporal injection of vascular endothelial growth factor (VEGF)
Gene transfer
Following castration, animals develop venous leak as a result of decreased testosterone [28]; and men often develop venous leak (see ‘Glossary’) following radical prostatectomy surgery (50% display venous leak) [29]. Rogers et al. [28] demonstrated that the administration of VEGF as a recombinant protein to castrated rats was able to produce erectile function and prevent venous leak through its angiogenic (see ‘Glossary’) and androgen-mediated effects [28]. Moreover, there was evidence of the restoration of neural and smooth muscle tissue, as well as of hyperplasia and hypertrophy of endothelial cells, in these rats. Recombinant VEGF protein could conceivably be useful in the treatment of post-radical prostatectomy patients who have a venous leak.
Gene transfer is an exciting potential modality for the restoration of erectile capacity by altering the molecular mechanisms involved with erectile physiology and dysfunction. The penis’ location outside the body makes it easily accessible for targeted injectable gene transfer. Current strategies are directed at over-expression of endogenous components of existing pathways to increase corporal and arterial smooth muscle relaxation, and thus promote erection (Fig. 3).
Tissue engineering Engineered autologous corpora cavernosal tissue
ED patients who have congenital defects, traumatic injuries, or corporal fibrosis of the penis respond poorly to medical therapy, and sometimes penile reconstruction is required [30]. The limits of tissue reconstruction are imposed by the low availability of existing penile tissue. However, reconstruction of the penis with non-functional materials will most probably leave the patient impotent. The ideal material
Nitric oxide synthase (NOS) isoforms One application for gene transfer that is being pursued actively is the over-expression of nitric oxide synthase (NOS), the main neurotransmitter in a normal erection. In the rat, three known NOS isoforms have been used eNOS (the endothelial constitutive type), PnNOS (the penile-specific neural constitutive type) and iNOS (the inducible form) [34–39]. Over-expression of eNOS using an adenovirus (Ad) vector in the aged and diabetic (streptozotocin-induced) rat model produced an improvement in erections that lasted about one to two days [36,37]. Studies using iNOS-based gene transfer show effects as early as two days, lasting for approximately 10 days [35,38]. In these iNOS studies, three techniwww.drugdiscoverytoday.com
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Figure 3. Gene and cell therapy techniques to treat erectile dysfunction.
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ques were applied: myoblast-cell-mediated therapy [35], and plasmid- or adenovirus-based gene therapies [34,35,38]. The use of myoblast-cell-mediated gene transfer opens the door for cell-based gene transfer. Additional studies of the transfection of Plasmid/PnNOS and Ad/PnNOS into the corpus cavernosum of rats using a plasmid demonstrated a significant improvement in erectile function for up to 18 days following injection [39]. Overall, NOS replacement therapy has shown no significant systemic effects but has produced short-lived improvements in erectile function in various animal models.
Prepro-calcitonin gene-related peptide (CGRP) CGRP is a potent vasodilator that has been localized to the cavernous nerves, arteries and smooth muscle cells [40]. Its activity also leverages the cAMP pathway described earlier in the description of PGE1. Bivalacqua et al. [41] demonstrated a significant increase in erectile response to cavernosal nerve stimulation in the aged rat model five days after adenoviralmediated gene transfer of prepro-CGRP. On the basis of these findings, CGRP over-expression might represent a novel therapy for the treatment of ED.
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Vascular endothelial growth factor (VEGF) We mentioned earlier that intra-corporal injection of VEGF was capable of maintaining erectile function in an animal model of venous leak [28]. In the same study, animals treated with Ad-VEGF showed a high intra-cavernosal pressure response to papaverine. However, VEGF-gene-therapy produced a smaller physiologic response than intra-cavernosal injection of recombinant VEGF protein or testosterone-replacement therapy.
RhoA/Rho kinase pathway The RhoA/Rho kinase pathway plays an important role in both resting and stimulated corpora smooth muscle [46]. It has been hypothesized that transfection of corporal smooth muscle cells with a mutant RhoA kinase should promote relaxation by disrupting the tonic contraction pathway of the corporal smooth muscle cell. Gene transfer of a dominant negative RhoA mutant in an Ad vector was associated with a significant increase in erectile function in rats [47]. The duration of the efficacy was seven days without any evidence of systemic effects.
Ion channels Brain-derived neurotrophic factor (BDNF) Electron microscopy and histology of rats with hypercholesterolemia (see ‘Glossary’) and ED revealed damage to the endothelial cells, intra-cavernosal smooth muscle cells and dorsal and intra-cavernosal nerves [42]. In an attempt to compensate for these changes, Gholami et al. [42] assessed the efficacy of intra-corporal gene transfer following the administration of adeno-associated virus–brain-derived neurotrophic factor (AAV–BDNF). In this study, intra-cavernosal injection of AAV–BDNF preserved erectile function by qualitative preservation of nerves and smooth muscles. In short, these studies indicate that adenoviral-mediated gene transfer of BDNF appears to be a promising strategy for preserving the morphology of the endothelial cell and smooth muscle cells in animals with hypercholesterolemia.
