Gene therapy moves up the road to Duke
From Regeneration Next Director, Ken Poss, Ph.D.:
On behalf of the Regeneration Next Initiative, I’m excited to welcome Aravind Asokan, Ph.D., to Duke University. This August, Aravind moves up the proverbial “8 mile rivalry road” from UNC to join Duke University as the School of Medicine’s Director of Gene Therapy in the Department of Surgery. Asokan will also be an affiliate of the Regeneration Next Initiative and hold appointments in Molecular Genetics & Microbiology and Biomedical Engineering.
A central goal of our Initiative is to strengthen our community of researchers in tissue regeneration, and the recruitment of Aravind was a wonderful example of Duke teamwork toward that goal. Regeneration Next was key in recruiting Aravind to Duke, and we are grateful to Dean Klotman and leadership in various School of Medicine units who partnered with us to make his recruitment a success.
The future of regenerative medicine is targeted delivery of molecular factors to stimulate healthy tissue regeneration. Having Aravind as our colleague will galvanize efforts here at Duke to develop and apply gene therapy vectors in research models, and ultimately as a means to deliver regenerative therapies. As you’ll read below, gene therapy holds enormous promise to transform how we treat conditions of tissue damage or loss such as diabetes, myocardial infarction, neurodegenerative disease, and joint disease.
Regeneration Next’s Executive Director Sharlini Sankaran, Ph.D., sat down with Asokan for an interview.
Aravind Asokan, Ph.D, Director of Gene Therapy at Duke University. Image courtesy Aravind Asokan.
SS: What excites you about your work?
AA: If I had to sum it up in one word, it would be: “Discovery.” You can take things that are in nature, for example viruses, and be able to tweak them, improve them, and discover new functionalities. That’s really the most exciting part of what we do. There’s just a lot of things we learn along the way. For example, in the case of gene therapy, we are able to engineer these viruses so they are useful, and you can use them to address challenges and questions that are being raised in the clinic.
SS: What is gene therapy?
AA: The rationale behind gene therapy is [that] the root cause of many of these diseases is at the genetic level. We understand some of them well, for instance, monogenic diseases where you have a mutation in a particular gene. In its simplest form, having a mutation in a single gene makes that gene nonfunctional and as a consequence there is an insufficiency of a critical protein coded for by that gene. So, how do you supplement that protein back in the patient?
What gene therapy does is address this in one of two ways: either provide the correct copy of the gene so that you can supplement the protein that needs to be made, or you can go in and edit the gene. In another scenario, perhaps the mutated gene product is toxic and needs to be silenced.
So no matter what modality you are looking at – whether it is gene replacement, gene editing, or gene silencing – essentially gene therapy is delivering the tools or the information that is going to correct that situation, in the form of DNA. The genetic material is the “cargo” and the virus is the “delivery vehicle.”
SS: Can you give me one example of a clinical question that you can answer in your research?
AA: We want to translate what we are finding in nature, and design it in a different way, to be useful in the clinic. So taking an example that focuses on the brain, one challenge in the neurology space we have tackled is – how do you get enough of the genetic material you are trying to deliver to enter the brain? In other words, how do you get these tools (viruses) effectively across the blood-brain barrier?
We tackled this problem by looking at some naturally primate-derived viruses that are able to cross the blood-brain barrier, then we learned the structural cues that allow them to get across. Once you find those out, you are able to graft those onto other “cousins” of these viruses and get those to cross the blood-brain barrier too. In other words, it’s like a bar code that you discover and can slap on to these viruses, that allows them to get across the blood-brain barrier and deliver the desired genetic material to targeted areas in an effective manner.
3-D model of a synthetic AAV capsid evolved in the Asokan lab. The different colors represent newly engineered footprints on the viral capsid surface that serve as barcodes for evading antibodies, homing to specific tissues, entering cells and delivering the genetic cargo. Image courtesy: Aravind Asokan
SS: Can you explain how gene therapy could help treat some common conditions?
AA: Gene therapy has already been approved for treatment of a couple of diseases. The most recent one is a currently available product called Luxturna, which treats a form of congenital blindness. Essentially there is a mutation in a gene called RPE-65, which is known to be responsible for a condition called retinitis pigmentosa. Luxturna is a gene therapy treatment that provides a correct copy of the gene to treat this congenital disease.
