More than a half-dozen biotechnology companies have been launched to develop and commercialize ribozyme-based diagnostics and therapeutics. The pioneer was Ribozyme Pharmaceuticals, Inc. (RPI), of Boulder, Colorado. Founded in 1992 by current HHMI President Thomas R. Cech, the company was organized to pursue the discovery from Cech's laboratory that some types of RNA, called ribozymes, can cleave other RNA molecules. RPI is developing therapeutic ribozymes to target the messenger RNA (mRNA) of proteins implicated in specific diseases. Like all proteins, disease-related proteins are encoded by genes, whose instructions are carried to the ribosome by mRNA. By synthesizing ribozymes that bind and cleave these mRNAs, RPI scientists are trying to prevent undesirable proteins from being produced.

After a decade of work, RPI has three ribozymes in early phase clinical studies to treat hepatitis C and cancers of the breast and colon. Another ribozyme is in clinical development to treat hepatitis B. Other companies that see promise in ribozyme-based therapeutics include Immusol, Inc., of San Diego; RiboTargets, of Cambridge, U.K. and Rib-X Pharmaceuticals, of New Haven, Connecticut, whose founders include HHMI investigator Thomas A. Steitz at Yale University.

Immusol uses ribozymes to "identify novel targets against which small-molecule-, antibody- or ribozyme-based drugs can be developed. Armed with a detailed knowledge of the structure of the ribosome and with techniques to screen large numbers of molecules at once, companies like RiboTargets and Rib-X are looking for ribozymes or other small molecules that will target the ribosome of a harmful bacterium and shut it down. In particular, they are targeting these potential antibiotic drugs to specific regions of the ribosome that don't seem to be susceptible to mutation. This means that the bacteria will be less likely to develop resistance to the drugs. RiboTargets is one of several firms also exploring the feasibility of using ribozymes to prevent or interrupt the process of replication in HIV, the virus that causes AIDS.

Still other young companies see ribozymes as the basis of new diagnostic tools. Archemix of Cambridge, Massachusetts, has licensed a technology developed at RPI to design a series of ribozymes whose activity is switched on or off by the presence of specific molecular targets. Called RiboReporters, these special ribozymes act as extremely sensitive biosensors. When they bind to target molecules, energy is generated that is detectable on various assays. According to Archemix, RiboReporters can be used to detect numerous molecules, ranging from ions to small molecules to proteins.

—Robert Kuska

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Reprinted from the HHMI Bulletin,
June 2002, pages 14-19.
©2002 Howard Hughes Medical Institute