Pre-clinical vs. clinical studies

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Fetal precursor cell transplantation has been used in clinical practice in its various forms for 95+ years, and enormous clinical experience has been accumulated in Germany, Switzerland, U.S.S.R., Peoples’ Republic of China, etc., on the basis of which certain facts have to be taken as ‘res ipsa loquitur’ today.


Since hundreds of thousands of patients have been treated by live cell transplantation, and millions of patients have been treated by lyophilized ‘cell-therapautica’ or by quickly frozen ‘celltherapeutica’, and by cells preserved by other methods, and every one of these various forms of fetal cell transplantation was originally developed by testing in vitro and on experimental animals, there is no need to start every time from ‘point zero’ by animal experimentation, when a new animal becomes a source of cell transplants.


The entire field of cell biology has developed on the basic premise that all eukaryotic cells are built and function according to the same laws.VI.BIBLIOGRAPHY [67] ‘Organospecificity’, that means that the principal cells of the same organ(s) or tissue(s) are the same or almost the same in Nature, regardless of species of origin, is another ‘res ipsa loquitur’. The entire development of ‘zellentherapie’ has been based on such essential data.


Likewise, U.S.FDA regulation of January 19, 2001 is treating all cell, tissue and organ xenotransplants together regardless of their animal source. This U.S. FDA regulation is tied to ‘Points to consider in human somatic cell therapy and gene therapy’ of 1991, that legalized human fetal tissue transplantation in U.S. and sanctioned the ongoing U.S. FDA approved clinical trial in the treatment of IDDM by human fetal islet cells. So U.S. FDA recognized that cell allo- and xeno-transplantation follow the same biological rules many years ago.


The review of respective medical literature in MEDLINE shows that different animals have been used as a source of cell xeno-transplants in the experiments with cell xeno-transplantation as a treatment of various diseases, such as mice, rats, rabbits, dogs, guinea pigs, cows, pigs, horses, fish, chickens, even wild animals, and no one considered it necessary to re-prove the effectiveness of the respective cells of each animal species by starting the research from the ground up, i.e. the concept of ‘organospecificity’ was tacitly accepted.


When we focus on islet cells, it has been learned that even quite distant non-mammal species, such as fish and chickens, maintain a carbohydrate metabolism relatively close to that of humans VI.BIBLIOGRAPHY [37], and that their insulin is practically the same as human. VI.BIBLIOGRAPHY [188] When the implanted islet cell xeno-transplants from whatever animal source lower the level of blood sugar in an experimental models of diabetes mellitus, that represents sufficient proof about their effectiveness in view of what has been known from the previous experience with other members of the animal kingdom (and that includes man).


The immunological issues were largely resolved at RITAOMH and other research institutes of U.S.S.R. while working with cell transplants of human, pig and cattle fetal origin, and the same rules were found to be applicable to those of rabbit fetal and neonatal origin, and apply to any other mammal or even vertebrate.


The above statement does not apply to the organ xeno-transplantation, where immunological problems remain formidable.


Transmission of infections seems to be a real problem of cell transplantation today, with one solution only: to use as a source of cell transplants only those members of animal kingdom that do not represent any danger of transmission of infections to humans. Human cadavers do not qualify for this purpose too well, while SPF (‘specific pathogen free’) animals are an excellent source, although difficult to produce and thereby expensive.


In vitro tests and experimental studies on laboratory animals with cell transplants of rabbit origin were done at RITAOMH more than 35 years ago. VI.BIBLIOGRAPHY [79, 83, 85, 94, 109] They followed similar studies done with bovine and porcine fetal cells and tissues, when cell xeno-transplantation was launched in U.S.S.R. in the 80-ies and developed into an approved therapeutic method. VI.BIBLIOGRAPHY [73, 109, 183] Insofar porcine fetal and neonatal cell and tissues is concerned, extensive work was done by two other top centers: the Republic's Transplantology Center in Riga (today Latvia) and the Republic's Research Center of Endocrine and Metabolic Diseases in Kiev (now Ukraine). These were again just a continuation of similar studies at RITAOMH with human fetal tissues in the 70-ies when cell allo-transplantation was developed into an approved therapeutic method. VI.BIBLIOGRAPHY [73, 109, 183]


