Efficacy of Invitro Expanded Bone Marrow Derived Allogeneic Mesenchymal Stem Cell Transplantation Via Portal Vein or Hepatic Artery or Peripheral Vein in Patients With Wilson Cirrhosis
Efficacy of Invitro Expanded Bone Marrow Derived Allogeneic Mesenchymal Stem Cell Transplantation Via Portal Vein or Hepatic Artery or Peripheral Vein in Patients With Wilson Cirrhosis
Wilson's disease is an autosomal recessive genetically inherited disorder of copper
 metabolism, causing neurological, psychiatric and liver disease. The ATP7B gene on the 13th
 chromosome is responsible for the disease. Liver has a critical role on copper metabolism. It
 is the main site of copper accumulation and bile secretion is the only physiologic way of
 copper elimination. Due to defective production of ceruloplasmin which carries copper, wide
 amount of free copper precipitates throughout the body but particularly in the liver, eyes
 and brain. Patients are bound to lifelong chelating agents such as penicillamine, trientine
 and tetramine dihydrochloride. Unfortunately, these medications may cause severe side-effects
 such as hypersensitivity reactions, bone marrow suppression, auto-immune disease and
 sideroblastic anemia. Medical treatment of liver cirrhosis, the last stage of the illness
 that leads to morbidity and mortality in the Wilson Disease, is difficult. Liver
 transplantation is still the most effective treatment for the patients with liver cirrhosis
 in Wilson Disease. However, serious problems are accompanied with liver transplantation. Lack
 of liver donors, complications during and after the surgery, graft rejection and high costs
 are the main problems.

 There are cells in the human body that are capable to renew themselves and differentiate to a
 diverse range of specialized cell types. These are called "stem cells". Stem cells can be
 differentiated to specialized cells in appropriate medias in the laboratory. Recently, the
 differentiation potential of mesenchymal stem cells into hepatocytes is proved by
 demonstrating hepatocytes containing Y chromosome in the female who has had bone marrow
 transplantation from male donors. In many laboratory studies, it is observed that human bone
 marrow derived mesenchymal stem cells, transplanted to animals with induced liver damage,
 differentiate into the albumin producing hepatocytes without fusion. By these studies, it is
 understood that mesenchymal stem cells are more potent than other bone marrow elements in
 context of differentiation to hepatocytes. Even though the number of studies on human for the
 same purpose is few, findings are supporting those of animal experiments. Mesenchymal stem
 cells are non-immunogenic. Safety and feasibility of allogeneic transplantations between
 individuals without need of immunosuppressive drug regimen are proven. Proofs of correcting
 metabolic defects by this way are also presented in some publications. For the reasons
 mentioned above, allogeneic mesenchymal stem cell transplantation is a promising treatment
 modality especially for the hereditary metabolic diseases. By this way, non-immunogeneic
 mesenchymal stem cells which have healthy genetic structure, can manufacture the required
 enzyme, will be repopulated in the damaged tissue and contribute to the clinical improvement.

 In this study, mesenchymal stem cells will be derived from healthy volunteer donor's bone
 marrow and be expanded in-vitro, and then 1 million cells per kg will be infused to patients
 with liver cirrhosis related to Wilson disease, 50 million cells via hepatic artery and the
 remaining cells via peripheral vein. It is aimed to enable liver regeneration, decrease
 fibrosis rate, improve patient's health conditions, increase ceruloplasmin synthesis,
 ameliorate disorder of copper metabolism, decrease the need for chelating agents, increase
 living standards of patients, and prolong waiting time for liver transplantation. Finally it
 is aimed to establish a new and regenerative treatment protocol alternative to liver
 transplantation. For observation of clinical and laboratory improvement, patients are planned
 to be monitored by histopathologic examination of liver biopsies before and at 6th month
 after the treatment, monthly biochemical and hematologic blood tests and periodic radiologic
 examinations. This is a hopeful, avant garde and sophisticated study which may constitute new
 horizons in context of cellular therapies.
Inclusion Criteria:

 -  Clinical, radiologic and pathologically proven Wilson's Disease with hepatic
 presentation

 -  Patients with no hepatic malignancies

 -  No co-existing serious respiratory and/or cardiovascular morbidities

 -  Patients who approved to join the study group with informed and written consent

 -  Patients with platelet count more than 30.000/mm3

 Exclusion Criteria:

 -  Clinical diagnosis of Wilson's Disease with neuropsychiatric presentation

 -  Current alcohol consumption

 -  Patients who have acute or chronic viral hepatitis infection