Transplantation can be a lifesaving treatment option but the immune system continues to pose the greatest challenge to transplantation becoming routine medical treatment, due to the rejection that occurs when the recipient’s immune system recognizes the transplanted organ as foreign.
The discovery of immunosuppressants (anti-rejection drugs) over 40 years ago, such as cyclosporine, has allowed survival of transplanted organs by preventing acute or early rejection. However, immunosuppressants fail to prevent the chronic or long-term rejection that occurs years after the initial transplantation procedure. About 40% of transplanted organs survive for no more than 5 years. Furthermore, immune suppression leads to significant undesirable side effects such as increased susceptibility to life-threatening infections and cancers because it is not specifically targeted towards the transplanted organs; rather, it indiscriminately and broadly suppresses immune function throughout the body.
New, focused therapeutic approaches are needed that modulate only the portion of immune cells that are involved in rejection of the transplanted organ, as this will be safer for patients than indiscriminate immune suppression. These approaches are referred to as immune tolerance. Therapeutically induced immune tolerance may not only be safer for patients, they could also potentially allow long-term survival of transplanted tissues and organs.
In the late 1990s, an academic research project on these approaches was being conducted at the Transplant Center in Loma Linda University (LLU). The project secured initial funding through grants from the Department of Defense (DOD), which was funding projects with high probabilities of commercialization and potential benefit to the DOD. The direct benefit in this case was for skin grafting for burn victims. Twenty years of research at LLU and an affiliated incubator led to a series of discoveries that have been translated into a large patent portfolio of therapeutic approaches, that may be applied to the modulation of the immune system to induce tolerance to self and transplanted organs.
We have an exclusive worldwide license for commercializing this nucleic acid-based technology called Apoptotic DNA Immunotherapy™ (ADi™), which utilizes a novel approach that mimics the way our bodies naturally induce tolerance to our own tissues (therapeutically induced immune tolerance).
While immune suppression requires continuous administration to prevent acute or early rejection of transplanted organs, therapeutically induced immune tolerance has the potential to retrain the immune system to accept the organ for longer periods of time. Thus, ADi™ may allow patients to live with transplanted organs with significantly reduced dependence on immune suppression.
This offering will be made only by means of an offering circular. An offering statement on Form 1-A relating to these securities has been filed with the U.S. Securities and Exchange Commission and has become qualified. The securities offered by Aditx Therapeutics, Inc. are highly speculative. Investing in shares of common stock of Aditx Therapeutics, Inc. involves significant risks. The investment is suitable only for persons who can afford to lose their entire investment. Furthermore, investors must understand that such investment could be illiquid for an indefinite period of time. No public market currently exists for the securities, and there can be no assurance that a public market will develop. For additional information on Aditx Therapeutics, Inc., the offering, risks, and any other related topics, please review the qualified Form 1-A offering statement that can be found at the following location: https://www.sec.gov/Archives/edgar/data/1726711/000161577418009881/s112809_253g2.htm
ADi™ utilizes a novel approach that mimics the way our bodies naturally induce tolerance to our own tissues. It is a technology platform which we believe can be engineered to address a wide variety of indications.
ADi™ includes two DNA molecules which are designed to deliver signals to induce tolerance. The first DNA molecule encodes a pro-apoptotic protein, which induces ‘programmed’ cell death. This is a core component of the technology because it is intended to greatly increase the recruitment of dendritic cells, which are implicated in regulating the immune system. The second DNA molecule encodes the protein of interest (guiding antigen), which is modified to promote a path of tolerance. The guiding antigen is intended to result in tolerance induction specific to the tissue where the protein is found.
ADi™ has been successfully tested in several preclinical models and its efficacy can be attributed to multiple factors:
The proof of concept experiment performed was a skin allograft transplantation procedure in which the donor skin was obtained from white BALB/c mice and transplanted to black C57BL/6 mice. The experiment was designed to address a more challenging scenario where the donor tissue was obtained from a donor which is genetically mismatched with the recipient.
Skin Grafting Facts:
Results shown are 5 weeks post-transplantation
Allograft has been completely lost, only the scab remains
Allograft not only survived, it remained fully functional with intact hair follicles from the white donor mouse
Skin allograft transplantation is one of the most stringent models of transplantation due to the immunogenicity (ability to provoke an immune response) of skin. In the proof-of-concept experiments, animals treated with immunosuppression alone lost the allograft in 21 days on average. Whereas, the addition of ADi™ technology to minimal immunosuppression resulted in a 3-fold increase in the longevity of the skin allografts (fully functional).
The ADi™ technology and its various components are protected by multiple families of patents and patent applications, including several U.S. and non-U.S. issued patents.
Currently, our patent portfolio licensed from Loma Linda University includes six (6) U.S. patents, three (3) U.S. pending patent applications, fifty-four (54) foreign patents, and twelve (12) foreign pending patent applications directed to ADi™ and related technologies. We also possess and/or in-license substantial know-how and trade secrets relating to the development and commercialization of our product candidates, including related manufacturing processes and technology. We plan to continue expanding and strengthening our IP portfolio with additional patent applications in the future.
