This week, Science in Vancouver profiles Dr. Sarah Hedtrich. Dr. Hedtrich is an Affiliate Professor at the Faculty of Pharmaceutical Sciences at UBC and an Associate Professor at the Berlin Institute of Health at Charité in Berlin, Germany. Her lab combines her expertise in pharmacology, biomedical engineering, and drug delivery to develop the next generation of gene therapy. We discuss her recent publication in ACS Publications, the challenges of creating gene editing-based therapies, and the impact this could have on patients as Dr. Hedtrich sets her sights on clinical trials.
This interview has been edited for brevity and clarity.
Can you provide a brief overview of your lab’s current research focus?
My lab strives to understand and tackle inflammatory and genetic diseases of human epithelia. We are focusing on the skin and the lungs primarily. We are bioengineering complex human disease models and using those models to study disease-related pathways and mechanisms in order to test and develop next-generation therapies.
The motivation behind my lab are the current failures in the drug development process. The vast majority of drug candidates never make it to the market and they don’t reach the patient because they often show unexpected toxicities or a lack of efficacy in human trials despite having proven efficacy and safety in animal models. We believe there’s a critical gap in the preclinical research that we want to fill with complex human disease models.
Particularly for the diseases we’re interested in—rare genetic skin diseases and atopic diseases—no good animal models exist. Utilizing human tissue models provides us with a more realistic preclinical model than any mouse model would be able to offer.
What is the significance of the findings in this publication?
In this publication, we set out to develop an in situ gene editing approach for rare monogenic skin diseases. Currently, we do have the tools available, like CRISPR-based editors for example, that are essential to make this a reality. So what we’ve shown in this publication is the properties the lipid nanoparticles (LNPs) should have and what our optimized compositions are in order to achieve editing in skin cells. We also describe how to aid the entry of the LNPs and their cargo into the skin epidermis.
We wanted to develop the first efficient therapy and potential cure for patients suffering from rare monogenic skin diseases, as there is a huge unmet medical need. These skin diseases are highly debilitating and stigmatizing, and in some cases—the most severe cases—also life-threatening, especially for newborns and infants. Current treatments are purely symptomatic and there is no cure. However, by using CRISPR-based gene editing, theoretically, we have an opportunity to correct the disease-causing mutation and we can provide an effective treatment and potentially even a cure.
Was there anything particularly challenging that stood out to you?
The problem is that the skin barrier is a very restrictive barrier even when diseased. You cannot just simply add the genetic tools on top, it wouldn’t go anywhere. So we had several problems that we needed to solve.
First, how can we get the genetic tools into the target cells in the skin? Ideally, we are targeting the stem cells in the basal layer of the skin. We teamed up with Dr. Peter Cullis’ Lab at UBC and NanoVation Therapeutics because of their LNP expertise. LNPs are excellent carriers for genetic cargo. We tested a wide range of nanoparticles to find the best lipid composition to effectively transfect and edit skin cells. That took us quite some time.
The other problem is not only getting the genetic cargo inside the cells but getting it to the cells themself. Although it is damaged, the outermost layer of skin is still effective enough that the nanoparticles and CRISPR are unable to penetrate down to the target cells. To solve this, we tested different approaches to facilitate skin entry and we came up with an approach that we hope is also clinically translatable. We used a laser-assisted ablation method to shoot precise, small holes into the top layers of human skin. This allowed our LNPs to penetrate into the pores and reach the target cells.
Another consideration was what format to deliver the gene editing tools in. The CRISPR-based gene editing tools can be delivered either as mRNA or as protein and there are certain advantages to both of them. We did a head-to-head comparison between the different cargo types. For us, we found that the mRNA was most advantageous because it can be packaged more easily into the LNPs.
Lastly, once we focused on mRNA delivery, we did a lot of studies in 2D to look at how the genetic cargo is trafficked inside the cells. However, when we transitioned to actual skin tissue, there was a significant drop in the gene editing efficacy, which was expected because there are different biological barriers. But the positive thing is that the editing rates we see are still sufficient to rescue the most severe symptoms. This makes us very hopeful that by further optimizing our approach, we can increase the editing efficacy. Even if we cannot improve it, where we are now would still provide a significant benefit to the patients.
How applicable do you think your particular approach is to say other types of organs?
It’s not easily transferable to other organs. However, we have run a comparison with other epithelia, more specifically with the lung, and we see similar trends, but the editing efficacy in the lungs isn’t what we can achieve in the skin. Skin is much easier to edit than lung tissue for whatever reason and this is poorly understood. So I don’t think that this can be a template for any other organ. Every organ has its own distinct properties and features. Tissue-specific formulations would need to be developed in order to maximize the clinical impact.
Do you have any tips or advice you’d give other researchers working in this same system, specifically the LNP delivery system?
I think the key is that you choose models wisely. I said at the beginning that if you want to develop a therapy for humans, running studies in mice, especially when targeting the skin or the lungs, can be quite misleading. I think the more realistic the model you use is, the better your outcome will eventually be and the bigger the impact will be.
What was the motivation behind your research and why in particular did you focus on skin diseases?
I started working on skin during my PhD. Skin fascinates me and to some people, it might seem boring, but it basically ensures our survival. We wouldn’t be able to survive without it and it connects us to our environment.
The other part of it is simply because the skin is what everybody sees the minute they meet you. It defines our appearance. So when patients are suffering from a skin disease, it can be highly stigmatizing. These people are suffering not just symptomatically, but also societally. Many experience high rates of depression. It’s heartbreaking, especially if you have children suffering and are lonely at places like school or daycare because they are stigmatized due to their appearance.
I truly believe that the technology that we have and the approach that we are pursuing can be a real game changer for those patients because they are currently underserved. I also get so much motivation from talking with patients. They’re excited about the research that we’re doing and they’re eager to help, especially when it comes to providing some cells from their skin in order to run tests. They are very interested and knowledgeable, so I get a lot of drive from our conversations.
What are the next steps for this research?
We have already started engaging with regulatory authorities and we plan to get into phase I clinical trials within the next three to four years. We are also in the process of spinning off a company based on those results to develop this further. Most of all, we are focused on generating all the data that is critical for us to be able to enter clinical trials.
This research is funded by the Canadian Institute of Health Research, the Faculty of Pharmaceutical Sciences at the University of British Columbia, the Nanomedicines Innovation Network, the Johanna-Quandt Foundation and the LEO Foundation.
