Guest Column | May 25, 2023

De-Risking Cell And Gene Therapy Clinical Trials

By Russell Lonser, M.D., Ohio State University College of Medicine, Department of Neurological Surgery; Professor and Chair, Department of Neurological Surgery; and Director, Ohio State University Gene Therapy Institute

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Historical overview

The direct delivery of gene therapy drugs to the brain is a nascent, promising, and rapidly evolving field. My interest was first piqued in 1996 - 98 when I was a fellow at the National Institutes of Health (NIH) with Dr. Ed Oldfield, who directed the first clinical trial of gene therapy within the central nervous system (CNS) during the mid 1990s. In 1994, citing poor penetration of drugs infused into brain parenchyma, Dr. Oldfield was one of the pioneers in a new drug delivery technique called convection-enhanced delivery (CED), which utilizes a continuous hydrostatic pressure gradient to distribute macromolecules into the interstitial spaces of the brain parenchyma.1 Since then, I have been fascinated with the intricate properties and morphologies of directed delivery into the brain, brainstem, and spinal cord. I returned to the NIH as faculty in 2001 and we conducted multiple gene therapy trials in tumors and evolving over the last 10 to 15 years, into neurodegenerative and other neurologic disorders. I became Chairman of the Ohio State University Wexner Medical Center in 2012 and earlier this year, launched the Gene Therapy Institute at Ohio State along with my colleague Dr. Krystof Bankiewicz.

From a chronological perspective, there have been many iterative steps that have brought us to where we are today; finally seeing successes in early-stage gene therapy trials via direct delivery to the brain. First, there were biologic and physical properties issues we had to understand. Then, from the early '90s into the mid-2000s, there were device-related challenges that were very different for tumors versus neurologic disorders. Furthermore, the evolution from preclinical to clinical and understanding where to place the drugs inside the brain, interpreting the properties and applying them to humans was extremely complex.

Limitations in Direct Delivery Led to Early Trial Failures

Local delivery of therapeutic agents into the brain has many advantages; however, the inability to predict, visualize, and confirm the infusion into the intended target has been the major hurdle.  I attribute five major reasons for the early failures in direct delivery gene therapy trials. The biggest challenge initially, was knowing where we were infusing and where the drug was going in the brain.

The second challenge was the technologies used to perform the procedures. For example, going back even 20 years, we were using ventricular catheters, which were not designed for infusion. In addition, there was no way to easily reposition or move the cannulas. So, available technology influenced our approach, which I would consider the third limitation. Early on, we approached the brain from the top, due to the available equipment at the time. We've since changed approaches to different areas within the brain including anterior, posterior or lateral.  

The fourth limitation, and still an issue today, concerns the experience of the institute or specialty center. We see this evolution with every new kind of surgical technology. Early phase trials in brain tumors, for example, had varying degrees of success (or not) based on the experience of the center and its clinicians / surgeons. Inconsistency in delivery across staff, sites and diseases resulted in skewed results. Like any complex surgery, its experience, know-how, and currency, that results in reproducible results.

And last, drug development plays a key role. We’ve seen drugs that had excellent results in small animal models, but those results did not carry over into humans.

Methods and Technologies to Increase the Efficacy of Direct Drug Delivery

Advancements in imaging, planning, and delivery platforms have enabled improved targeting, accurate catheter placement, better drug distribution, and real-time visualization of infusions, resulting in reduced risks and enhanced success in clinical trials. Furthermore, a redesign of the cannula has resulted in more reliable, efficient, and increased distribution of agents.2 Collectively, these enhancements have opened a whole new era that we didn't have in the '90s.

New image guided systems provide real-time visualization of the infusion using a gadolinium-based co-infusate, enabling instantaneous alteration of infusion parameters, including flow rate, catheter repositioning or termination when necessary.3  

The ClearPoint Neuro Navigation platform brings the frameless stereotactic MR compatible system together with the SmartFlow cannulas for targeted placement, making us highly accurate in the operating room. Because the platform is MR compatible, it allows us to view our cannula infusions in real-time with a high degree of accuracy and reliability. The cannulas were specifically designed to do gene therapy, which resolves previous problems such as clumping or adherence. And they allow us the flexibility to reposition them during the infusions.