ADi™ is a nucleic acid-based technology (e.g., plasmid DNA-based) which we believe selectively suppresses only those immune cells involved in the rejection of tissue and organ transplants. It does so by tapping into the body’s natural process of cell death (apoptosis) to reprogram the immune system to stop unwanted attacks on self or transplanted tissues. In short, it retrains the immune system to become accepting of the organ much like how natural apoptosis reminds our immune system to be tolerant to our own “self” tissues. Thus, ADi™ may allow patients to live with transplanted organs with significantly reduced dependence on immune suppression.
While efforts have been made by various groups to promote tolerance through cell therapies and ex vivo manipulation of patient cells (takes place outside the body typically requiring hospitalization), to our knowledge, we will be unique in our approach of using in-body induction of apoptosis to promote tolerance to specific tissues. In addition, ADi™ treatment itself does not require hospitalization, only an injection in minute amounts directly into the skin.
While immunosuppressants control acute rejection during the early time-period after receiving an organ, chronic rejection of the organ that occurs one or more years after the transplant procedure continues to pose a major challenge for organ recipients.
Chronic rejection has been likened to autoimmunity (a misdirected immune response that occurs when the immune system goes awry), where specific tissues in the transplanted organ are attacked by the immune system. In other words, chronic rejection may not be caused just by differences between the donor and the recipient, but rather by an immune response by the recipient to specific tissues in the organ. With ADi™’s ability to tolerize to specific tissues in a transplanted organ, it has the potential to reduce incidences of chronic rejection.
Moreover, preclinical studies have demonstrated that ADi™ treatment significantly and substantially prolongs graft survival, in addition to successfully “reversing” other established immune-mediated inflammatory processes.
Studies in animal models have shown that conditioning/desensitizing the animals to receive the transplant, prolongs the survival of the transplanted tissue or organ. These studies have used repeated exposure to low doses of protein components in specific organs to reduce immunologic recognition and attack on the transplanted organ.
Based on some of our data, we believe that with ADi™ treatment, recipients can be conditioned/desensitized ahead of transplantation, thereby retraining the immune system to more readily accept the organ and also reduce the levels of immunosuppressive drugs needed post-transplantation.
Studies have shown that hypersensitivity increases the rate of organ rejection. Hypersensitivity can occur in previously-transplanted patients, patients who have given birth, and patients who have previously received blood transfusions. With more than 116,000 patients on transplant waiting lists in the U.S. alone, hypersensitive patients have much lower chances at qualifying to receive organs due to their increased risk of rejection – even with immune suppression.
Sadly, transplanted patients have a probability of needing re-transplantation at some point due to eventual chronic rejection of their transplanted organ, with the possible exception of some newborn recipients. With increased incidence of hypersensitivity, these patients may never have the opportunity to receive another organ. Based on experimental data, we believe that ADi™ may have the potential to address this hypersensitivity issue providing these individuals better opportunities at receiving an organ transplantation.
Therapeutic products are typically administered systemically (i.e., by mouth in pill form or injected intramuscularly/intravenously). This requires repeated large doses of the drug to allow sufficient concentrations to reach the affected sites. ADi™ is a DNA-based product that can be injected directly into the skin where the target cells of the immune system reside, thereby significantly simplifying the delivery of the product and reducing the amount of product needed.
DNA-based products are generally considered safe. In fact, over the last twenty years, several DNA-based vaccines have been evaluated in clinical trials for cancer and infectious diseases and no severe adverse events have been reported. In addition, DNA-based products generally do not result in allergic responses, which lend themselves to repeat dosing as may be required by ADi™ based therapeutics.
ADi™ products are DNA-based and cost-effective to manufacture. Furthermore, DNA-based products are very stable and do not require adherence to cold chain (temperature-controlled) protocols for shipping. This also makes the product ideal for global distribution.
We believe that tolerance induction using ADi™ may potentially obviate the need for hospitalization because it can be simply injected into the skin. This approach reduces treatment costs and complexities in treatment delivery. The anticipated administration of ADi™ will include an initial priming regimen that will require injections administered once a week for several weeks. Thereafter, booster or maintenance doses will be provided on an individual basis as determined by immune and inflammation testing. ADi™ treatments will be significantly more convenient and comfortable for patients because they do not require removal of patient cells for ex vivo manipulation.
Our team of scientific experts and innovation commercialization entrepreneurs come from a variety of fields and backgrounds, with a collective experience that range from founding startup biotech companies, to developing and marketing biopharmaceutical products, to designing clinical trials, and management of private and public companies.
Dr. Bailey is an internationally recognized authority on congenital heart surgery and infant heart transplantation. His pioneering work in infant heart transplantation has enabled babies born with otherwise fatal heart deformities to be given a second chance at life and resulted in babies being added to the national organ transplant registry. He performed the first successful human-to-human heart transplantation in a newborn baby and has performed countless lifesaving procedures at Loma Linda University Children’s Hospital, where he served as Surgeon-in-Chief. Dr. Bailey retired from LLU in 2018 where he served as a distinguished professor of transplantation surgery and was part of the team that developed ADi™.
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