Cell therapies in hypoparathyroidism

Introduction

Attempts to transplant parathyroid glands began almost a cen­tury ago, only two decades after the organ had been discov­ered, with the demonstration by histologic means that canine parathyroid autografts survived. Graft function was as­sessed only fifty years later, with the demonstration that parathyroid transplanted tissue in rodents functions sufficiently to maintain the host in a normocalcemic state. However, parathyroid allografts were successful only in immunosup- pressed canine and human recipients. Indications for parathyroid allotransplantation are rare, as hy- poparathyroid patients who cannot be controlled on a medical regimen are also unusual. In these subjects the symptoms and associated complications of hypoparathyroidism cannot be controlled sufficiently with oral calcium and vitamin D. Due to these problems, alternate treatment modalities, involving more physiological and longer-acting systems for parathyroid hor­mone (PTH) delivery, needs to be pursued. Various methods of immunomanipulation have been proposed to overcome allograft rejection, which include immunosuppres­sion, immunomodulation and immunoisolation. By using the im- munoisolation concept the transplant is enclosed in a biocom- patible material to immobilize the transplant and at the same time preventing an immune response of the recipient. In 1964, T.M.S. Chang proposed the idea of using ultrathin polymer membrane microcapsules for the immunoprotection of trans­planted tissues and cells. When implanted into rats, the mi- croencapsulated pancreatic islets corrected the diabetic state for several weeks. Since then, bioencapsulation has provid­ed a range of promising therapeutic treatments for diabetes, hemophilia, cancer and renal failure. In addition, the ap­plicability of cell encapsulation in humans has also been report­ed in several clinical trials. Indeed, cell encapsulation in biocompatible and semipermeable polymeric membranes has been an effective method for immunoprotection, regardless of the type of recipient, as encapsulated cells can maintain their viability while allowing for the secretion of desired thera­peutic agents, either continuously or in response to specific physiologic stimulations.

Also for the treatment of refractory hypoparathyroidism, im- munoisolated allogeneic transplantation of parathyroid tissue is regarded as a promising therapy concept, which has been successfully applied in iso-, allo-, and xeno-transplantations in animals by using purified alginates. Alternatively, isolat­ed parathyroid cells are under investigation. Up to now, a substantial challenge has been the lack of clinical grade polymers and the demanding task is to accomplish spe­cific material requirements of high quality standards. By using homogeneous raw material and a standardized purification pro­tocol a new class of clinical grade biopolymers was developed which establish the basis for the clinical application of encapsu­lation technology. The batches of the purified alginate have to be standardized as for the endotoxin, protein and phe­nolic content and also for the physical properties such as the distribution of the molar mass and the viscosity. In the present study, we report in vitro data for the use of clini­cally suitable alginate-encapsulated human parathyroid tissue microspheres as a novel allo- and xeno-transplantation method for the delivery of PTH. online pharmacy store offers