180. Use of Skeletal Muscle for Regulated Expression of Parathyroid Hormone To Treat Hypoparathyroidism

Abstract

Hypoparathyroidism is a condition in which reduction of serum calcium levels causes muscle cramps and spasms, and in extreme cases seizures and death. Current treatment for hypoparathyroidism involves daily oral supplements of the vitamin D analog calcitriol. This treatment is able to control some of the symptoms, including hypocalcemia and hyperphosphatemia, but the associated hypercalciurea remains poorly controlled, and if left untreated can lead to renal failure. Recent clinical studies showed that daily subcutaneous injections of recombinant hPTH1-34 normalized both serum and urine calcium levels in hypoparathyroid patients. Two daily injections achieved better control over calcium levels and required a lower daily dose (Winer et al, J Clin Endocrinol Metab. 2003, 88(9):4214–20). While these results suggest a new option for treating hypoparathyroidism, this approach requires the delivery of high PTH doses at each injection time to maintain adequate circulating levels, increasing the risk of side effects. More frequent administration of lower doses requires multiple daily injections, thus raising patient compliance issues. Both of these problems could be addressed via a gene therapy approach in which an externally regulated PTH expression cassette was transduced into skeletal muscle, and induced with a small orally available molecule. Careful dosing of the amount of transgene and the inducer molecule could then lead to production of therapeutic levels of circulating hormone.