Several trends have been identified:
a) Breakthroughs in controllable gene therapy technology have allowed therapeutic transgene expression to be regulated with precision over a period of months to years. The technology features low baseline transgene expression, a high induction ratio, and control via an orally available, cell permeant small molecule. Feasibility has been established in a series of elegant studies that employ recombinant adeno-associated viral (rAAV) vectors. These breakthroughs are unique to gene therapy, i.e., similar levels of pro-drug stability and control simply do not exist for more traditional drug substances (small molecules, peptides, and proteins).
b) One may see enormous improvements in patient care pathways. For diabetes and other endocrinopathies, the standard of care may change from "multiple daily injections" to a "single injection of gene therapy followed by ingestion of multiple tablets each day." Drug therapy could truly be personalized: once individual disease patterns are established (e.g., via sensor technology), the patient and physician could work together to develop a rational, personalized regimen of small molecule administration that would be expected to yield improved compliance and better control of disease; this in turn should lessen the cost of disease to U.S. society.
c) Given the availability of a panel of cell-permeant small molecules, gene therapy becomes a combined validation/development platform in which the therapy is a stable pro-drug that remains controllable for years following initial injection of tissues such as skeletal muscle. The small molecule panel would likely form an important core element of a company's intellectual property.
d) Given the biological and technological complexity associated with genome analysis technology, an interdisciplinary spirit will be required to advance our knowledge base in basic science and drug development. Although significant technological hurdles must be traversed, the potential advantages are enormous if controllable gene therapy can realize its potential as a validation and delivery platform. Drug discovery and development may one day be routine (a more-or-less turnkey process), characterized by direct, efficient transitions from database query to rational isolation of the relevant cDNA to preclinical validation, to validation in human clinical trials (Fig. C.1). Because the "drug substance" typically will consist of a recombinant gene and a small-molecule controller, many aspects of formulation, manufacturing, biodistribution, and toxicity would be well understood prior to initiation of a new development program. Obviously, companies would operate in an environment of significantly reduced risk relative to the current situation; this environment would allow companies to explore a much broader range of drug targets than typically is explored today.
e) Finally, we envision a pharmaceutical industry that possesses the technological tools and economic incentives to take full advantage of the power of genomics. Specifically, the vision proposed here is that in 10 to 15 years the U.S. private sector will have a drug discovery/drug development pathway that is significantly more cost effective (more turnkey and less risky) than what we now have and is capable of taking full advantage of the promise of the human genome sequence. (Pharmaceutical companies could actually take calculated risks!) If this vision is realized, one can easily imagine how the process of technology transfer from the developed to the undeveloped world would be incentivized for the first time.
Was this article helpful?