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Stanford s Mark Kay Discusses RNAi and Founding a Therapeutics Start Up

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At A Glance

Name: Mark Kay

Position: Professor, pediatrics and genetics, Stanford University

Background: Associate professor, pediatrics and genetics, Stanford University — 1998-2001; Associate professor, medicine, University of Washington — 1997-1998; Adjunct professor, pediatrics/biochemistry/pathology, University of Washington — 1994-1997; Postdoc, Baylor College of Medicine — 1990-1993; Internship/residency, Baylor College of Medicine — 1987-1990; MD, Case Western Reserve University — 1987; PhD, developmental genetics, Case Western Reserve University — 1986; BS, physical sciences, Michigan State University — 1980

Though he has spent essentially his entire career in academia, Mark Kay recently co-founded the RNAi-based therapeutics company Avocel, which sought to commercialize his discoveries and was eventually bought out by RNAi-based therapeutics developer Benitec.

Kay now advises Benitec on its drug-development programs, while maintaining his faculty position at Stanford University. Recently, Kay spoke with RNAi News about his work and where he sees it taking him.

How did you get involved with RNA interference?

My interest in it came from the point that for 10 years or 11 years we’ve been interested in developing therapies against viral hepatitis. We weren’t really married to any particular type of therapy, we just wanted the one that worked the best.

In the early day, we had worked with ribozymes and had done some antisense — things like that. When RNAi became something that people started to look at in lower organisms, we got interested in it from the standpoint of trying to use it to treat hepatitis. That’s when a postdoc in my lab asked me about trying RNAi, because he had been working with ribozymes with minimal success.

At the time we started these studies, it wasn’t clear that RNAi even worked in mammalian systems. Around the time we started generating our data, there was a paper that came out saying it worked in mammalian cells, but at the time it still was unclear whether it worked in whole mammals. We actually published a paper in Nature in 2002 showing that RNAi worked in whole mammals, which were mice.

How did all this lead up to the creation of Avocel?

What happened was we filed through Stanford a patent application like we do on anything — we just send disclosures to the Stanford office of technology licensing. I started getting phone calls from VC folks and individuals who were interested in pursuing this from the standpoint of commercializing it. Some of those initial contacts, truthfully, I wasn’t that interested in; my major interest is academic … and it was clear from some of the people I talked to that they didn’t have a full understanding of what this was all about, that it was going to take a lot of work.

Then I was contacted by [Avocel co-founder] Sara Cunningham who I had dealt with when she was at Clontech and she had licensed an adenovirus kit that we had developed. She was working with a different company, and actually needed someone to go to Japan and speak at a meeting on RNAi. Somebody had brought her an article we had published and she said: I know him from other things. So we started talking, and [eventually] she came to me and said: Would you be interested in starting a company around this? It was clear that she really understood the science behind this and had the business background to do this, so that’s when I said: Yeah, this is a good idea.

Truthfully, my goal in this primarily is to find a way to get this into the clinic. From the time we started doing this work in the early days until the time when we started Avocel, I had been involved in a joint effort with Avigen … on developing clinical trials for a hemophilia gene therapy. As a result of those trials, it became clear that having an industry partner had a lot of advantages. So it was clear to me that getting this into the clinical arena in the most efficacious manner would be to do it through some sort of corporate liaison kind of thing. That was really the thinking behind trying to start Avocel.

In terms of the technology itself that the company was working on, and still is under the umbrella of Benitec, can you give an overview of that?

The progression [of the technology’s development] was that we had filed some patents on in vivo mammalian use of RNAi — both expressed RNAi short hairpins, as well as delivered RNAi [compounds]. With my gene therapy background and the fact that … there really isn’t a way to deliver the RNA into the liver efficiently enough, in my opinion from what I’ve seen, to have some sort of efficacy, we decided to pursue the expression of RNAi or shRNAs as a therapy. Based on that, we hired three scientists to basically make up the scientific structure of Avocel. Their role was to take the HCV work and do all the development to get something that could be used in a clinical trial.

Then, Benitec’s patent issued on expressed RNAi, and they started talking to us about some sort of joint thing. It became clear that the merger of the IP and the infrastructure that we had set up would be advantageous to both. So they acquired us in May.

What was your position with Avocel? Were you just on the scientific side?

I was the chief scientific advisor and the chairman of the SAB. Based on still having my academic position at Stanford, I had some limitations on what my involvement [could be].

So you’re an academic kind of guy? You’re not looking to get into industry?