Superoxide dismutase (SOD) Along with neural and penile tissue damage, vascular dysfunction contributes to the etiology of ED. Oxidative stress from the formation of reactive oxygen metabolites is a significant contributor to coronary vascular disease [43]. Bivalacqua et al. [44] found a threefold increase in super oxide formation in cavernous tissue from the penises of aged animals. On the other hand, SOD provides a major cellular defense against oxidative injury [45]. In an aged rat model, in vivo adenoviral gene transfer of extra cellular (EC) SOD resulted in a significant increase in erectile response to cavernosal nerve stimulation. SOD replacement therapy is a novel tool to repair the ravages of vascular disease and potentially to treat ED in the elderly population.
A complicated regulatory relationship exists in cavernous smooth cells among membrane potential, the activity of calcium-dependent potassium channels and voltage-activated calcium channels. Ion-channel gene transfer is currently directed toward increased expression of the large conductance calcium-sensitive K+ channel (Maxi-K). Increasing expression of the Maxi-K channel in corporal smooth muscle appears to increase the hyperpolarizing ability of the corporal smooth muscle cell network, thus increasing the responsiveness of the erectile apparatus to a potentially diminished supply of endogenous smooth muscle cell relaxants [48]. The main physiologic endpoint is the restoration of a degree of corporal smooth muscle relaxation, which is sufficient to result in normal penile erection in the absence of additional therapeutic modalities [49]. The efficacy of gene transfer with the Maxi-K channel has been shown to last for up to six months after a single intra-corporal injection [50].
Strategy comparison Increased understanding of ED has led to a better characterization of the plethora of pathophysiological mechanisms involved. As already documented by the popularity of PDE5 inhibitors, successful ED treatment can lead to far-reaching patient and partner satisfaction. Building on the success of the PDE5 inhibitors, future strategies will focus on the correction of altered pathways, the identification of appropriate molecular targets, and the restoration of erectile function using cell- and gene-based techniques, including regenerative medicine. Preclinical studies have already shown gene transfer to be an effective strategy for restoration of erectile funcwww.drugdiscoverytoday.com
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Related articles Lue, T.F. (2000) Erectile dysfunction. N. Engl. J. Med. 342, 1802–1813 Andersson, K.E. and Wagner, G. (1995) Physiology of penile erection. Physiol. Rev. 75, 191–236 Christ, G.J. (2004) Gene therapy treatments for erectile and bladder dysfunction. Curr. Urol. Rep. 5, 52–60 Yokoyama, T. et al. (2001) Gene therapy and tissue engineering for urologic dysfunction: status and prospects. Mol. Urol. 5, 67–70 Karicheti, V. and Christ G.J. (2001) Physiological roles for K+ channels and gap junctions in urogenital smooth muscle: implications for improved understanding of urogenital function, disease and therapy. Curr. Drug Targets 2, 1–20
tion, and a Phase I clinical trial is currently underway (for more details see: http://www.ionchannelinnovations.com/). With respect to gene transfer, local application of these agents ensures efficient delivery, and thus, might avoid many of the systemic side effects commonly associated with the administration of genetic materials. Therapies such as gene transfer and tissue regeneration/engineering that have the potential to restore function without the need for on-demand therapy appear to be the next revolution for ED therapy.
Conclusions The introduction of PDE5 inhibitors represents the beginning of a new generation of therapies, for which the standards of safety, efficacy and ease of use have been raised to a higher level. Novel and improved therapies for ED will undoubtedly come from an improved mechanistic and molecular understanding of erectile physiology and dysfunction. These therapies are probable to arise from three broad areas: (1) improved pharmacotherapy, (2) regenerative medicine, and (3) cell and gene transfer. Ultimately, it is envisioned that both polypharmacy and/or combination therapy of these three general therapeutic categories will be used to treat ED successfully. Outstanding issues Development of alternative treatments for patients in whom PDE5 inhibitors fail. Development of a mechanism-based, patient-specific treatment approach as a result of a better understanding of erectile physiology and pathophysiology. Development of treatments that focus on the restoration of endogenous erectile function, thereby eliminating on-demand therapy. Improvement of the selectivity and efficacy of central-acting pharmacotherapies. Apply technologies of regenerative medicine to restore erectile capacity in extensively damaged tissue.