Techniques have also evolved as a result of enhanced technologies. I’ve spent the bulk of my research, focusing on ways to image directed delivery utilizing an interventional MRI (iMRI) system for catheter placement and visualization of infusion. We applied CED of therapeutic agents with iMRI across several different clinical trials in neuro-oncology and movement disorders. We learned we could match surrogate tracers with the drug to see with a great degree of precision, where the therapeutic is going.

That informs us about the properties in various disease types of delivery. It also enhances our accuracy because we can see leak back along the cannula track and can slow the rate. As well it enhances safety because we'll only infuse the areas necessary and then stop the flow.

Another thing we've learned is ‘infuse as you go,’ which is moving the cannula in real time so that we can paint the structure that we're infusing because there are very few or no purely spherical structures in the brain. The ability to see, in real time, where the drug is infusing and continuously correct to get the optimal infusion volume is very advantageous, because gene therapy dosing in the brain is all about the amount of the structure you're covering. Obviously, your vector is important, but once you’re tracking, the goal is to completely fill the structure you want to treat, dissimilar to giving a drug intravenously or through other methods.

Imaging also informs us about efficacy. If we treat the targeted area and there is no impact, that is probably not an efficacious drug. On the other hand, as we're learning, if we treat larger areas, we have a dose effect based on the volume treated. This has been tremendously valuable in our understanding of how to better deliver and how to define efficacy.

Continued developments and accumulated experience with the techniques and technologies of drug formulations, CED platforms, and intraoperative MR systems is making local therapeutic delivery into the brain more accurate, efficient, effective, and safer.

Collaboration to Speed Success

As clinicians, we work closely with both pharma companies and industry. At the Gene Therapy Institute, we have 10 active clinical trials in gene therapy. My advice to pharma companies is select trialists that are currently conducting cell and gene therapy trials and involve them early in the process. We are often approached when the pharma company has already set up their IND enabling studies in a way that we wouldn't in a clinical trial, so then you may lose one or two years reconfiguring your trial. I have the greatest respect for the scientists – they are the disease experts. And we are the treatment experts. Close collaboration between the scientists and the surgeons during this stage of the trial is really critical.  And this is a shift in thinking from 10 or 15 years ago, when preclinical trials were viewed as ‘do it the way it would make sense from a small animal model’ versus looking at the much larger human brain size related issues you must overcome for success. We also actively partner with industry in the development of the hardware, software and targeting that we use. Again, this helps to streamline the process and results in products designed specifically for our needs.

Enhanced Success Rate in Phase 1 / Phase II

The benefits of direct delivery of certain therapies are immense for both the patients and the pharma industry. From an efficacy standpoint, there's significant early data in phase one and two that look exceptionally promising across several disorders. A recent example is MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons in children. Phase one results were striking in terms of health  improvement, and the study demonstrated midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function. The trial continues in a more extended phase one.4

There’s a lot of optimism now that some trials have shown early success. For diseases where we understand the circuitry, we can use the directed delivery and place concentrated levels of drug into targeted areas and therapeutically manipulate those circuits. Increasingly, through targeted delivery, we are also reducing the potential for off-target effects, which commonly occur with therapeutics delivered systemically.

Planning for the Future

In the United States, we have approximately 60 centers that have intra-operative MRI, and only a few that do directed gene therapy into the brain. I think as these agents advance in the clinic and become approved for therapy, that will create an opening for this technology. And technology advancement begets training, fellowships, and certifications just like any new surgical or interventional therapy. It’s not just placing the catheter to a specific spot, it’s learning how to shape those infusions, learning how to manage different anatomic borders between gray and white, between the brain and the ventricular system because those create different infusion profiles or delivery profiles, than simply placing it into an area with homogeneous consistency.

