Dysfunction Therapy Trials

Dysfunction Therapy Trials

response. Additionally, naked DNA does not cause Because of limitations of current ED therapies, there

an allergic or immune response as witnessed with is a clinical demand and a scientific interest in gene

viral vectors, and it is not integrated into host transfer therapy for ED. The safety and efficacy of

chromosomes.

many of the vectors used to allow for delivery of the The preclinical evidence employing the maxi-K gene of interest is of paramount importance to the

vector injected intracavernosally as naked DNA has regulatory bodies. These concerns, for the most part,

demonstrated efficacy and long duration of action in have limited the widespread application and pro-

both diabetic and aging rat model experiments gress in the field of gene therapy for ED. (Table 10.2).

At the time of writing, there is only one ongoing The USFDA approved a human trial studying human clinical trial of gene transfer for the treat-

hSlo maxi-K under an investigational application in ment of ED [18]. The group from Albert Einstein in

August 2003. A phase I sequential dosing trial was New York City has exploited the mechanism of

initiated in early 2004 and enrollment has proceeded action of ion channels over the last decade.

slowly, mainly because of the unknown issues of Unlike gene transfer therapy for cancer, where

gene therapy.

100% of the cells must be affected, only a small per-

A total of 15 men were screened for this trial and centage of cells in the corpora need to be transfected

the preliminary results after transfer in six men at with the gene of interest in order to obtain the

two dose levels was recently published [18]. At this desired erectile response. Because of gap junctions, a

time, three dose levels (500, 1000, and 5000 mg) small stimulus can be rapidly propagated from cell to

were administered into three groups of men each cell in a collective syncytial response. This has rele-

[22]. Preliminary data has revealed no gene trans- vance in a number of clinical situations (e.g. radical

fer-related serious adverse events in any of the trial prostatectomy and diabetes mellitus) where the

participants. There has been no evidence of trans- neural signaling may be impaired, but the local

fer of any hSlo maxi-K into the semen as measured cavernous response may be intact.

by polymerase chain reaction analysis (an impor-

Future Treatment Aspects of Erectile Dysfunction: Gene Therapy and Tissue Engineering 119

Table 10.3 Gene therapy approaches for the treatment of ment options for penile deformation and erectile dys- erectile dysfunction.

function. Eur Urol 2004;46:162. 2 Kwon GK, Yoo JJ, Atala A. Autologous penile corpora

• NO/cGMP System cavernous replacement using tissue engineering tech- • Ion Channels and Gap Junctions

niques. J Urol 2002;168:1754. • Control of Oxidative Stress

3 Atala A. Tissue engineering applications for erectile dys- • Growth Factors

function. Int J Impot Res 1999;11 (Suppl 1):S41. • RhoA/Rho kinase System

4 Falke G, Yoo JJ, Machado MG, Moreland R, Atala, A. • Stem Cells

Formation of corporal tissue architecture in vivo using human cavernosal muscle and endothelial cells seeded on collagen matrices. Tissue Eng 2003;9:871– 879.

tant requirement by the FDA). In the first two 5 Kershen R, Yoo JJ, Moreland RB, Krane RJ, Atala A. groups of 500 and 1000 mg (suboptimal dosing as

Novel system for the formation of reconstitution of per comparative rat model studies where 10–20-

human corpus cavernosum smooth muscle tissue in times higher doses were safely used for efficacy),

vivo. Tissue Eng 2002;8:515. there was no evidence of efficacy as determined by

6 Scollay R. Gene therapy: a brief overview of the past, the international index of erectile function (IIEF)

present, and future. Ann N Y Acad Sci 2001;953:26. and Rigiscan data. However, in the third group

7 Ferber D. Gene therapy. Safer and virus-free? Science (5,000 mg), one participant reported significant im- 2001;294:1638. 8 Azadzoi KM, Kim N, Brown ML, Goldstein I, Cohen

provement as per Q3 and Q4 of the IIEF at three RA, Saenz de Tejada I. Endothelium-derived nitric months after transfer. This benefit has been cor-

oxide and cyclooxygenase products modulate corpus roborated by his partner. These investigators plan

cavernosum smooth muscle tone. J Urol 1992; sequential instillations at two higher doses in the

near future. The efficacy and safety of this first gene 9 Lerner SE, Melman A, Christ GJ. A review of erectile transfer study will undoubtedly direct future re-

dysfunction: new insights and more questions. J Urol search efforts in the field of gene therapy for ED in

the years to come. 10 Bivalacqua TJ, Hellstrom WJ. Potential application of gene therapy for the treatment of erectile dysfunction. J Androl 2001;22:183.

Conclusion

11 Garban H, Marquez D, Magee T, Moody J, Rajavashisht T, Rodriguez JA, Hung A, Vernet D, Rajfer J, Gonzalez-

The past decade has seen an explosion of informa- Cadavid NF. Cloning of rat and human inducible penile tion regarding the physiology, pathophysiology, and

nitric oxide synthase. Application for gene therapy of pharmacology of the erectile mechanism. Creative

erectile dysfunction. Biol Reprod 1997;56:954. research in the coming decades will stimulate new

12 Gerlach JC, Zeilinger K. Adult stem cell applications in tissue engineering that will comple-

technology–prospects for cell based therapy in regener- ment our surgical reconstructive endeavors. The

ative medicine. Int J Artif Organs 2002;25:83. introduction of gene- and cell-based therapies for

13 Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, the treatment of ED will attract more scientific and

Douglas R, Mosca JD, Moorman MA, Simonetti DW, media attention. Though one may simplistically

Craig S, Marshak DR. Multilineage potential of adult codify a number of current gene-based approaches

human mesenchymal stem cells. Science 1999; (Table 10.3), only time and data generated from 284:143. 14 Van Damme A, Vanden Driessche T, Collen D, Chuah

human controlled trials will provide the answers. MK. Bone marrow stromal cells as targets for gene therapy. Curr Gene Ther 2002;2:195.

References

15 Stopeck AT, Vahedian M, Williams SK: Transfer and expression of the interferon gamma gene in human

1 Schultheiss D. Regenerative medicine in andrology: endothelial cells inhibits vascular smooth muscle cell Tissue engineering and gene therapy as potential treat-

growth in vitro. Cell Transplant 1997;6:1.

120 Chapter 10 16 Wessells H, Williams SK. Endothelial cell transplanta-

19 Christ GH, Rehman J, Day N, et al. Intracorporal injec- tion into the corpus cavernosum: moving towards cell-

tion of hSlo cDNA in rats produced physiologically based gene therapy. J Urol 1999;162:2162.

relevant alterations in penile function. Am J Physiol 17 Tirney S, Mattes CE, Yoshimura N, et al. Nitric oxide

1998;275 (2 pt 2): H600–8. synthase gene therapy for erectile dysfunction: com-

20 Melman A, Zhao W, Dzvies KP, Bakal PR, Christ GH. The parison of plasmid, adenovirus, and adenovirus-

successful long-term treatment of age related erectile transduced myoblast vectors. Mol Urol 2001;5:37.

dysfunction with hSlo cDNA in rata in vivo. J Urol 18 Melman A, Bar-Chama N, McCullough A, Davies K,

Christ G. The first human trial for gene transfer therapy 21 Christ GJ: Gene therapy treatments for erectile and for the treatment of erectile dysfunction: Preliminary

bladder dysfunction. Curr Urol Rep 2004;5(1):52–60. Results. Eur Urol 2005;48:314–318.

22 Melman A. Personal communication, August 2005.

CHAPTER 11

Vacuum Constriction Devices

Sidney Glina and Hartmut Porst

of its mechanism resulting in a more unnaturally