Disease treatment via developing non-syngeneic graft transplantation

a non-syngeneic graft and disease technology, applied in the direction of extracellular fluid disorder, prosthesis, drug composition, etc., can solve the problems of not satisfactorily preventing the debilitating and lethal consequences of diabetes, and not satisfactory/optimal treatment options, etc., to achieve effective/optimal treatment

Inactive Publication Date: 2015-01-08
YEDA RES & DEV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Pancreatic diseases such as diabetes, hematological / metabolic diseases such as hemophilia A and Gaucher disease, and pulmonary diseases such as lung failure are diseases of great medical and economic impact for which no satisfactory / optimal treatments are available.
Diabetes is a debilitating and potentially lethal disease that develops in nearly 5 percent of the world's population.
The standard therapy for diabetes, daily injections of insulin, does not satisfactorily prevent the debilitating and lethal consequences of this disease.
Pulmonary failure is a highly debilitating and potentially lethal affliction which can arise from numerous types of diseases, including cystic fibrosis, emphysema, pulmonary fibrosis or pulmonary hypertension.
While lung transplantation may be employed as a last resort for treating such diseases, there is an insufficient supply of donor organs, with one quarter of the candidates dying on the waiting list and the limit for inscription being often set at 60 years of age.
Due to the resultant clotting deficiency, those afflicted with the disease suffer severe bleeding episodes due to small injuries, internal bleeding, and joint hemorrhage, which leads to arthropathy, the major cause of morbidity in hemophilia.
Koepke, J. A., Churchill Livingstone, N.Y., pp: 347-371, 1990); however, patients suffering from mild to moderate hemophilia A typically have plasma levels well below 2-60 ng / ml, while levels below about 2 ng / mL result in severe hemophilia.
However, enzyme replacement therapy has numerous significant disadvantages, including the need to administer the replacement enzyme via injection, a painful, inconvenient, and expensive process.
The discontinuous dose administration of a replacement enzyme furthermore fails to achieve continuously adjusted physiological levels of the enzyme according to physiological need, as would be achieved by a normal enzyme producing cell population.
Thus, enzyme replacement therapy of hematological / metabolic diseases fails in many cases to achieve satisfactory / optimal disease treatment.
Such a treatment modality, however, suffers from considerable disadvantages.
Allogeneic transplantation of differentiated pancreatic or pulmonary organs / tissues is impossible to implement in a great many cases due to the unavailability of suitable immunologically matched transplant donors.
Furthermore, use of human donors to provide organs / tissues for transplantation often presents health risks and ethical dilemmas.
Thus, large numbers of patients who would otherwise benefit from therapeutic transplantation succumb to diseases associated with pancreatic or pulmonary failure while awaiting matched transplant donors.
Moreover, even when suitably haplotype matched transplant donors are found, permanent and harmful immunosuppressive treatments, such as daily administration of cyclosporin A, are generally required to prevent graft rejection.
Use of drugs such as cyclosporin A may be undesirable but the benefit of a life saving transplant outweigh the risk of immunosuppressive treatment.
Immunosuppressive therapy nevertheless is highly undesirable since these cause severe side effects such as carcinogenicity, nephrotoxicity and increased susceptibility to opportunistic infections.
Immunosuppressive treatments contribute to the drawbacks of allogeneic transplantation since these are often unsuccessful in preventing rejection in the short term, and are generally incapable of preventing rejection in the long term.
Acute rejection of transplanted grafts is often fatal.
However, to date, xenogeneic organ / tissue grafts have been ruled out for human transplantation due to their heretofore insurmountable immunological incompatibility with human recipients.
As described above, however, the state of the art of therapeutic transplantation generally remains associated with critical disadvantages.
However, all previous approaches involving transplantation of developing non-syngeneic pancreatic, pulmonary or lymphoid / hematopietic organs / tissues suffer from some or all of the following drawbacks:
(v) inadequate availability of transplantable organs / tissues; and / or
Previous approaches employing developing non-syngeneic grafts have been uniformly suboptimal since the optimal gestation time for implantation based on risk for teratoma, growth potential and immunogenicity, all of which might vary between different organs in fetal development, was not sufficiently characterized.