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27 Wessells, H. and Williams, S.K. (1999) Endothelial cell transplantation into the corpus cavernosum: moving towards cell-based gene therapy. J. Urol. 162, 2162–2164 28 Rogers, R.S. et al. (2003) Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int. J. Impot. Res. 15, 26–37 29 Mulhall, J.P. and Graydon, R.J. (1996) The hemodynamics of erectile dysfunction following nerve-sparing radical retropubic prostatectomy. Int. J. Impot. Res. 8, 91–94 30 Atala, A. (2002) Tissue engineering perspectives for reconstructive surgery. In Campbell’s Urology (Walsh, P.C., Retik, A.B., Vaughan, E.D., Wein, A.J. eds), pp. 2593–2622, Saunders 31 Falke, G. et al. (2003) Formation of corporal tissue architecture in vivo using human cavernosal muscle and endothelial cells seed on collagen matrices. Tissue Eng. 9, 871–879 32 Kwon, T.G. et al. (2002) Autologous penile corpora cavernous replacement using tissue-engineering techniques. J. Urol. 168, 1754–1758 33 Kim, B.S. et al. (2002) Engineering of human cartilage rods: potential application for penile prosthesis. J. Urol. 168, 1794–1797 34 Garbon, H. et al. (1997) Cloning of rat and human inducible penile nitric oxide synthase. Application for gene therapy of erectile dysfunction. 35 Chancellor, M.B. et al. (2003) Nitric oxide synthase gene transfer for erectile dysfunction in a rat model. BJU Int. 169, 691–696 36 Champion, H.C. et al. (1999) Gene transfer of endothelial nitric oxide synthase to the penis augments erectile response in the aged rat. Proc. Natl. Acad. Sci. USA 96, 11648–11652 37 Bivalacqua, T.J. et al. (1999) Gene transfer of endothelial nitric oxide synthase partially restores nitric oxide synthesis and erectile function in streptozoocin diabetic rats. J. Urol. 169, 1911–1917 38 Tirney, S. et al. (2001) Nitric oxide synthase gene therapy for erectile dysfunction: comparison of plasmid adenovirus and adenovirus-transduced myoblast vectors. Mol. Urol. 15, 37–43
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39 Magee, T.R. et al. (2002) Gene therapy of erectile dysfunction in the rat with penile neuronal nitric oxide synthase. Biol. Reprod. 67, 20–28 40 Stief, C.G. et al. (1990) A possible role for calcitonin-gene-related peptide in the regulation of the smooth muscle tone of the bladder and penis. J. Urol. 143, 392–397 41 Bivalacqua, T.J. et al. (2001) Gene transfer of prepro-calcitonin generelated peptide restores erectile function in the aged rat. Biol. Reprod. 65, 1371–1377 42 Gholami, S.S. et al. (2003) The effect of vascular endothelial growth factor and adeno-associated virus mediated brain derived neurotrophic factor on neurogenic and vasculogenic erectile dysfunction induced by hyperlipidemia. J. Urol. 169, 1577–1581 43 Cai, H. and Harrison, D.G. (2000) Endothelial dysfunction in cardiovascular diseases: the role of oxidant stress. Circ. Res. 87, 840–844 44 Bivalacqua, T.J. et al. (2003) Gene transfer of extra cellular SOD to the penis reduces O2 and improves erectile function in aged rats. Am. J. Physiol. Heart Circ. Physiol. 284, H1408–H1421 45 Squadrito, G. and Pryor, W. (1998) Oxidative chemistry of nitric oxide: the role of superoxide, peroxynitrite and carbon dioxide. Free Radic. Biol. Med. 25, 392–403 46 Jin, L. et al. (2003) Inhibition of the tonic contraction in the treatment of erectile dysfunction. Expert Opin. Ther. Targets 2, 265–276 47 Chitaley, K. et al. (2002) Adeno-associated viral gene transfer of dominant negative RhoA enhances erectile function in rats. Biochem. Biophys. Res. Commun. 298, 427–432 48 Christ, G.J. (2004) Gene therapy treatments for erectile and bladder dysfunction. Curr. Urol. Rep. 5, 52–60 49 Christ, G.J. et al. (1998) Intracorporal injection of hSlo cDNA in rats produces physiologically relevant alterations in penile function. Am. J. Physiol. 275, H600–H608 50 Melman, A. et al. (2003) The successful long-term treatment of age related erectile dysfunction with hSlo cDNA in rats in vivo. J. Urol. 169, 285–290
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Drug Discovery Today: Therapeutic Strategies Editors-in-Chief Raymond Baker – formerly University of Southampton, UK and Merck Sharp & Dohme, UK Eliot Ohlstein – GlaxoSmithKline, USA DRUG DISCOVERY
TODAY THERAPEUTIC
STRATEGIES
Genitourinary diseases
Novel therapeutic strategies for the treatment of erectile dysfunction Jason Hafron1, George J Christ2,* 1
Department of Urology, Montefiore Medical Center, Albert Einstein College of Medicine, 3400 Bainbridge Avenue, Bronx, NY 10467, USA Department of Urology and Physiology and Pharmacology, Wake Forest Institute for Regenerative Medicine, Medical Center Blvd, Wake Forest University Medical School, NRC Building, Room 110, Winston-Salem, NC 27023, USA 2
The success of phosphodiesterase (PDE)5 inhibitors has revolutionized the treatment of erectile dysfunction (ED). Although these drugs cause few side effects, the lack of a spontaneous erection in response to sexual stimulation, the identification of specific patient groups with poor response rates and the presence of medical contraindications to PDE5 inhibitors are all reasons for displeasure with the current therapy. Taken together, these clinical limitations point towards the need to develop novel therapeutic strategies. The thesis of this report is that the new generation of therapeutics will probably involve mechanism-based, patient-specific restoration of erectile function, reducing the necessity for on-demand therapy. Introduction Erectile dysfunction (ED) is defined as the consistent inability to achieve and maintain an erection sufficient for satisfactory sexual intercourse [1]. It is estimated to affect up to 30 million men in the United States [2], with 52% of men between the ages of 40 and 70 reporting difficulty with erectile function [3]. In the year 2025, it is estimated that 322 million men worldwide will suffer from some degree of sexual dysfunction [4]. Briefly, an erection is the result of a neurovascular cascade of integrative pathways that are triggered by peripheral (i.e. tactile) stimulation and/or higher central activation (i.e. auditory, visual, and olfactory cues). Parasympathetic cavernous *Corresponding author: (G.J. Christ) [email protected] 1740-6773/$ ß 2004 Published by Elsevier Ltd.