I spent six months at Avigen on a leave [from Stanford], and I got to appreciate things from the industrial side. I think it gave me a new respect for the issues that they have to deal with. But from my own interest at this point in time, I’m more interested in academics.

When we started Avocel, Sara was primarily responsible for the business side and I was responsible for running the science side of things.

Where does it stand now with the company being acquired by Benitec?

I’m the deputy chair of the Benitec SAB and I’m called a strategic consultant.

What does that entail?

Basically, I still consult with them on a weekly basis on the HCV program, and [I’ll be] assisting to run the SAB meeting.

How is the hep C program progressing?

I’m not sure how much I’m allowed to say, but we are identifying the final candidates, the sequences that we’re interested in using. We’ve probably not made it a secret that we’re really interested in using AAV as a potential vector to deliver the expression sequences.

What about you at Stanford?

We’ve really focused most of our efforts on hepatitis B, and the reason is that [for] hepatitis B there are at least mouse models — they’re not perfect but there are mouse models. It’s been very difficult to get even a cell culture model of HCV, let alone animal models. The only animal models are chimpanzees, which are obviously very expensive and difficult to work with. There really are no good small animal models [for hepatitis C].

What we’ve really gotten interested in is using the hepatitis B mouse model to answer a lot of questions both related to therapeutics, as well as mechanistically what happens when you express lots of shRNA in a complete organ — things along those lines.

Our lab is focused mostly on HBV, but the point is that we’re using it as a model. What we’re trying to do is address issues of what’s the best vector system, what’s the best kind of sequences to put into the vector to try to inhibit hepatitis B replication, as well as make sure that things are safe and not causing problems.

Are you finding that to be a fairly large challenge?

Well, we’re making pretty reasonable progress. We have had toxicity issues, but a lot of those have been resolved basically by using lower doses.

In the old days of gene therapy, we would get excited if we would see one transduced cell or a couple of transduced cells in a whole organ. Now, we have tools … that can basically transduce every cell in organs, in animal models at least. This has been quite a difference over the last 10 years.

What about safety issues?

First of all, people have gotten hung up on this issue of off-targeting effects. If you think about it, any drug, even small molecule drugs, are going to [cause] changes in gene expression profiling. For example, if you give somebody aspirin, one of the oldest drugs known to mankind, I’m sure you’re going to change gene expression profiles.

The issue is: If you use this type of technology, you have to realize its limitations. One is: How do you determine what changes are clinically relevant? And number two, you have to realized that you’re limited to RNA level measurements by these profiling assays, and things that affect the final product — that is, protein — at the translational level might not be picked up by these types of analyses. So you have to think of it from that standpoint.

Secondly, I think that gene therapy, for reasons that are probably not totally justified, has this mystical sense about it. The case in point is … these X-linked SCID patients, who were originally touted as the first use of gene therapy to cure a disease. Then two of the initial 10 patients who were treated developed leukemia. That’s really made a huge amount of press — that gene therapy has these problems again. But if you think about it, the fact is that eight of those first 10 kids were cured, and [with] any kind of really devastating disease, and this is clearly a lethal illness … a certain number of people can actually succumb to the therapy itself.

I think that the message that’s being lost in some of the press that’s come out is that eight of the 10 first kids had essentially restoration of their immune responses, which basically stopped them from having a fatal illness.

Beyond [hepatitis], do you see your RNAi work extending into other diseases?

Oh yeah. John Rossi’s group [at the City of Hope] has done a lot of work on HIV, and there is a cooperation between the City of Hope and Benitec to pursue that as a clinical trial.

I would say that RNAi has potential for autosomal dominant diseases where there’s a gain of function based on a mutation, and also things like cancer where abnormal gene expression contributes to the malignant phenotype.

Is that something you yourself would anticipate getting into?

In my academic lab … probably not. My general philosophy has been to focus on one or two diseases, and really focus on the issues and technical barriers and try to solve those. If you solve those then the solution might be useful for a lot of different applications. I prefer doing that than trying to treat 50 different disorders with a technology that’s not mature yet, or still has some flaws to be worked out.

We’ve never been married to a particular vector or approach in my lab — it’s not like we work on one vector and try to find all the diseases [we can treat with it]. We work on a couple of diseases and try to work towards a way to treat them. Clearly, with all the post-transcriptional gene silencing strategies that we’ve tried in our lab, there’s no doubt that RNAi is leaps and bounds more effective at what we’re trying to do.

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