Prior to our start of fetal cell xeno-transplant manufacturing, described in the section on ‘Manufacturing of fetal cell xeno-transplants’, internal ‘pre-production testing’ of ‘zero-series’ of various fetal cell transplants prepared from fetal and neonatal rabbits were carried out. VI.BIBLIOGRAPHY [191] All other fetal cell transplants listed VI.BIBLIOGRAPHY [111] were similarly tested. Studies by BCRO were done solely to work out the details of patented industrial technology of preparation of fetal cell transplants, and not to carry out formal pre-clinical studies, since after over 5,000 patients have been treated during the period of 10 years by cell xeno-transplants of rabbit neonatal and fetal origin by RITAOMH and IIBM/BCRO in Russia, and elsewhere (56 of them U.S. patients treated in U.S.A.), and adequate reports are available, this would have been pointless. VI.BIBLIOGRAPHY [71, 75, 81, 82, 95, 97, 98, 99, 100, 115]


After all, it is commonly known that the value of experimental studies in the field of fetal cell transplantation has been seriously questioned since it has been observed, for example, that many of the animals do have a spontaneous return of function of their islets after Streptozotocine induction of DM, which does not ever happen with diabetic patients. VI.BIBLIOGRAPHY [37]. Thus Russian and various foreign patients treated in Russia, U.S. patients, treated in U.S.A., patients from Qatar, treated in Qatar, Slovak patients treated in Slovakia during the development of the described in this text manufacturing method, have served as ‘human volunteers’, on whom fetal cell transplants of rabbit origin were tested, or actually used for treatment in a standard clinical manner without any ill effects.


In the field of cell transplantation (whether allo- or xeno-), the value of pre-clinical tests on laboratory animals can in no way be compared to the value of actual patient treatment, and particularly when the patient treatment has been going on for as long as 35 years. Under these circumstances the pre-clinical studies have become obsolete and immaterial, as the vast clinical experience can never be duplicated by any pre-clinical study. It is against any logic to start experimental work and clinical trials in countries such as Russia, where cell allo- and xeno- transplantation has been a standard clinical practice since 1984, or Germany where the same situation existed for five decades.


The rabbit insulin differs from the human one by just two aminoacids, and so should be as clinically effective as porcine used in human medicine.VI.BIBLIOGRAPHY [188] The rabbits do not have enough blood so that they were never used commercially for the production of biologicals in general, while just the opposite applies to pigs.


RITAOMH scientists found out that the histology of adult and fetal rabbit tissues varied noticeably, particularly when considering the proportion of the exocrine to endocrine portion of pancreas, and of the quantity of collagen fibers. While the method of tissue culture for adult rabbit tissues did not differ in principle from the method developed and used succesfully for bovine, porcine and human fetal source, the method of tissue culture for rabbit fetal tissues had to be changed, mainly by elimination of enzymatic dissolution of tissues. But the tissue cultures of both adult and fetal rabbit tissues were succesful, and the cultures were actively producing insulin by RIA testing.


The adult rabbit tissues were used as cell xeno-transplants at first, and in 1987 first two patients with diabetes mellitus were so treated.VI.BIBLIOGRAPHY [85] Subsequently RITAOMH switched to the fetal rabbit tissues in their clinical practice. Ultimately newborn rabbits were investigated by RITAOMH scientists as the animal source, purely for pragmatic reasons, since they were easier to get than fetuses, and since no difference was found in their characteristics, as compared with fetal rabbits, they were introduced into a clinical practice as an animal source for fetal precursor cell transplants of various endocrine organs. VI.BIBLIOGRAPHY [79, 83] The progress of this work with cell transplants of rabbit origin was followed internally within RITAOMH VI.BIBLIOGRAPHY [94], and was reported during U.S.S.R. and international meetings, and published.