DOI: 10.1016/j.ddstr.2004.08.023
Section Editor: David P. Brooks – Department of Renal and Urology Research, GlaxoSmithKline, King of Prussia, PA 19406-0939, USA The ‘‘discovery’’ that sildenafil, and subsequently vardenalfil and tadalfil, are effective in erectile dysfunction has revolutionized the therapy for this disorder, which had previously involved the use of surgically implanted prostheses or often painful penile injections of a vasodilator. The PDE5 inhibitors work by inhibiting the breakdown of cyclic GMP, the cellular mediator of nitric oxide. Although extremely effective in a large proportion of patients, there remains a group of patients for whom this class of agents is less effective or contraindicated. Christ and his colleagues in NY have been leaders in investigating novel targets and strategies for this disorder.
(see ‘Glossary’) nerves release nitric oxide (NO), causing relaxation of the sinusoidal arterial and corporal smooth muscle cells (see ‘Glossary’) and thus increased penile blood flow [5,6]. The increased pressure from the expanded penile blood flow leads to compression of the emissary veins draining the corpora and causes penile engorgement and a rigid erection [7]. The pathophysiological basis of erectile dysfunction is clearly diverse. Despite the potentially large numbers of physiologic deficits that can contribute to ED, the etiology of ED in the vast majority of impotent men is probably related to relatively subtle alterations in the effects of endogenous contracting and relaxing pathways on the corporal and arterial smooth muscle cells. In fact, it is thought that ED most frequently results in heightened contractility, impaired relaxation or both [8]. In this scenario, the treatment possibilities are enormous. Phosphodiesterase (PDE)5 inhibitors are excellent therapy for the treatment of ED and represent the current first-line www.drugdiscoverytoday.com
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Glossary Angiogenic: increases new blood vessel formation. Chondrocyte: a cell type found in cartilage. Corporal sinusoids: the trabecular mesh-work structure formed by the corporal smooth muscle cells and collagen matrix. The corporal sinusoids serve as an expandable reservoir for the blood originating from the helicine arterioles within the tissue proper. Corporal smooth muscle cells: specialized vascular smooth muscle cells that regulate blood flow into and out of corporal sinusoids during flaccid and erect states. Corpus cavernousum: the singular term for one of the two parallel tube-like vascular tissues that run the course of the penis. The corpus cavernosum is enclosed in a connective tissue sheath called the tunica albuginea. Hypercholesterolemia: abnormally high levels of cholesterol in the blood. Parasympathetic cavernous nerves: branches of the pelvic plexus that innervate the penis and are responsible for tumescence. Sinusoidal endothelium: a monolayer of endothelial cells lining the corporal smooth muscle cells in the penis. Venous leak: abnormal venous outflow from the corpora cavernosa preventing a rigid erection. In many cases, incomplete relaxation of the corporal smooth muscle cells prevents trapping of blood in the penis (via compression of the veins against the tunica albuginea).
treatment option. Nonetheless the success of PDE5 inhibitors, and their popularity has focused attention on an increasing group of patients who are dissatisfied with current therapies. Sources of dissatisfaction include the irreversibility of surgical treatments (i.e. penile prosthesis), the general aversion to penile injection (with alprostadil), the medical contraindications of PDE5 inhibitors and the lack of spontaneity associated with virtually all of these treatment options (i.e. the need to plan for intimacy). To improve efficacy and to make treatment options more ‘user friendly’, we envision
three main areas in which novel therapeutic strategies will be developed: (1) improved pharmacotherapy, (2) tissue regeneration or tissue engineering, and (3) cell and gene transfer (Table 1).
Pharmacotherapy The enhancement of the extant physiologic pathways that mediate the erectile response is the most frequent strategy employed for the treatment of ED. Current FDA-approved therapies are largely targeted to the end organ (the penis), but more targets in the central nervous system (CNS) (the brain) are anticipated in the future (Fig. 1). Three PDE5 inhibitors (sildenafil, vardenafil and tadalafil), and prostaglandin E1 (alaprastodil) have been approved by the FDA to date [9].
