Preclinical and preliminary clinical evaluation of genetically transduced dermal tissue implants for the sustained secretion of XXXX and interferon a.

@entity1 @entity32 @entity19 @entity1307 @entity915 @entity734 @entity454
UNASSIGNED: Protein drugs are currently delivered by bolus injection and although treatment frequently is successful, these methods also have major drawbacks, which call for the development of alternative technologies allowing prolonged delivery of these drugs. We developed a new ex vivo gene therapy platform called Transduced Autologous Restorative Gene Therapy (TARGT) for sustained long term production and secretion of autologous therapeutic proteins. A biopsy of dermal tissue taken from the @entity1 is transduced ex vivo with a viral vector encoding the required gene under a constitutive promoter. Following measurement of protein secretion ex vivo, the transduced dermal tissue is implanted back into the @entity1 , where it secretes the therapeutic protein into the circulation for several months or longer. A major hurdle to this approach is potential immunogenicity of the transduced tissue following implantation. In this paper we describe the preclinical and early clinical development of this technology, which allowed overcoming these hurdles. To that end, we have used the @entity734 ( @entity734 ) adenoviral vector with newly designed expression cassette containing genetic elements to optimize transgene expression. Moreover, we have developed procedures for TARGT tissue implantation, with measures to improve engraftment and reduce @entity32 and rejection. Implantation of @entity1 TARGT to immune-deficient @entity915 @entity19 indicated long-term production of active proteins in the blood. Preliminary results of a clinical trial from two @entity454 @entity1 , implanted with TARGTs expressing the @entity1 @entity1307 ( @entity1307 ) gene, demonstrated prolonged secretion with physiologic blood level of the hormone and Hemoglobin maintenance in the desired range, for a period of at least five months without exogenous @entity1307 administration. We believe that the TARGT technology has the potential to become a platform for the sustained delivery of therapeutic proteins in various clinical indications.
