I. INTRODUCTION
Organ transplantation is the only curative treatment for end-stage organ failure or congenital abnormalities in many diseases. However, there are several critical problems that remain unsolved in clinic transplantation, for example, short preservation time of donor organs, immune rejections, toxicity and lifetime use of immune suppressive drugs. All of these factors hurts grafted organs, which resulted in damages of grafts, lost of functions of organs, and eventually lead to failure of transplantation. The transplant grafts suffer triple damages: First, organ injuries that occur before taking donor organs (warm ischemia injury) and during preservation at low temperature (cold ischemia injury). Second, organ injuries occur during transplantation (ischemia-reperfusion injury). Third, the foreign organs are rejected by recipient’s immune system after transplantation.
By using most advanced gene silencing technology, called small interfering RNA (siRNA) that is 1000-fold more potent than other clinically using methods, ToleroTech developed novel organ solutions that aim to improve life quality of graft recipients and increase graft survival in organ transplantation. These new solutions contain siRNAs that specifically inhibit molecules responsible for graft injury and immune rejections, therefore the siRNA solution will offer a practical alternative to i) prolong organ preservation time before transplantation; ii) prevent I/R injury during transplant operation; and iii) modify graft immunogenecity, and, hence, to improve graft quality and prolong graft survival.
The current market for organ solutions is over $300 million USD. siPerfuse Storagetm solution is predicted to potentially increase the storage life of an organ by at least 50%. Given the average storage lives are only 4-6 hours for hearts, 12-18 hours for livers and 20-24 hours for kidneys, an increase of 50% or greater represents a radical product improvement and competitive advantage. Ischemic siPerfusiontm will be developed to minimize the destructive effects of ischemia by silencing the relevant genes. The Transplantation siPerfusiontm solution will be developed to minimize apoptosis and maintain organ viability, again through silencing the appropriate genes. The fourth solution, Anti-Rejection siPerfusiontm, will be developed to maximize immune tolerance and minimize chronic rejection of the transplanted organ.
II. TOLEROTECH’S SIRNA SOLUTIONS
ToleroTech has developed 3 different siRNA solutions that solve different clinical problems in transplantation: 1) siRNA Solution I (siPreservationTM) for prolonging preservation times of donor organ; 2) siRNA Solution II (siIschemiaTM) for preventing ischemia-reperfusion injuries; 3) siRNA Solution III (siRejectionTM) for preventing graft rejection.
1. siRNA Solution I (siPreservationTM): Prolongation of organ preservation time before transplantation. This solution contains siRNA specifically targeting molecules responsible for tissue injuries. Preserving organs in this solution can prolong preservation times of donor organ. [read more]
2. siRNA Solution II (siIschemiaTM): Prevention of ischemia-reperfustion injury during transplantation. This solution blocks multiple signaling pathways including inflammation, apoptosis, cytokines, chemokines, Toll-like receptors, and transcription factors. This solution has been tested preventing ischemia-reperfusion injuries in various donor organs, such as livers, hearts and kidneys. [read more]
3. siRNA Solution III (siRejectionTM): Prevention of immune rejection after transplantation. This solution contains a group of siRNA that specifically silence immune genes. After preservation organs in siRejectionTM, immunogenecity of donor organ is significantly decreased. Thus this solution inhibits immune rejection-associated genes in donor organ therefore blocking donor immune cell-triggered rejection (ie., direct rejection pathway). Prevention of allogeneic heart and kidney transplantation was successful in animal models. [read more]
III. UNIQUENESS AND SIGNIFICANCE OF SIRNA SOLUTIONS
The ToleroTech’s siRNA solution uniquely possesses following advantages for clinic use and for business development.
1) The siRNA solutions are composed the most advance siRNA technology, the IPs are protects by 6 patent fillings.
2) The siRNA solutions dramatically improve graft function and increase transplant graft survival, having significance in health care and meeting great demands in transplant clinics.
3) The solutions I & II can prolong donor organ preservation time and prevent ischemia-reperfusion injury, thus are far superior to clinically using organ solutions, leading to replacement of the current market leaders.
4) The siRNA solution may expand donor sources and increase availability of donor organs, as a result of decreasing the sensitivity to ischemia injury of elderly and marginal donor organs that can not be used as suitable donor organs in clinic.
5) The Solution III may prevent immune rejections through immune modulation. Once immune tolerance established, the transplant patient will no longer need to use of immune suppressive drugs.
6) Solutions I, II, and III are ex vivo using devices thus will be less complexity in product development and should be fast in market launches.