Webinar Q and A transcription: ‘Gene-modified mesenchymal stem cells as a potential treatment for Huntington’s disease: preparing for a planned Phase I clinical trial’

Transcription of the live webinar Q and A session

Thank you everyone who attended the live webinar ‘Gene-modified mesenchymal stem cells as a potential treatment for Huntington’s disease: preparing for a planned Phase I clinical trial’. Below is a transcription of the Q&A session held during the webinar. We hope this is a useful resource and thank our attendees and our speakers, Jan Nolta, Vicki Wheelock and Kyle Fink (UC Davis, CA, USA), for their time.

Will these engineered stem cells be a potential cure for HD?

Vicki: The studies that we’re doing right now using the MSCs overexpressing BDNF will not be a cure for HD. The goal of our study is to see if we can potentially slow down the progression of HD, but working with BDNF will not be able to cure the disease. However, the studies that Kyle and Jan are doing with small interfering RNA or also with gene editing would be something that could potentially be a cure. So we want to distinguish our study as a neuroprotective strategy currently, but we would like to move over toward something that could be more curative.

When do you expect the HD-CELL trial to start?

Vicki: This is now a future planned trial, and as I mentioned we are going forward with the regulatory approval right now; we’re interacting with the FDA, getting their feedback, applying for the pre-IND, which was submitted yesterday. We are then going to wait for their feedback and then go forward with the actual IND and we would hope to be able to start the study in the early part of 2016. However, we definitely await the regulatory review and approval before we can go forward. So, HD-CELL is still a future planned trial, it’s not actually ready to launch until we have regulatory approval.

Why does the FDA not allow more than two copies per cell?

Jan: The lentiviral vector that we will use will integrate pretty randomly into the DNA however it’s only in our “delivery trucks”, only in the MSCs, it’s not integrated into the brain. We want to make sure that that’s as safe as possible so we can’t have something like 10 copies per cell even though that would make more BDNF per cell. It’s just a rule of thumb that the FDA has for increased safety.

I’ve been reading about CRISPR. Does it potentially play a role to snip the extra CAG repeat groups? Kyle describes something similar.

Kyle: There are several different groups and a lot of people studying gene editing and gene-editing technologies have really become advanced in the labs since a few years now, first starting with meganucleases and then moving to zinc fingers, which the company Sangamo has done some wonderful work on for HD. The zinc-finger nucleases, the TALEN protein and the CRISPR are the new kids on the block. The CRISPR/Cas9 system is really great and really good to use and we were looking into it; however, when we were first designing these target sites, we were working with a wonderful person on our main campus in the UC Davis Genome Center, Dr David Segal. I sat down with him and had several conversations about which sites I felt were the most potent and the best ones to test in HD, and he was advising which system would be the best to target those. We came to the conclusion that Transcription Activator-Like Effectors would actually be a little more beneficial for HD. We are exploring currently more target sites and doing some other sequencing within the juvenile HD patients to see if the CRISPR/Cas9 system would apply there, and just trying to move forward with both of these. The TALE and the CRISPR work through similar mechanisms, it’s just a case of adapting the gene-editing platform for the gene itself, so that’s where we currently are. But for other genetic diseases and hopefully potentially for HD, CRISPR/Cas9 will play a role in the future.

How long until the trials for JHD?

Jan: We are very committed to this research; we need the funding for those studies. We’ve been very lucky to have the MSC/BDNF trial funded by CIRM (California institute for Regenerative Medicine). So far we have some donor money and some foundation money for JHD, but to perform these large IND-enabling studies for JHD we’ll need to get a bigger grant leveraged from these foundation donations. We’re working very aggressively toward that and so I can’t really predict it at the moment, but please know that that’s first in my heart.

Is there any differentiation from these MSC?

Jan: No, interestingly once they are transplanted they do not differentiate. We can force them into differentiation in the tissue culture dishes as I mentioned, by putting them into substrates that can make them into different fat or whatever we want to look at, but in vivo they really don’t change. You can take them out and they’re basically unchanged and they really don’t divide once we put them in, maybe one division, but they don’t keep on dividing, so that’s a very important question.

What is the timeline that you think it will take to get a patient’s sample, harvest the cells, engineer it, then inject it back to the patients?

Jan: We will have unaffected healthy donors for the MSCs, and the beauty of these cells is that they can be transplanted from patient to patient with no immune suppression. They have like a little force field around them that they hide from the immune system and so we are making up a large batch of MSCs from a healthy and extensively screened donor in our good manufacturing practice facility and that will be enough for all the patients in the planned HD-CELL trial.

View the webinar on demand here, and the Q&A follow-up here.