Gene therapy in urology initially focused on urinary tract malignancies such as bladder and prostate cancer. However, in the last half decade new research endeavors in tissue engineering, and gene and cell-based therapies, have become more widespread for the treatment of erectile dysfunction (ED). Tissue engineering aims to replace complete tissues or organs, while gene and cell-based therapies act at the cellular level to improve specific cellular and enzymatic functions.

Tissue engineering and erectile dysfunction

Various surgical techniques have been developed to restore genital abnormalities, e.g. epispadias, micropenis, penile carcinoma, genital trauma, corporal fibrosis, and Peyronie’s disease. In many of these cases there is a limited amount of cavernosal tissue and surgeons have relied on prosthetic devices to recover the patient’s erectile function.

Reconstruction of normal erectile tissue using autologous cells, derived from the patient’s own body, is an intriguing concept for the treatment of this severe form of erectile dysfunction (ED). Atala and colleagues have proposed a tissue regeneration approach that involves patching isolated cells to support structures that possess suitable surface chemistry for guiding cell reorganization and growth.

Initial experiments were performed in order to determine the feasibility of creating corporal smooth muscle and endothelial cells in vivo, using cultured human corporal smooth muscle cells seeded onto biodegradable polymers. Their results were confirmed with human corporal smooth muscle and endothelial cells seeded on acellular matrices processed from donor rabbit corpora cavernosa.

Three and six months after implanting these tissue-engineered constructs into the corpora cavernosa of the animals from which the respective cells had been harvested, animals with tissue-engineered corporal segments exhibited much better functional and morphologic results compared to unseeded control animals, as assessed by cavernosography cavernosometry, mating behavior, cell-specific immunochemistry, and Western blot analyses. Currently, this group has been working on engineering corporal tissue for the purposes of phallic reconstruction, and tunical tissue for reconstruction of severe cases of Peyronie’s disease.

Gene therapy and erectile dysfunction

Basic science research on erectile physiology has focused on the pathogenesis of erectile dysfunction and has provided convincing evidence that erectile dysfunction is predominantly a disease of vascular etiology. The oral phosphodiesterase-5 (PDE-5) inhibitors are uniformly recommended as first-line therapy because of their convenience and high rate of efficacy in a diverse population of erectile dysfunction patients. Unfortunately, not all erectile dysfunction patients benefit from PDE-5 inhibitor therapy, and the development of new approaches, including gene and cell-based therapies, is required.

Initially, gene therapy had been reserved for the treatment of life-threatening disorders, including cancer, hereditary and acquired diseases. Although there have been some concerns and regulatory changes due to the loss of a young volunteer who was treated with the intrahepatic administration of a recombinant adenoviral vector containing ornithine transcarbamylase in 1999, there are still hundreds of gene therapy trials being conducted worldwide. Gene therapy is an attractive therapeutic possibility for the treatment of erectile dysfunction (ED). A simple concept about erectile dysfunction is that in most men only a very small alteration in the balance between contracting and relaxing stimuli can cause significant effects on cavernosal and penile vascular smooth muscle tone. The penis is also a convenient tissue target for gene therapy because of its external location, the ubiquity of endothelial-lined spaces, and low level of blood flow.

The objective of gene therapy is to introduce new or repair damaged genetic materials (DNA or RNA) into the cells of a target (i.e. the penis) in order to recover the organ’s function.

The ideal vector for gene transfer is one that allows for efficient transduction and long-term stable trans-gene expression while having few or no adverse effects, such as risk of infection, immunogenicity, or host-cell mutagenesis. Various vectors, such as viral vectors (adenovirus, adeno-associated virus, adeno-myoblast, and retrovirus) and nonviral vectors (naked DNA, plasmid DNA, liposomes, and myoblastmediated), have been used to date for the transfer of genetic material to the target cell or tissue. Each has advantages and disadvantages with regards to their safety, efficiency, and immunogenicity.

The essential component of the mechanism for penile erection is cavernosal smooth muscle relaxation. Therefore all molecules and enzyme systems that are involved in signal transduction for either relaxing or inhibiting contraction of corporal smooth muscle are potential targets for gene therapy to the penis. Many research centers have conducted or are conducting studies to exploit this recognized mechanism.

Gene therapy can be divided into two simplistic strategies:

1 Increase the supply of stimulus, by increasing the expression of endogenous vasomodulators.

2 Alter the demand, such that the end organ or receptor becomes more sensitive to relaxatory stimuli. Therefore, gene therapy restores the normal  balance between contracting and relaxing stimuli to the cavernosal smooth muscle. Since the first preclinical study in an in vivo rat model using iNOS, a variety of gene therapy trials have been conducted for the treatment of erectile dysfunction (ED). Because of its significant role in the physiology of normal erectile function, many gene therapy studies have focused on the NO/GC/cGMP pathway. The rationale for this target is that overexpression of important endogenous cavernosal smooth muscle relaxants and vasodilators could assist with the diminished erectile response, as witnessed in men suffering from erectile dysfunction (ED). Follow-up approaches suggest other means of genetic manipulation: nerve and vascular growth factors, (e.g. brain-derivated nerve growth factor [BDNF], vascular endothelial growth factor [VEGF]), the cyclic adenosine monophosphate (cAMP) cascade (i.e. calcitonin gene-related peptide [CGRP] receptor), the calcium sensitization pathway, and K+ channel gene expression (a cellular convergence point for mediating the effects of all of the above).