Method used

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  • Disease treatment via developing non-syngeneic graft transplantation
  • Disease treatment via developing non-syngeneic graft transplantation
  • Disease treatment via developing non-syngeneic graft transplantation

Examples

Experimental program
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Effect test

example 1

Miscellaneous Materials and Methods

[0171]Transplantation of fetal tissue under the renal capsule: Transplantation of a graft under the renal capsule may be desired for grafts other than renal grafts. Transplantation of fetal tissue under the renal capsule of recipient mice was performed as previously described (Dekel, B. et al., 1997. Transplantation 64, 1541-1550). Whole fetal human or porcine organs or whole or 1-2 millimeter-diameter fragments of tissues at later stages of gestation were used in transplantations. For growth assays, transplantation was performed 7-10 days following reconstitution of irradiated hosts with NOD / SCID bone marrow. Alternatively, fetal tissues were transplanted into SCID recipient mice. For transplantation, fetal tissues were maintained in sterile conditions at 4 degrees centigrade for approximately two hours in either RPMI 1640 or Dulbecco's modified Eagle's medium supplemented with 10 percent fetal calf serum (FCS; Biological Industries, Beit Haemek, ...

example 2

Transplantation of 12-16 Week Fetal Human and Animal Pancreatic Organ / Tissue Grafts into a Host

[0173]Fetal human or porcine organs / tissues transplanted into a host are capable of generating structurally and functionally differentiated, host-integrated organs / tissues optimally tolerated by alloreactive / xenoreactive human lymphocytes. Thus, while conceiving the present invention, it was hypothesized that transplanting fetal human or animal pancreatic organs / tissues harvested at a defined time window into a host will generate pancreatic organs / tissues displaying significant development, as follows.

[0174]Materials and Methods:

[0175]Donor pancreatic tissues: Human 12- to 16-week gestational stage pancreatic tissues were obtained following curettage, with warm ischemia time of less than 30 minutes. Following dissection, the pancreatic tissues were kept at 4 degrees centigrade in UW solution for less than 45 minutes in sterile conditions. The study protocol was approved by the hospital (Ka...

example 3

Generation of Diabetic Mice

[0183]Materials and Methods:

[0184]Diabetes is induced in mouse hosts by streptozotocin treatment, as previously described (Soria et al., 2000. Diabetes 49, 1-6) or by alloxan (reviewed in T. Szkudelski, 2001, Physiol. Res. 50: 536-546).

[0185]Briefly, diabetes is induced in mouse hosts via a single intraperitoneal injection of 200 milligram streptozotocin (Sigma) freshly dissolved in citrate buffer (pH 4.5) per kilogram body weight. Onset of diabetes is then confirmed and monitored by the presence of weight loss, polyuria, and blood glucose levels of less than 500 milligrams / dl. Blood for glucose tests is obtained by tail snipping and measured between 9 and 11 A.M. under non-fasting conditions and analyzed with a portable glucose meter. Two weeks following injection of streptozotocin, diabetic recipients are engrafted with donor pancreatic tissues, and glucose levels are monitored as described above in order to ascertain restoration of glycemic control.

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Abstract

A method of providing a pancreatic, lymphoid / hematopietic or pulmonary organ and / or tissue function to a mammalian subject is provided. The method comprises transplanting into the subject a developing mammalian pancreatic, lymphoid / hematopietic or pulmonary organ / tissue graft, respectively, thereby generating a functional pancreatic, lymphoid / hematopietic or pulmonary organ and / or tissue, respectively, for providing the pancreatic, lymphoid / hematopietic or pulmonary organ and / or tissue function, respectively, to the subject.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001]The present invention relates to methods of providing organ / tissue-specific functions to a subject by transplantation of developing organs. More particularly, the present invention relates to methods of treating pancreatic, hematological / metabolic and pulmonary diseases in mammals by transplantation of developing xenogeneic / allogeneic porcine / human pancreatic, lymphoid / hematopietic or pulmonary organs / tissues, respectively.[0002]Pancreatic diseases such as diabetes, hematological / metabolic diseases such as hemophilia A and Gaucher disease, and pulmonary diseases such as lung failure are diseases of great medical and economic impact for which no satisfactory / optimal treatments are available.[0003]Diabetes is a debilitating and potentially lethal disease that develops in nearly 5 percent of the world's population. In the United States alone, an estimated 18 million people have diabetes mellitus, and each year about 1 million Americans aged 20...

Claims

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Application Information

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Patent Type & AuthorityApplications(United States)
IPC IPC(8): A61K45/00A61P7/04A61K35/26A61K35/28A61K35/39A61K35/42
CPCA61K31/436A61K35/26A61K35/28A61K35/42A61L27/3641A61K35/39A61L27/3604A61P7/04A61K2300/00A61L2430/40
InventorREISNER, YAIRDEKEL, BENJAMINEVENTOV-FRIEDMAN, SMADARKATCHMAN, HELENASHEZEN, ELIASARONOVICH, ANNATCHORSH, DALIT
OwnerYEDA RES & DEV CO LTD