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Behind The Science

XenoTherapeutics’ mission is rooted in the science of xenotransplantation, the discipline of transplanting the tissues or organs of one species into a different species, a concept proposed over a century ago. Terminally sterilized xeno-derived medical products have been used over the last several years in limited quantities (porcine heart valves, for example). However, there does not exist a widely used, FDA-approved medical device that utilizes the incredible potential of live-cell xeno technology to treat human patients. The xeno products on the market today cannot vascularize and integrate into human bodies, rendering them extremely limited in their effectiveness and hindering incredible therapeutic possibilities. Xenotherapeutics seeks to eliminate this critical deficiency by developing Xeno-Skin, a first of its kind, live-cell skin tissue of specially bred porcine donors. Its first medical indication will be to treat human burn patients.

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Burn Injuries & Burn Care

Burn injuries are devastating and are associated with many debilitating outcomes including disfigurement, infection and even death, if not treated promptly and properly. The ultimate clinical treatment course for burns entails the early excision of burned skin tissue and rapid subsequent replacement with autologous skin grafts taken from unaffected areas of the patient's own body. However, in the most severe burns that penetrate deeply and cover more than 20% of the victim's total body surface area, the available supply of uninjured autologous tissue from the victim is significantly limited and its procurement from an unstable patient clinically inadvisable. Therefore an alternative method of temporary coverage to preserve barrier function is critical.1

In these extreme cases, the next best option to autologous grafting is temporary coverage of burn wounds. Currently, such temporary coverage is most often provided by human cadaver skin (allograft), a medium well accepted for its effectiveness in reducing morbidity and mortality of severe burns.2 While allograft ultimately does not survive indefinitely, its acceptable performance is principally due to its "live-cell" status, which allows for temporary vascularization between the graft and burn victim. This biologic barrier, albeit relatively short lived, has been shown to reduce patient mortality and comorbidities by preserving the skin's "natural" function, preventing fluid loss and subsequent hypovolemia, reducing exposure to foreign pathogens, limiting infection, and avoiding catastrophic homeostatic electrolyte and pH imbalances.3 While cadaver allograft survival rates vary per patient, they provide (on average) effective coverage until around post-operative day 8, when the wounds are often reassessed and dressings are changed.4 This window of coverage is a critical clinical advantage, and is far superior to that provided by all other terminally sterilized burn products commercially available today.

Unfortunately, while numerous surgical and critical reports highlight the effectiveness of human cadaver allograft, many experts simultaneously emphasize the paucity of supply, both in the U.S. and abroad.5 By its very nature, cadaver allograft can only be obtained from willing, clinically acceptable, deceased volunteers. Thus, a viable alternative with ample supply is highly desired. Such a material would have significant clinical impact worldwide. The impact could be increased even further with a product that could not only act as a replacement for, but also serve as a complement to cadaver allograft.

Xeno-Skin is uniquely designed to fill both the replacement and complementary roles. It does not crosssensitize the patient's inherent immune response to cadaver allograft.6 Thus, complementary use of Xeno-Skin with cadaver allograft can greatly extend the critical period of temporary coverage, allowing clinicians more time to effectively treat burn victims by giving patients more time to heal successfully. The aforementioned supply issues associated with allograft can also be addressed by Xeno-Skin, as the latter product can be safely and ethically produced in sufficient quantities and stored for any unexpected emergency.

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30 Years of R&D

Despite the clear need for a humanitarian product like Xeno-Skin and the natural physiologic similarities between swine and humans, xenotransplantation between the two species had previously been largely unsuccessful due to a key scientific roadblock: hyperacute rejection of the porcine donor graft. This heightened immunological reaction was an instinctive, intrinsic response of the preformed antibodies in the human recipient to the α-1,3 galactose (Gal) moiety found on the cell surface of all membranes and tissues in nearly all other species, including swine. However, over the past 30 years Dr. David Sachs and his team at the Transplantation Biology Research Center (TBRC) at Massachusetts General Hospital (MGH) have developed a specialized breed of genetically modified miniature swine. They purposely removed the offending Gal antigen, making xenotransplantation without hyperacute rejection a reality. Dr. Sachs, a world renowned physician and scientist, who famously discovered the MHC Class II molecule, an early breakthrough in Immunology, is the recipient of numerous awards for his lifetime contributions to the field of transplantation, including the prestigious Thomas Starzl and Medawar Prizes (2012 and 2014 respectively). He now serves as Chief Scientific Advisor to XenoTherapeutics.

The skin of donors from this specialized line of swine has already been tested successfully in several nonhuman primate models.7 Thus, the next logical step is a human clinical trial aiming to demonstrate the safety and efficacy of this humanitarian device to the Food and Drug Administration (FDA). Fortunately, swine and human share few pathogens in common, reducing disease transmission risks, especially compared to potential contamination associated with human derivative products like cadaver allograft.

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Safety Considerations

Though safety concerns are lessened, there are still a few to be addressed before an FDA approved clinical trial can commence. In the 1990s, the momentum of xenotransplantation was temporarily halted with the discovery of PERV, a porcine retrovirus, which at the time was feared to share characteristics with Human Immunodeficiency Virus (HIV). Several studies were commissioned in the late 1990s and early 2000s; their published results found no evidence that the virus could produce infectious particles in other species.8 To date, there has still been no record of a PERV infection episode in a human subject exposed to porcine tissues.9 In fact, retrospective surveys of approximately 200 patients treated with living porcine tissues have not revealed evidence of in vivo PERV infection.10 Dr. Jay Fishman of Massachusetts General Hospital is a world-renowned expert in the field of infectious disease and has extensive experience conducting PERV-related research; he is the author of the World Health Organization’s guidelines for addressing PERV. He has summarized his findings as follows: “The risk of xenogeneic infection will never be zero. Routine microbial surveillance of source animals can now exclude many potential human pathogens. Data generated over the past years suggest that the risks of human infection resulting from xenotransplantation are manageable and that the spread of infection to contacts of the xenograft recipient appears to be unlikely.”11. Despite these findings, achieving market entry for live-cell xeno products will require demonstrating to the FDA that PERV represents either an insignificant or acceptable risk to human patients – a principle aim of XenoTherapeutics’ proposed human clinical trial.