End-organ pharmacotherapy PDE5 inhibitors
During sexual activity, nitric oxide is released from the cavernous nerves and activates soluble guanylyl cyclase, which in turn raises intracellular cGMP levels [10]. Activation of cGMP-dependant protein kinase (PKG) results in multiple intracellular changes, with a primary end result being a lowering of free intra-cytosolic calcium levels that starts smooth muscle relaxation. PDE5 inhibitors block the degradation of cGMP within the corpora cavernous tissue, thereby promoting smooth muscle relaxation in both the corpus cavernousum (see ‘Glossary’) and the surrounding vessels [11]. Increased dilation of the corporal sinusoids (see ‘Glossary’) increases blood flow to the penis, creating a more rigid erection. The efficacy and safety of oral phosphodiesterase inhibitors have made them an excellent first-line therapy for the treatment of ED.
Table 1. Comparison of the different therapeutic strategies to treat erectile dysfunction Pharmacotherapy
Regenerative medicine
Gene transfer
Pros
Oral, topical, intra-urethral and intra-nasal therapy
Options for medical therapy failures, congenital and traumatic defects
Restoration of erectile function, spontaneous erections
Cons
On-demand only
Lack of clinical studies
Lack of clinical studies
Latest developments
CNS directed therapeutics: apomorphine, PT-141a
Formation of corporal tissue in vivo using human cavernosal muscle and endothelial cells seeded on collagen matrices Recombinant VEGFb protein
Gene transfer: hSLOc, Ad/VEGFd, Ad/EC-SODe, Ad/PnNOSf, Ad/eNOSg, Ad/iNOSh, Ad/CGRPi, Ad/BDNFj, Ad/Rhok Cell-based therapy: endothelial cells with eNOS and myoblasts with iNOS
[24,25,27,28,30–33]
[34–50]
Penis directed therapeutics: alprostadil/topiglan (topical) References
[11,13,14,16–22]
a
Cyclic heptapeptide melanocortin analog. b Vascular endothelial growth factor. c Plasmid-derived (‘‘naked’’) DNA. d Adenoviral-mediated vascular endothelial growth factor. e Adenoviral-mediated extracellular superoxide dismutase. f Adenoviral-mediated penile nitric oxide synthase. g Adenoviral-mediated endothelial nitric oxide synthase. h Adenoviral-mediated inducible nitric oxide synthase. i Adenoviral-mediated calcitonin gene related peptide. j Adenoviral-mediated brain derived neurotrophic factor. k Adenoviral-mediated mutant RhoA kinase.
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Figure 1. Current and future strategies using pharmacotherapy.
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Prostaglandin E1 (PGE1)
PGE1 modulates cAMP systems; specifically, it activates the EP2/4 receptor on the corporal smooth muscle to increase the activity of adenylate cyclase and the accumulation of cAMP [12]. An increase in cAMP leads to a cascade of intracellular changes that culminate in decreased intracellular calcium, and in turn, in the relaxation of the corporal smooth muscle cells and an erection [13]. Delivery of PGE1 is limited to intracavernosal and transurethral mechanisms, which are successful but have high discontinuation rates because of discomfort, the pain of local injection or local fibrosis. Current research is directed at improving the delivery system, specifically on topical applications that represent a potentially exciting non-invasive method for the treatment of ED. Recently, a topical PGE1 with a transdermal penetration enhancer produced an adequate erectile response in an animal model [14].
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ing in the US. Although the clinical efficacy of apomorphine has been somewhat disappointing, this drug has clearly pointed to the tremendous potential of using CNS targets to moderate erectile function. Melanocortin pathway
Another potential target in erectile physiology/dysfunction being critically evaluated in the CNS are the melanocortins. Two agents that induce penile erection by CNS mechanisms are a-melanocyte-stimulating hormone (a-MSH) and oxytocin. Injection of these agents in the CNS of rat models indicates that supraspinal MSH and oxytocin receptors, as well as spinal oxytocin receptors, are involved in erectile function [8]. This concept has been further developed with an intra-nasal a-MSH agonist, PT-141, which in early trials appears to be a promising candidate for further evaluation as a treatment for ED [22]. Clearly, the melanocortin pathway promises to be a fruitful area of future investigation.
Dopaminergic pathway
The complexities of the modulation of erectile function by the CNS are beyond the scope of this report, but several excellent reviews are available (see [15]). Pertinent to this article is the fact that various areas of the cortex send impulses, depending on the source of stimulation, to the paraventricular nucleus and/or the medial preoptic area (MPOA) of the hypothalamus [16–18]. In fact, in both animals and humans, centrally mediated dopamine-induced penile erection involves the D1- and D2-like receptors [19]. Manipulation of the MPOA has not yet advanced past the preclinical research stage, but already, numerous clinical trials have examined apomorphine hydrochloride, a non-selective dopaminergic receptor agonist that activates D2-like receptors [20,21]. Apomorphine hydrochloride has been approved in Europe and Japan for the treatment of ED and has been withdrawn pending a new-drug application and further test-
Tissue regeneration or tissue engineering If damage to the cavernous nerves or corporal tissue has been caused – for example, by trauma, pelvic surgery, pelvic irradiation or congenital defects – then the response to any current ED treatment might be incomplete. The technologies of regenerative medicine, that is the repair or replacement of damaged tissues, cells or organs, have been applied to ameliorate these conditions and hence to treat ED (Fig. 2).
