A humanized system for pharmacologic control of gene expression

  title={A humanized system for pharmacologic control of gene expression},
  author={Victor M. Rivera and Tim Clackson and Sridaran Natesan and Roy M. Pollock and Jane F. Amara and Terence P. Keenan and Shannon R. Magari and Tom Phillips and Nancy L. Courage and Franklin Cerasoli and Dennis A. Holt and Michael Z. Gilman},
  journal={Nature Medicine},
Gene therapy was originally conceived as a medical intervention to replace or correct defective genes in patients with inherited disorders. However, it may have much broader potential as an alternative delivery platform for protein therapeutics, such as cytokines, hormones, antibodies and novel engineered proteins. One key technical barrier to the widespread implementation of this form of therapy is the need for precise control over the level of protein production. A suitable system for… 

Enhancing biological therapy through conditional regulation of protein stability

  • S. Thorne
  • Biology
    Expert Reviews in Molecular Medicine
  • 2010
Recent advances in controlling the stability or function of proteins through the interaction of small-molecule effectors and fusion domains on the protein have raised the possibility that direct and highly specific external control of therapeutic protein function in humans will be feasible.

Pharmacologic control of a humanized gene therapy system implanted into nude mice.

In vivo experiments demonstrate precise in vivo control of protein expression from cells that are engineered to secrete human growth hormone (hGH) in response to stimulation by rapamycin.

Lentiviral Vector for Gene Transfer A Versatile Tool for Regulated Gene Expression, Gene Silencing and Progenitor Cell Therapies

This study demonstrates the applicability of HIV-1 based vectors as a basic research tool and a potential gene therapy vector, particularly for ex vivo approaches such as progenitor cell therapies.

A gene expression system offering multiple levels of regulation: the Dual Drug Control (DDC) system

This study demonstrates the feasibility of combining two discrete drug-regulated expression systems in a temporally sequential cascade, without loss of dynamic range of signal induction.

Gene transfer of a chimeric trans-activator is immunogenic and results in short-lived transgene expression.

It is demonstrated that intramuscular injection of plasmid or adenoviral vectors encoding rtTA-M2 in outbred primates generates a cellular and humoral immune response to this transcription factor, which prompts the development of new gene transfer vectors enabling safe and efficient pharmacologic gene regulation in clinic.

Regulated expression of adenoviral vectors-based gene therapies: therapeutic expression of toxins and immune-modulators.

This third generation TetON regulatable system, incorporating a doxycycline (DOX)-sensitive rtTA(2)S-M2 inducer and tTS(Kid) silencer, is non-toxic, relatively non-immunogenic, and can tightly regulate reporter transgene expression downstream of a TRE promoter from adenoviral vectors in vitro and also in vivo.

Regulated production of proteins from muscle using gene transfer: potential therapeutic applications

This review focuses on regulated gene therapy systems that are being evaluated for use in muscle, and discusses two classes of system: Those dependent on exogenously administered drugs and those dependent on endogenously produced metabolites.



Long-term production and delivery of human growth hormone in vivo.

It is demonstrated here that, on implantation, these clonal cell strains stably and reproducibly deliver pharmacologic quantities of protein for the lifetime of the experimental animals.

Human growth hormone as a reporter gene in regulation studies employing transient gene expression

The human growth hormone transient assay system is appropriate for analyses of regulation of gene expression and was utilized here to investigate the effect of the simian virus 40 enhancer on the herpes simplex virus thymidine kinase promoter and theeffect of zinc on the mouse metallothionein-I promoter.

Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line.

Together, the pBabe vectors and omega E cell line should prove useful in experiments where highest frequencies of gene transfer, or concomitant expression of several different genes within a single cell are required with minimal risk of helper virus contamination.

Molecular cloning and overexpression of the human FK506-binding protein FKBP

The complementary DNA and derived amino-acid sequences of human FKBP from Jurkat cells and also the efficient overexpression in Escherichia coli of fully active, recombinant human FkBP are reported.

T–cell mediated rejection of gene–modified HIV–specific cytotoxic T lymphocytes in HIV–infected patients

An immunotherapy trial in which individuals seropositive for human immunodeficiency virus receive CD8+ HIV–specific cytotoxic T cells modified by retroviral transduction to express a gene permitting positive and negative selection suggests that strategies to render gene–modified cells less susceptible to host immune surveillance will be required for successful gene therapy of immunocompetent hosts.

Creating conditional mutations in mammals.

Dimeric ligands define a role for transcriptional activation domains in reinitiation

It is reported that maintaining the transcription of endogenous genes in vivo, in both yeast and human cells, requires the continuous presence of the activation domain and the use of synthetic ligands as a transcriptional on–off switch represents a powerful means of controlling the transcription in vitro and in vivo.

A mammalian protein targeted by G1-arresting rapamycin–receptor complex

A mammalian FKBP–rapamycin-associated protein (FRAP) is isolate whose binding to structural variants of rapamycin complexed to FK BP12 correlates with the ability of these ligands to inhibit cell-cycle progression.

Signal transduction in T lymphocytes using a conditional allele of Sos.

It is demonstrated that membrane localization of Sos is sufficient for Ras activation in T cells and indicates that the role of Grb-2 is to realize the biologic advantages of linker-mediated dimerization: enhanced specificity and favorable kinetics for signaling.