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The Promise of Xeno

Looking ahead, the same basic biologic processes that make Xeno-Skin an ideal augment to the treatment of severe burns are also applicable to treat another growing epidemic both in the US and abroad: chronic wounds. We envision that our next frontier will be the utilization of Xeno-Skin to treat diabetic foot ulcers and other growing wound maladies. The potential impact of this groundbreaking product does not stop there. According to the U.S. Department of Health and Human Services, a new person is added to the transplant list every 10 minutes, while approximately 22 Americans die each day waiting for a transplant that is never performed due to a critical shortage of transplantation material.12 Successful use of Xeno-Skin, a live-cell xeno-derived product, will help pave a regulatory for other xeno-solutions and offer hope to patients in need solid organ transplants. This problem is not limited to the United States; a dearth of life-saving transplantable organs exists globally. XenoSkin will serve as a catalytic proof of principle for the clinical reality of xenotransplantation.

References

1 Jones I, Currie L, and Martin RA guide to biological skin substitutes. Br. J. Plast. Surg. 55: 185, 2002 and Saffle JR. Closure of the excised burn wound: temporary skin substitutes. Clin Plast Surg. 2009 Oct;36(4):627-41.
2 Tzeng YS, Chen SG, Dai NT, et al. Clinical experience using cadaveric skin for wound closure in taiwan. Wounds. 2012 Oct;24(10):293-8 and Hamilton KT, Herson MR.. Skin bank development and critical incident response. Cell Tissue Bank. 2011 May;12(2):147-51.
3 Jones I, Currie L, and Martin RA guide to biological skin substitutes. Br. J. Plast. Surg. 55: 185, 2002 and Saffle JR. Closure of the excised burn wound: temporary skin substitutes. Clin Plast Surg. 2009 Oct;36(4):627-41.
4 Hamilton KT1, Herson MR.Skin bank development and critical incident response. Cell Tissue Bank. 2011 May;12(2):147-51 and Tzeng YS1, Chen SG1, Dai NT1, Fu JP1, Chang SC1, Deng SC1, Lin FH2, Chen TM3.Clinical experience using cadaveric skin for wound closure in taiwan. Wounds. 2012 Oct;24(10):293-8.
5 Schaffer,A. Cadaver skin fills the gap in burn cases. The New York Times. 2006 May 2. http://www.nytimes.com/2006/05/02/health/02skin.html?n=Top%2FReference%2FTimes%20Topics%2FSubjects%2FS%2FShortages&_r=0; Stewart E. Skin donation shortage leaving bushfire victims at risk, tissue bank warms. Australian Broadcasting Corporation. 2016 January 11. http://www.abc.net.au/7.30/content/2015/s4386733.htm.
6 Albritton A, Leonard DA, Leto Barone A, Keegan J, Mallard C, Sachs DH, et al. Lack of cross-sensitization between a- 1,3-galactosyltransferase knockout porcine and allogeneic skin grafts permits serial grafting. Transplantation 2014;97(12):1209–15.

7 Albritton A, Leonard DA, Leto Barone A, Keegan J, Mallard C, Sachs DH, et al. Lack of cross-sensitization between a- 1,3-galactosyltransferase knockout porcine and allogeneic skin grafts permits serial grafting. Transplantation 2014;97(12):1209–15; Barone AAL, et al. Genetically modified porcine split-thickness skin grafts as an alternative to allograft for provision of temporary wound coverage: preliminary characterization. Burns. 2015; 565-574 and Weiner J, Yamada K, Ishikawa Y, Moran S, Etter J, Shimizu A, et al. Prolonged survival of GalT-KO swine skin on baboons. Xenotransplantation 2010;17:147–52 and Holzer PW, Leonard DA, Shanmugarajah K, Moulton K, Kurtz J, Cetrulo CL, Sachs DH: Temporary coverage of wounds with fresh vs. frozen allograft and xenografts. Journal of Burn Care and Research, Submitted for publication in 2016.

8 The New Zealand Biotechnology Learning Hub. History of Xenotransplantation. December 7, 2011. http://biotechlearn.org.nz/themes/xenotransplantation_and_organ_donation/history_of_xenotransplantation
9 Martin SI, Wilkinson RA, Fishman JA. Genomic presence of recombinant porcine endogenous retrovirus in transmitting miniature swine. Virology Journal 2006, 3:1743-422 (http://www.virologyj.com/content/3/1/91).
10 Wilhelm M, Fishman JA, Pontikis R, Aubertin A-M, Grierson DS, Wilhelm FX. Susceptibility of Recombinant Porcine Endogenous Retrovirus Reverse Transcriptase to Nucleoside and Non-nucleoside Inhibitors. Cellular and Molecular Life Science, 2002, 59:2184-90.
11 Fishman JA. Screening of source animals and clinical monitoring for xenotransplantation. Xenotransplantation 2007, 14:349-352

12 U.S. Department of Health and Human Services. The need is real: data. OrganDonor.Gov: Donate the Gift of Life. Last Updated January 11, 2016. http://www.organdonor.gov/about/data.html