RNAi Therapeutics: From Bench to Bedside
An Interview with Dr. Barry Polisky of Sirna Therapeutics
RNAi
research is accelerating rapidly. Two clinical trials are in progress to
determine RNAi's effectiveness for treating age-related macular
degeneration, and many products have already reached the market to test
the promise that RNAi holds. As RNAi technology progresses, many companies
are now trying to increase their shares in the research market by shifting
some of their resources to in vitro and in vivo work.
RNAi
Therapeutics: Challenges in Drug Development and Delivery is a new CHA Advances Report that thoroughly evaluates the
field of RNAi therapeutics, with particular attention to the prospects and
challenges faced in RNAi delivery. In this article, one of many experts interviewed for the report, Dr. Barry Polisky,
Senior Vice President of Research
and CSO at Sirna Therapeutics, discusses key issues and developments in
this technology. For more information about this report, please visit http://www.advancesreports.com/all_reports/2005_58_RNAi/overview.html
Cambridge Healthtech Advisors (CHA): To
start with a fundamental question, we all know the central dogma of
molecular biology, namely, DNA - RNA (mRNA) - Protein. Scientists are
completely puzzled that nowhere in this dogma is there any indication that
RNA has the dramatic role we are discovering as we learn more and more
about RNAi. Do you agree with this? If you do, why do you think it took so
long to discover this “man behind the scene?”
Barry
Polisky (BP): There
are many examples of RNA playing unexpected roles in different fundamental
processes that have been uncovered over the past 10 to 15 years. Examples
include ribozymes and RNA in replication control, among others.
CHA:
RNAi has been
called the biggest discovery since the double helix. Is this justified? If
so, why?
BP:
It is hard to
“rank” discoveries. RNAi and microRNAs are important to our
understanding of the variety of mechanisms evolution has used to regulate
gene expression. In my opinion, RNAi is nowhere near as fundamental a
discovery as the double helix.
CHA:
Do you think
the pace of RNAi technology has been too fast and that we may suffer
disappointment again, as with antisense and gene therapy, on which
research has been going on for years? Theoretically, these two
technologies gave a lot of hope, but nothing much has come out so far, at
least clinically. Why do you think gene silencing technology using RNAi
gives us so much optimism, and do you believe that such high optimism is
rational?
BP:
The key to a
clinical application of siRNA is in its conversion from a laboratory tool
to a therapeutic. This involves different skills from that of the research
scientist. Traditionally, these skills have resided in big pharma.
However, big pharma has no experience with nucleic acids as drugs and the
special developmental issues they require. Consequently, this must be done
by small biotechnology companies with limited resources. Because the
problem is not trivial, this takes more time than venture capitalists
(VCs) and others would like.
CHA:
Do you think
that some RNAi work has been hyped too much? We know the difficulty of
going from in vitro to animal models to humans. In your opinion,
which major disease that is currently not responding well to the existing
drugs might respond to interfering RNA? Given a choice, would you target a
disease for which the delivery is easy and more a local phenomenon, like
the Phase I clinical trials on wet AMD, in which the RNAi is injected
directly into the eye?
BP:
Even for local
delivery, for example, into the eye, formulations will probably help. To
demonstrate proof-of-principle for a new platform technology, however, we
believe that it is best to first attempt injection of the naked,
stabilized molecule directly into the eye to show that this approach is
viable and will benefit patients. Second and third generations of these
compounds will be developed.
CHA:
Targeting,
validation, and optimization are all very important, but the biggest
hurdle in RNAi therapeutics is going to be delivery. The pharma industry
has been plagued by delivery problems for many years, especially when it
comes to protein drugs. Considering all the delivery technologies we have,
both viral and nonviral, what do you think is the possibility of
developing a delivery methodology that will work better than others? Or
can there ever be a “universal” delivery technology for RNAi?
BP:
Delivery for
nucleic acids has not yet been competently explored. The process is just
beginning. Right now it looks like there might be a need to tailor
delivery reagents to the particular tissue. I do not see universal
solutions to this yet. I believe there are also niches in which viral
delivery will be best, for example, Huntington’s disease, for which
permanent correction is likely to be required.