Tissue regeneration Neural auto transplantation
Injury to the cavernous nerves resulting from radical pelvic surgery, irradiation or perineal trauma is a common cause of erectile dysfunction [23]. In the rat, a large single ganglion, the major pelvic ganglion, represents the pelvic plexus, which innervates the penis, prostate and rectum [24]. When
Figure 2. Strategies using regenerative medicine to treat erectile dysfunction.
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the major pelvic ganglion was auto-transplanted into the corpus cavernousum of the penis, it survived for up to 90 days and showed good expression of nitric oxide synthase, protein gene product 9.5 and growth-associated protein 43 [25]. Even though electrostimulation of the transplanted ganglion was unable to produce a full erection, it appears that the sinusoidal structure of the corpus cavernousum with its extensive blood supply might be a suitable host for transplanted neural tissue. Furthermore, the syncytial corporal smooth muscle cell network, which is provided for by intercellular communications through gap junctions, might require only modest innervation density [26]. On the basis of these promising results, the potential ability of fetal neuron transplantation to repair injured nerves warrants further studies. Cavernous muscle cell auto transplantation
Autologous endothelial cells transplanted into the corpus cavernousum of a rat model were shown to adhere to the sinusoidal endothelium (see ‘Glossary’) for up to two weeks [27]. The ability to auto-transplant endothelial cells further opens the possibility of cell-based gene transfer. In theory, one could expose cells to genetic therapy ex vivo, and then reimplant these cells for treatment of ED. In preliminary studies, the penis appears to be a suitable host for auto-transplantation of neurons as well as of corpus cavernousum endothelial cells [25,27].
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would be a functional, non-imunogenic, biocompatible material. Autologous tissue engineering with human cavernosal smooth muscle and endothelial cells seeded on acellular matrices can form tissue structures (in vivo, ex situ) that mimic corporal tissue [31]. Recently, Falke et al. [32] were also able to demonstrate that engineered corporal cavernosal tissue was able to maintain erectile function in a rabbit model. The use of autologous-engineered functional tissue replacement for the reconstruction of penile defects seems promising. Autologous tissue engineered penile prosthesis
Penile prostheses are mechanical devices developed in the 1970s that permit excellent penile rigidity and are usually reserved for patients who fail medical therapy. However, biocompatibility has been a problem for several patients and autologous tissue engineering has been investigated as a possible route to eliminating this problem. Kim et al. [33] demonstrated that a natural penile prosthesis could be created from chondrocytes (see ‘Glossary’) isolated from the human ear. The chrondrocyte cells are expanded in culture on a rod-shaped polymer scaffold. Transplantation of the chondrocytes resulted in well-formed, milk-white cartilaginous rods. After approximately two months, the rods displayed comparable mechanical properties to the silicone prostheses used today. The preliminary results have significant potential in treating some of the most difficult cases of ED.
Intra-corporal injection of vascular endothelial growth factor (VEGF)
Gene transfer
Following castration, animals develop venous leak as a result of decreased testosterone [28]; and men often develop venous leak (see ‘Glossary’) following radical prostatectomy surgery (50% display venous leak) [29]. Rogers et al. [28] demonstrated that the administration of VEGF as a recombinant protein to castrated rats was able to produce erectile function and prevent venous leak through its angiogenic (see ‘Glossary’) and androgen-mediated effects [28]. Moreover, there was evidence of the restoration of neural and smooth muscle tissue, as well as of hyperplasia and hypertrophy of endothelial cells, in these rats. Recombinant VEGF protein could conceivably be useful in the treatment of post-radical prostatectomy patients who have a venous leak.
Gene transfer is an exciting potential modality for the restoration of erectile capacity by altering the molecular mechanisms involved with erectile physiology and dysfunction. The penis’ location outside the body makes it easily accessible for targeted injectable gene transfer. Current strategies are directed at over-expression of endogenous components of existing pathways to increase corporal and arterial smooth muscle relaxation, and thus promote erection (Fig. 3).
Tissue engineering Engineered autologous corpora cavernosal tissue
ED patients who have congenital defects, traumatic injuries, or corporal fibrosis of the penis respond poorly to medical therapy, and sometimes penile reconstruction is required [30]. The limits of tissue reconstruction are imposed by the low availability of existing penile tissue. However, reconstruction of the penis with non-functional materials will most probably leave the patient impotent. The ideal material
Nitric oxide synthase (NOS) isoforms One application for gene transfer that is being pursued actively is the over-expression of nitric oxide synthase (NOS), the main neurotransmitter in a normal erection. In the rat, three known NOS isoforms have been used eNOS (the endothelial constitutive type), PnNOS (the penile-specific neural constitutive type) and iNOS (the inducible form) [34–39]. Over-expression of eNOS using an adenovirus (Ad) vector in the aged and diabetic (streptozotocin-induced) rat model produced an improvement in erections that lasted about one to two days [36,37]. Studies using iNOS-based gene transfer show effects as early as two days, lasting for approximately 10 days [35,38]. In these iNOS studies, three techniwww.drugdiscoverytoday.com
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Figure 3. Gene and cell therapy techniques to treat erectile dysfunction.
