Download Interfering with the genome: A new generation of disease treatments

Interfering with the genome:
A new generation of disease treatments
by Dr. David L. (“Woody”) Woodland
(as published in the Summit Daily News of November 16, 2015)
Advances in our understanding of the role of individual genes in specific diseases are opening
up new opportunities for the development of radically novel drugs. One exciting area is so-called
RNA interference, or RNAi. This new technology involves the creation of drugs that specifically
control the expression of genes contributing to a disease state.
Genes exist as segments of DNA on chromosomes that are trapped within the cell’s nucleus.
The sequence of nucleic acids in the gene encodes a set of instructions that tells the body
when, where and how to build the protein encoded by the gene. The protein is the functional
product of the gene and usually plays a vital role in the body’s biology. For example, the
hemoglobin gene contains instructions for making the hemoglobin protein responsible for
transporting oxygen around our body.
But how is the gene’s information translated into a protein? The answer is that there is a second
type of genetic material called RNA. Like DNA, RNA is comprised of nucleic acids, although
RNA nucleic acids are subtly different from those of DNA. When a gene is being expressed, the
relevant section of the DNA molecule unwinds to expose the underlying code, and RNA nucleic
acids then create an inverse (or negative) copy of the gene’s sequence. This short RNA
molecule is called a messenger RNA because it is able to diffuse out of the nucleus and into the
body of the cell where proteins are built. Once out of the nucleus, the inverse RNA code is read
and translated to generate the final protein. The process effectively translates the gene’s
sequence of nucleic acids into an amino acid sequence that defines the final protein.
RNAi drugs target the process of information transfer from the nucleus to the cell’s proteinbuilding machinery. The underlying idea is to develop drugs that destroy specific messenger
RNA molecules before they be translated into protein – i.e., “interfere” with messenger RNA
translation. The iRNA drug binds to the “so-called” RISC (RNA-induced silencing complex),
which cuts the targeted messenger RNA in half, effectively destroying it. The process is referred
to as gene silencing and, as might be expected, the genes being targeted by scientists are
those involved in causing disease. Two leading RNAi drug candidates target the production of a
mutant gene responsible for a disease called familial amyloid poly neuropathy. This disease is
caused by a mutated gene that encodes a protein causing abnormal and damaging
accumulation of proteins in the body’s tissues. It is anticipated that the first RNAi drug for this
disease will hit the market in 2017. Other diseases potentially treatable with this technology
include both infectious diseases, such as hepatitis B, and metabolic diseases, such as type 2
diabetes.
Currently, most RNAi drugs under development are targeted to the liver, since the liver naturally
absorbs RNA-based drugs. However, other organs could be targeted with more sophisticated
approaches. One concept is to package the drug in a delivery vehicle, such as a nanoparticle or
a benign virus engineered to target a particular organ or tissue. In the case of the viral delivery
vehicle, the iRNA drug is actually produced in the cell, which could potentially make it much
more durable and effective, although appropriate dosing can be challenging. This approach may
be particularly effective for treating cancer. Indeed, the strength of the RNAi technology lies in
its specificity; the ability to target specific gene sequences offers physicians and scientists a
great deal of targeting precision to modify the activity of individual genes.
Perhaps the most fascinating aspect of RNAi technology is that it harnesses a natural cellular
mechanism designed to protect cells from invading pathogens. Through millions of years of
evolution, the cell has figured out how to capture segments of genetic material from infectious
agents and insert these segments into the RISC. This enables the cells to specifically cleave
and inactivate some of the pathogen’s genes and thwart the infection. This is a tremendously
clever strategy which illustrates the amazing power of an evolutionary process driving the neverending battle between our bodies and the pathogens that attack us. Importantly, it also offers a
strategy for developing drugs that treat genetic defects as well as infectious disease.
David L. “Woody” Woodland, Ph.D. is the Chief Scientific Officer of Silverthorne-based
Keystone Symposia on Molecular and Cellular Biology, a nonprofit dedicated to accelerating life
science discovery by convening internationally renowned research conferences in Summit
County and worldwide. Woody can be reached at 970-262-1230 ext. 131 or
[email protected].
For more (Petri) Dish columns, visit the “News” section of www.keystonesymposia.org.