Other gene therapy treatments that look promising and hopefully poised for FDA approval in the near future are those for spinal muscular atrophy, musculoskeletal disorders, and hemophilia. These trials are all moving forward at a fast clip and I think we are at the cusp of this paradigm shift we are going to see, where viruses carrying therapeutic DNA cargo are going to become a form of medical treatment.
SS: What needs to happen before gene therapy becomes a widely-accepted and safe treatment available to patients?
AA: Clinical trials and preclinical studies in the field have taught us that there are three levels at which we should look at safety aspects of gene therapy.
First, at the virus level, it’s really important to understand that while the viruses are derived from non-human primate sources, or are novel viruses that are engineered in labs, none of them carry their own DNA; they are only shells that carry the therapeutic genetic material. So, understanding the properties of the viral protein shell and its interactions with the host are important.
At the second tier of safety: what does the DNA cargo do? There is a question of genotoxicity – can the material integrate into different regions in the genome leading to unwanted consequences? For instance, could the cargo accidentally turn on genes that were off or vice versa.? In case of the virus that I work with, the AAV or adeno-associated virus, the clinical safety profile in this regard has been good. One of the reasons is that this virus doesn’t tend to integrate its therapeutic cargo into our DNA very effectively. It actually ends up closing in on itself to form a mini circle, which persists on its own. There are several groups working to further understand and improve the safety profile of these already safe viruses.
The third safety aspect is the potential for immunotoxicity. We all have immune responses to viruses and foreign proteins that are presented to our immune system. In some cases of patients with rare diseases, they have a mutation or deletion of a gene so the protein is not made at all. When you introduce this protein through gene therapy, these patients’ bodies are seeing that protein for the first time and that may trigger an immune response. The immune responses to gene therapy that we have seen in clinical trials have been moderate thus far, and have been addressed by anti-inflammatory steroids. But, there are nuances about the immunological aspects that we are only just beginning to understand and the hope is to continue to improve the safety profile on all fronts.
SS: Which areas can we expect to see expansion of gene therapy applications?
AA: From a single-gene, rare-disease genetic disorder, “let’s provide a copy of this gene” approach, there are a couple of approved products already with more on the horizon for this year and next year. So it’s really going to take off on that front, as far as the next class of medicines that are going to be approved. There are all these new paradigms that are going to be really exciting to explore as we expand the scope of gene therapy.
SS: How does the strong community of regeneration researchers at Duke factor into your future research plans?
AA: The exciting long-term research breakthroughs are going to be: where else can we use this [gene therapy] approach? For instance, can we use these viral tools successfully for genome editing? Can we expand past monogenic diseases? For example in regenerative medicine, could we genetically manipulate tissues of interest then use them for transplantation into patients? Or are we going to be able to manipulate tissues in situ and reprogram tissues to regenerate?
I have my whole crew, we are just moving across I-40 and up 15-501. We’re hoping to hit the ground running and have already engaged in active discussions with folks at Duke that we are really excited about. Expanding into the regenerative medicine aspect of research is something we’ve all talked about, particularly in the cardiac space, and there is quite a bit of excitement in my lab about getting started on this new journey at Duke.
SS: What are you most looking forward to as you begin a new chapter at Duke?
AA: One thing I appreciated during my recruitment to Duke is that there are a LOT of people and departments who plugged into the process. It started as conversations with Charlie Gersbach (Biomedical Engineering) and Bruce Sullenger (Surgery). And from there, Priya Kishnani (Pediatrics) in the Alice and Y.T. Chen Center for Genetics and Genomics and other folks in Neurology and Molecular Genetics & Microbiology (MGM) were plugged in. Ken (Poss) of Regeneration Next and then Allan Kirk (Surgery) drove the whole process to fruition thereafter.
I have been actively seeking opportunities this past academic year. To other institutions’ credit, they all have their strengths, wonderful people and some amazing programs. But the spectrum of research and the collaborations at Duke excited me the most.
One of the things I am most excited about is the spectrum of folks that I am going to be able to work with. I think this is unprecedented: the critical mass that can be generated by establishing cross cutting applications of our work can enable everything from developmental biology to gene therapy and genome editing.