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ques were applied: myoblast-cell-mediated therapy [35], and plasmid- or adenovirus-based gene therapies [34,35,38]. The use of myoblast-cell-mediated gene transfer opens the door for cell-based gene transfer. Additional studies of the transfection of Plasmid/PnNOS and Ad/PnNOS into the corpus cavernosum of rats using a plasmid demonstrated a significant improvement in erectile function for up to 18 days following injection [39]. Overall, NOS replacement therapy has shown no significant systemic effects but has produced short-lived improvements in erectile function in various animal models.
Prepro-calcitonin gene-related peptide (CGRP) CGRP is a potent vasodilator that has been localized to the cavernous nerves, arteries and smooth muscle cells [40]. Its activity also leverages the cAMP pathway described earlier in the description of PGE1. Bivalacqua et al. [41] demonstrated a significant increase in erectile response to cavernosal nerve stimulation in the aged rat model five days after adenoviralmediated gene transfer of prepro-CGRP. On the basis of these findings, CGRP over-expression might represent a novel therapy for the treatment of ED.
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Vascular endothelial growth factor (VEGF) We mentioned earlier that intra-corporal injection of VEGF was capable of maintaining erectile function in an animal model of venous leak [28]. In the same study, animals treated with Ad-VEGF showed a high intra-cavernosal pressure response to papaverine. However, VEGF-gene-therapy produced a smaller physiologic response than intra-cavernosal injection of recombinant VEGF protein or testosterone-replacement therapy.
RhoA/Rho kinase pathway The RhoA/Rho kinase pathway plays an important role in both resting and stimulated corpora smooth muscle [46]. It has been hypothesized that transfection of corporal smooth muscle cells with a mutant RhoA kinase should promote relaxation by disrupting the tonic contraction pathway of the corporal smooth muscle cell. Gene transfer of a dominant negative RhoA mutant in an Ad vector was associated with a significant increase in erectile function in rats [47]. The duration of the efficacy was seven days without any evidence of systemic effects.
Ion channels Brain-derived neurotrophic factor (BDNF) Electron microscopy and histology of rats with hypercholesterolemia (see ‘Glossary’) and ED revealed damage to the endothelial cells, intra-cavernosal smooth muscle cells and dorsal and intra-cavernosal nerves [42]. In an attempt to compensate for these changes, Gholami et al. [42] assessed the efficacy of intra-corporal gene transfer following the administration of adeno-associated virus–brain-derived neurotrophic factor (AAV–BDNF). In this study, intra-cavernosal injection of AAV–BDNF preserved erectile function by qualitative preservation of nerves and smooth muscles. In short, these studies indicate that adenoviral-mediated gene transfer of BDNF appears to be a promising strategy for preserving the morphology of the endothelial cell and smooth muscle cells in animals with hypercholesterolemia.
Superoxide dismutase (SOD) Along with neural and penile tissue damage, vascular dysfunction contributes to the etiology of ED. Oxidative stress from the formation of reactive oxygen metabolites is a significant contributor to coronary vascular disease [43]. Bivalacqua et al. [44] found a threefold increase in super oxide formation in cavernous tissue from the penises of aged animals. On the other hand, SOD provides a major cellular defense against oxidative injury [45]. In an aged rat model, in vivo adenoviral gene transfer of extra cellular (EC) SOD resulted in a significant increase in erectile response to cavernosal nerve stimulation. SOD replacement therapy is a novel tool to repair the ravages of vascular disease and potentially to treat ED in the elderly population.
A complicated regulatory relationship exists in cavernous smooth cells among membrane potential, the activity of calcium-dependent potassium channels and voltage-activated calcium channels. Ion-channel gene transfer is currently directed toward increased expression of the large conductance calcium-sensitive K+ channel (Maxi-K). Increasing expression of the Maxi-K channel in corporal smooth muscle appears to increase the hyperpolarizing ability of the corporal smooth muscle cell network, thus increasing the responsiveness of the erectile apparatus to a potentially diminished supply of endogenous smooth muscle cell relaxants [48]. The main physiologic endpoint is the restoration of a degree of corporal smooth muscle relaxation, which is sufficient to result in normal penile erection in the absence of additional therapeutic modalities [49]. The efficacy of gene transfer with the Maxi-K channel has been shown to last for up to six months after a single intra-corporal injection [50].