The Gene Therapy Institute at Ohio State holds one of the largest first-in-human clinical trial portfolios in nervous system gene therapy. Throughout the year, we invite doctors and pharma to come and watch our procedures. Several have begun creating their own kind of training regimen, whereby a surgeon who wants to initiate these infusions will come here, view several cases, and then we'll go and watch them do several cases at their home institution. And prior, their institution will be reviewed for infrastructure, workflow and the like, because in Phase I and Phase II trials, you need that consistency to show what your therapeutic is doing. You can’t have a portion of your patients being treated inconsistently – it’s impossible to win that back in a trial.

From an economic standpoint, we need to find ways to further streamline the time in the operating room, the time it takes an intraop MR, and then ultimately, we need new technologies that won't require us to use the intraop MR imaging to facilitate real-time understanding of where the drug is going. That may be predictive software, and it may be a whole host of things that will allow us to do that.

Predictions for Gene Therapy

I think the future of gene therapy is super exciting. I predict a few things will occur. For example, as we garner greater biologic insight into the underlying causes of a number of these degenerative and other disorders, we'll have better targeted gene therapies that can narrow in on very specific targets. This, in turn, will allow us to disrupt and therapeutically improve disordered circuits within the brain. And there is some evidence that we can keep this behind the blood-brain barrier, which would reduce potential for a negative immune impact. Less certain, is whether we could potentially redose a patient. These are things we're studying today.

Secondly, and in parallel, hardware and software technologies will continue to evolve at a rapid pace, which will also improve our understanding of delivery and how to do it efficiently and impactfully. Lastly, expertise will increase and become more prevalent.

And when I discuss the future, it is not 10 years away, rather we will see these changes, in significant ways, in the next 2 to 5 years. These advancements are creating an electrifying future for gene therapy. FDA predictions for registration submissions of gene therapeutics are expected to rise exponentially over the next several years and that's across all gene therapeutics. And it looks like we are within reach of achieving FDA’s prediction that it will be approving 10 to 20 cell and gene therapy products per year by 2025.5 Now that is very motivating for pharma, industry, and patients!

About the Author

I am a neurological surgeon who specializes in the resection of brain, spinal cord, pituitary and brainstem tumors. I also serve as professor and chair of the Department of Neurological Surgery at The Ohio State University College of Medicine. I hold the Dardinger Family Chair in Neurosurgical Oncology. Previously, I was chief of the Surgical Neurology Branch at the National Institutes of Health.

My research includes nervous system drug delivery, gene therapy and tumor biology. I have authored more than 300 publications. I received the Tumor Young Investigator Award and the Mahaley Clinical Research Award from the American Association of Neurological Surgeons (AANS)/Congress of Neurological Surgeons (CNS) Tumor Section. Additionally, I was the AANS/CNS Tumor Section Bittner Lecturer and the American Academy of Neurological Surgery Edward H. Oldfield Lecturer.

I have served as treasurer and president of the CNS, and I am currently the Secretary of the American Board of Neurological Surgeons. I was the head of the research subcommittee in Head, Neck and Spine Injury Committee for the National Football League and have served on the editorial boards of NEUROSURGERY, World Neurosurgery, Journal of Neurosurgery, PLoS One and Science Reports. I am also consulting editor for Neurosurgery Clinics of North America and have edited three neurosurgical textbooks.

1 Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH. Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A. 1994;91:2076–2080. 

2 Yin D, Forsayeth J, Bankiewicz KS. Optimized cannula design and placement for convection-enhanced delivery in rat striatum. J Neurosci Methods. 2010;187(1):46–51. doi: 10.1016/j.jneu-meth.2009.12.008.

3 Richardson RM, Kells AP, Martin AJ, et al. Novel platform for MRI-guided convection-enhanced delivery of therapeutics: preclinical validation in nonhuman primate brain. Stereotact Funct Neurosurg. 2011;89(3):141–151. doi: 10.1159/000323544.

4 Pearson, T.S., Gupta, N., San Sebastian, W. et al. Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons. Nat Commun 12, 4251 (2021).