CHA:
For cancer,
which is not a monogenic disease and is very complex, theoretically how
many genes should we target and silence, at least to stabilize the
disease, if not cure it? Also, do you expect the FDA to approve RNAi to be
used as a single agent, or do you think it will initially be used only in
combination with other existing cancer drugs or radiation, as is normally
the current practice with antisense or cancer gene therapy? If you were to
decide on a cancer target, which cancer or cancers would you choose?
BP:
I expect that
any cancer applications using a single or multiple siRNAs in a cocktail
will be used in combination with other drugs operating via a different
mechanism. The genetic heterogeneity, combined with the inherent
difficulty of efficient delivery to tumors, makes this among the most
challenging applications of siRNA. In my opinion, it is still almost
impossible to make intelligent target selections in this area. One can get
tumors to regress in mice fairly easily, but the clinical fate is often
different.
CHA:
We have read
that there is considerable disagreement among scientists as to whether it
is essential to stabilize the dsRNA before delivering it (in humans). Some
say this is essential to avoid excretion/degradation; others believe it is
sufficiently robust to be stable for a long enough time that an adequate
amount can enter and be delivered to the cell. Where do you stand on this
debate? Would it also depend to which organ in the body RNAi needs to be
delivered?
BP:
We are
convinced that chemical modification is essential for therapeutic
applications of siRNA; in my opinion, this is not even worth debating.
Unmodified RNA, in addition to its instability, also activates the innate
immune system via interaction with toll-like receptors in dendrite cells,
leading to production of inflammatory cytokines. We have observed that
this induction is abrogated by chemical modification of siRNA. Also, we
have directly compared potency and duration of effect of target knockdown in
vivo between unmodified and modified siRNAs. We see a dramatic impact
of modified siRNA on both these parameters.
CHA:
I have a few
questions about the use of vectors. Viral vectors used to dominate the
field of gene therapy, but it looks like more and more people are trying
nonviral vectors.
1.
Is it because one death has occurred with adenoviral gene transfer and
three children developed leukemia (one of whom died) after retroviral gene
therapy for X-SCID? What is your opinion?
2.
Have you or anyone ever tried both viral and nonviral vectors to silence
the same gene with RNAi and compare results? What do you think of the
strategy?
3.
Lentivirus, which can infect both dividing and nondividing cells, has
shown great promise, including transfection of primary cells. Can it ever
be a standard mode of delivery, because it seems to scare people off when
they hear it has been derived from HIV?
BP:
I am not an
expert on viral-mediated gene therapy. Deep knowledge about immune
reactions to the viral proteins combined with more control over
integration, or elimination of integration issues, is required for
successful gene therapy. My opinion is that, like many areas of
biotechnology, there is value here, but realizing that value requires a
deeper basic scientific knowledge of the processes being impacted. Sirna
is currently involved in an AAV-mediated gene therapy program in
collaboration with Targeted Genetics (Seattle), the University of Iowa,
and the University of California at San Francisco to develop a therapy for
Huntington’s disease. I believe that several features of the disease and
AAV give this program an excellent chance of providing patients with a
useful therapeutic for a disease that is currently untreatable.
CHA:
You are the
only company other than Acuity Pharmaceuticals to run a Phase I clinical
trial. You have in your portfolio the maximum number of disease targets.
Do you have an order of preference for the clinical trials that Sirna will
run (other than a Phase II clinical trial for AMD) and the expected date?
BP:
We expect to
start our Phase II trial for AMD in 2006. We expect to have a Phase I
trial initiated for HCV in 2006 as well.
CHA:
Finally, do
you believe there are going to be a lot of patent litigations over who did
what and when? This applies to both in vitro and in vivo.
Could this tie up the timeline for what we need most— going from the
bench to the bedside?
BP:
It is always
difficult to predict IP conflicts. I would be very surprised if they
caused delays, however. If we see good performance in the clinic, there
will be powerful forces ensuring that any conflicts are dealt with
quickly. Big pharma will not sit by waiting for resolution here. I believe
they will take an active role in this process. That being said, we believe
that Sirna has the best IP portfolio in the field.