Strategy comparison Increased understanding of ED has led to a better characterization of the plethora of pathophysiological mechanisms involved. As already documented by the popularity of PDE5 inhibitors, successful ED treatment can lead to far-reaching patient and partner satisfaction. Building on the success of the PDE5 inhibitors, future strategies will focus on the correction of altered pathways, the identification of appropriate molecular targets, and the restoration of erectile function using cell- and gene-based techniques, including regenerative medicine. Preclinical studies have already shown gene transfer to be an effective strategy for restoration of erectile funcwww.drugdiscoverytoday.com
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Related articles Lue, T.F. (2000) Erectile dysfunction. N. Engl. J. Med. 342, 1802–1813 Andersson, K.E. and Wagner, G. (1995) Physiology of penile erection. Physiol. Rev. 75, 191–236 Christ, G.J. (2004) Gene therapy treatments for erectile and bladder dysfunction. Curr. Urol. Rep. 5, 52–60 Yokoyama, T. et al. (2001) Gene therapy and tissue engineering for urologic dysfunction: status and prospects. Mol. Urol. 5, 67–70 Karicheti, V. and Christ G.J. (2001) Physiological roles for K+ channels and gap junctions in urogenital smooth muscle: implications for improved understanding of urogenital function, disease and therapy. Curr. Drug Targets 2, 1–20
tion, and a Phase I clinical trial is currently underway (for more details see: http://www.ionchannelinnovations.com/). With respect to gene transfer, local application of these agents ensures efficient delivery, and thus, might avoid many of the systemic side effects commonly associated with the administration of genetic materials. Therapies such as gene transfer and tissue regeneration/engineering that have the potential to restore function without the need for on-demand therapy appear to be the next revolution for ED therapy.
Conclusions The introduction of PDE5 inhibitors represents the beginning of a new generation of therapies, for which the standards of safety, efficacy and ease of use have been raised to a higher level. Novel and improved therapies for ED will undoubtedly come from an improved mechanistic and molecular understanding of erectile physiology and dysfunction. These therapies are probable to arise from three broad areas: (1) improved pharmacotherapy, (2) regenerative medicine, and (3) cell and gene transfer. Ultimately, it is envisioned that both polypharmacy and/or combination therapy of these three general therapeutic categories will be used to treat ED successfully. Outstanding issues Development of alternative treatments for patients in whom PDE5 inhibitors fail. Development of a mechanism-based, patient-specific treatment approach as a result of a better understanding of erectile physiology and pathophysiology. Development of treatments that focus on the restoration of endogenous erectile function, thereby eliminating on-demand therapy. Improvement of the selectivity and efficacy of central-acting pharmacotherapies. Apply technologies of regenerative medicine to restore erectile capacity in extensively damaged tissue.
References 1 NIH Consensus Development Panel on Impotence (1993) NIH Consensus Conference: impotence. J. Am. Med. Assoc. 27, 83–90 2 Benet, A.E. and Melman, A. (1995) The epidemiology of erectile dysfunction. Urol. Clin. North Am. 22, 699–709
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27 Wessells, H. and Williams, S.K. (1999) Endothelial cell transplantation into the corpus cavernosum: moving towards cell-based gene therapy. J. Urol. 162, 2162–2164 28 Rogers, R.S. et al. (2003) Intracavernosal vascular endothelial growth factor (VEGF) injection and adeno-associated virus-mediated VEGF gene therapy prevent and reverse venogenic erectile dysfunction in rats. Int. J. Impot. Res. 15, 26–37 29 Mulhall, J.P. and Graydon, R.J. (1996) The hemodynamics of erectile dysfunction following nerve-sparing radical retropubic prostatectomy. Int. J. Impot. Res. 8, 91–94 30 Atala, A. (2002) Tissue engineering perspectives for reconstructive surgery. In Campbell’s Urology (Walsh, P.C., Retik, A.B., Vaughan, E.D., Wein, A.J. eds), pp. 2593–2622, Saunders 31 Falke, G. et al. (2003) Formation of corporal tissue architecture in vivo using human cavernosal muscle and endothelial cells seed on collagen matrices. Tissue Eng. 9, 871–879 32 Kwon, T.G. et al. (2002) Autologous penile corpora cavernous replacement using tissue-engineering techniques. J. Urol. 168, 1754–1758 33 Kim, B.S. et al. (2002) Engineering of human cartilage rods: potential application for penile prosthesis. J. Urol. 168, 1794–1797 34 Garbon, H. et al. (1997) Cloning of rat and human inducible penile nitric oxide synthase. Application for gene therapy of erectile dysfunction. 35 Chancellor, M.B. et al. (2003) Nitric oxide synthase gene transfer for erectile dysfunction in a rat model. BJU Int. 169, 691–696 36 Champion, H.C. et al. (1999) Gene transfer of endothelial nitric oxide synthase to the penis augments erectile response in the aged rat. Proc. Natl. Acad. Sci. USA 96, 11648–11652 37 Bivalacqua, T.J. et al. (1999) Gene transfer of endothelial nitric oxide synthase partially restores nitric oxide synthesis and erectile function in streptozoocin diabetic rats. J. Urol. 169, 1911–1917 38 Tirney, S. et al. (2001) Nitric oxide synthase gene therapy for erectile dysfunction: comparison of plasmid adenovirus and adenovirus-transduced myoblast vectors. Mol. Urol. 15, 37–43
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