Cell-based approaches and erectile dysfunction

One of the most important recent discoveries in biomedical research is that stem cells are found in many tissues of adults that can provide new cells for normal tissue turnover and can regenerate damaged and diseased tissue. Marrow stromal cells (mesenchymal stem cells) are adult stem cells from bone marrow that have multilineage differentiation potential and contribute to the regeneration of mesenchymal tissues, including bone, cartilage, muscle, and fat. As marrow stromal cells are relatively easy to isolate, expand ex vivo, and gene engineer, genetically modified marrow stromal cells with desired genes have recently been used for gene delivery and tissue regeneration in the treatment of various diseases, including erectile dysfunction, with little or no host immune response.

Another potential application for erectile dysfunction is the (re)-implantation of genetically modified cells into the corpus cavernosum. The aim is to seed the corpora cavernosa with cells having desired, genetically modified physiologic characteristics. Endothelial cells have the ability to adhere and self-aggregate once they are transplanted into another organ, such as the penis. Wessels et al. first demonstrated that autologous endothelial cells could be transplanted into the corpus cavernosum, and undergo cell adherence and persistence in the cavernosal sinusoids for up to two weeks and eventually become part of the sinusoidal lining of the penis. This is the basis for the rationale of cell-based gene therapy for the treatment of erectile dysfunction (ED). Studies have documented that muscle cell-mediated gene therapy was even more efficacious in delivering 1NOS into the corpus cavernosum. Transplanted cells are of considerable interest, and future studies using marker genes and functional transgenes will further our knowledge about the survival, replication, and function of endothelial cells within the corpus cavernosum.

Current Status of Human Erectile Dysfunction Therapy Trials

Because of limitations of current erectile dysfunction therapies, there is a clinical demand and a scientific interest in gene transfer therapy for erectile dysfunction (ED). The safety and efficacy of many of the vectors used to allow for delivery of the gene of interest is of paramount importance to the regulatory bodies. These concerns, for the most part, have limited the widespread application and progress in the field of gene therapy for erectile dysfunction (ED). (Table Gene therapy approaches for the treatment of erectile dysfunction).

Table Gene therapy approaches for the treatment of erectile dysfunction (ED).

Supply side

  • Increase NO
  • eNOS
  • nNOS
  • Superoxide dismutase
  • Increase nerve supply
  • BDNF
  • Increase vascular supply
  • VEGF
  • Increase CGRP

Demand side

  • Decrease amount of stimulus required for relaxation
  • Alter potassium/calcium channels (via hSIo)
  • Alter calcium sensitization (via RhoA)

At the time of writing, there is only one ongoing human clinical trial of gene transfer for the treatment of erectile dysfunction. The group from Albert Einstein in New York City has exploited the mechanism of action of ion channels over the last decade.

Unlike gene transfer therapy for cancer, where 100% of the cells must be affected, only a small percentage of cells in the corpora need to be transfected with the gene of interest in order to obtain the desired erectile response. Because of gap junctions, a small stimulus can be rapidly propagated from cell to cell in a collective syncytial response. This has relevance in a number of clinical situations (e.g. radical prostatectomy and diabetes mellitus) where the neural signaling may be impaired, but the local cavernous response maybe intact.

The vector that meets both efficacy and FDA safety requirements is the maxi-K methodology. Though naked DNA has poor transduction efficiency, only a small amount is needed for obtaining the required response. Additionally, naked DNA does not cause an allergic or immune response as witnessed with viral vectors, and it is not integrated into host chromosomes.

The preclinical evidence employing the maxi-K vector injected intracavernosally as naked DNA has demonstrated efficacy and long duration of action in both diabetic and aging rat model experiments.

The USFDA approved a human trial studying hSlo maxi-K under an investigational application in August 2003. A phase I sequential dosing trial was initiated in early 2004 and enrollment has proceeded slowly, mainly because of the unknown issues of gene therapy.

A total of 15 men were screened for this trial and the preliminary results after transfer in six men at two dose levels was recently published. At this time, three dose levels (500, 1000, and 5000mg) were administered into three groups of men each. Preliminary data has revealed no gene transfer-related serious adverse events in any of the trial participants. There has been no evidence of transfer of any hSlo maxi-K into the semen as measured by polymerase chain reaction analysis (an important requirement by the FDA), fn the first two groups of 500 and 1000 mg (suboptimal dosing as per comparative rat model studies where 10-20-times higher doses were safely used for efficacy), there was no evidence of efficacy as determined by the international index of erectile function (IIEF) and Rigiscan data. However, in the third group (5,000mg), one participant reported significant improvement as per Q3 and Q4 of the IIEF at three months after transfer. This benefit has been corroborated by his partner. These investigators plan sequential instillations at two higher doses in the near future. The efficacy and safety of this first gene transfer study will undoubtedly direct future research efforts in the field of gene therapy for erectile dysfunction in the years to come.


The past decade has seen an explosion of information regarding the physiology, pathophysiology, and pharmacology of the erectile mechanism. Creative research in the coming decades will stimulate new applications in tissue engineering that will complement our surgical reconstructive endeavors. The introduction of gene- and cell-based therapies for the treatment of erectile dysfunction will attract more scientific and media attention. Though one may simplistically codify a number of current gene-based approaches (Table Gene therapy approaches for the treatment of erectile dysfunction), only time and data generated from human controlled trials will provide the answers.

Table Gene therapy approaches for the treatment of erectile dysfunction.

  • • NO/cGMP System
  • • Ion Channels and Gap Junctions
  • • Control of Oxidative Stress
  • • Growth Factors
  • • RhoA/Rhokinase System
  • • Stem Cells


Selections from the book: “Standard Practice in Sexual Medicine”, edited by Hartmut Porst, Jacques Buvat, and The Standards Committee of the International Society for Sexual Medicine, 2006.

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