Engineering Triggered Nanomechanical Therapeutics The goal of this program of research is to develop the molecular foundations for a new therapeutic paradigm based on triggered nanomechanical transduction using synthetic nucleic acid devices. Traditional drugs may be viewed as 'structural therapeutics'that bind specifically to a target molecule that serves as both the marker for the disease and the means of treating the disease. This dual role is undesirable if the target is not specific to diseased cells (exemplified by toxicity side effects with cancer chemotherapies), or limiting if the target does not facilitate potent treatment. Here, we propose to develop 'mechanical'therapeutics in which the activity of the treatment domain is under the mechanical control of an independent diagnosis domain: if and only if the diagnosis domain binds to its target (selected for its specificity as a disease marker), the initially inactive treatment domain switches to an activated conformation capable of binding to a second unrelated target (selected for its potent activation of a therapeutic pathway). The use of distinct diagnosis and treatment domains allows independent optimization of specificity and potency;the introduction of triggered mechanical transduction between these domains provides active suppres- sion of the drug's activity until a positive diagnosis is achieved at the molecular level (minimizing side effects). Mechanical transduction also provides the flexibility to implement elementary molecular logic, permitting triggered activation following diagnosis based on multiple disease markers. This dynamic functionality will be encoded in the sequences of therapeutic RNA molecules that interact and change conformation to implement two conceptually powerful therapeutic strategies: If gene A is detected, silence gene B via triggered RNA interference. If gene A is detected, kill the cell via triggered immune response. In both cases, the key point is that the activity of the drug (i.e., gene silencing or cell death) is triggered by the detection of an unrelated disease marker. The concept of triggered nanomechanical transduction suggests potentially transformative therapeutic strate- gies for treating broad classes of disease, including cancers, autoimmune diseases such as multiple sclerosis, and mosquite-borne viral infections such as dengue fever. Our current objective is to demonstrate the promise of nanomechanical transduction by robustly triggering gene silencing and cell death in mammalian cells, providing a proof-of-principle to motivate further exploration of this new therapeutic concept. 1

Public Health Relevance

Engineering Triggered Nanomechanical Therapeutics The goal of this program of research is to develop drugs that diagnose and treat disease one cell at a time, activating treatment within a cell only after a positive diagnosis is achieved at the molecular level. This concept suggests potentially transformative therapeutic strategies for treating broad classes of disease, including cancers, autoimmune diseases such as multiple sclerosis, and mosquite-borne viral infections such as dengue fever. 1

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140759-04
Application #
8270640
Study Section
Nanotechnology Study Section (NANO)
Program Officer
Li, Jerry
Project Start
2009-07-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
4
Fiscal Year
2012
Total Cost
$322,899
Indirect Cost
$123,579
Name
California Institute of Technology
Department
Engineering (All Types)
Type
Schools of Engineering
DUNS #
009584210
City
Pasadena
State
CA
Country
United States
Zip Code
91125
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