Sail for Epilepsy, Part 5: Realities of Selecting Clinical Dose Levels

Emily Walsh Martin, PhD - June 17, 2022

Check back to our blog every week to learn more about Dr. Walsh Martin's journey and the emerging gene therapy efforts in syndromic and monogenic epilepsies.

Below we explore, element by element, where most development teams struggle with achieving the perfect scenario. A comment before we dive in, I hope by the end of this blog you’ll leave with an understanding of the challenges faced by gene therapy developers and a balance between:  

  1. an appreciation of the tenacity and ingenuity used to try to answer questions about starting dose prior to dosing the first patient with a therapy, and  
  2. a deeper understanding of the unknowns that may not be apparent at first glance 

Tropism and transduction efficiency not conserved between species 

Many programs use AAV serotypes where tropism and/or transduction efficiency is known not to be perfectly conserved between species (e.g. AAV6, AAV8, etc..) or they target cell types where it is difficult to establish comparative datasets (e.g. human muscle/liver biopsies may be possible but CNS biopsies are not readily acquired). In these cases, development teams try to identify which nonclinical species might be the most reliable to predict the transduction in humans and use that to help estimate dose requirements. Of course, in order to bridge that experience to the clinic, published translation data on nonclinical animal models and clinical efficacy endpoints for other programs using the same vector to transduce similar target cells is invaluable. 

Gene activity not conserved between species 

Sometimes, the conservation of the gene’s activity is not identical across species due to compensatory activities of similar genes. In other cases, there is only a single animal model, usually a rodent, which reduces confidence around the likelihood of conserved gene function. Or worse, sometimes two animal disease models exist but the data from each results in different conclusions about efficacious dose levels, leaving investigators wondering which animal model is more predictive of the human gene activity. In these cases, teams often pick a dose that is conservatively likely to provide benefit regardless of model. However, this can be problematic in cases where that conservative dose is quite close to the maximum tolerated dose. 

Percent or types of cells needing correction unknown or not the same between species 

Often programs do not have historical data on the target cell types or percent of cells required for correction, rather they are generating this data themselves so the data may arrive late in the development process after much investment in the program. And if you aren’t completely sure what cells you need to transduce, you can’t do such dose-scaling effectively. This obstacle is quite challenging for teams when projecting the expected efficacious dose, as most diseases don’t have large animal disease models and thus many teams are confirming dose scaling in large animals by asking what dose is required to mimic the percent target cells transduced in the rodent. If these data are further clouded by differences in tropism or transduction efficiency across species, then teams struggle with confidently projecting clinical doses. 

Overexpression or misexpression of the gene target not well tolerated 

For some diseases we know that overexpression of the normal gene might itself have negative consequences (e.g. Rett). This means that the development program will need to devise thoughtful strategies to ensure the gene expression is not too high, but also not too low. This is a particularly challenging situation when there is a narrow therapeutic window between the doses that yield efficacy and doses that result in toxicity. Moreover, it creates challenges in interpreting organ-level expression data because taking the average expression could hide a scenario where half of the cells are under expressing at levels that won’t provide clinical benefit and the other half are overexpressing at levels that will cause toxicity. These scenarios lead to significant unknowns in whether the doses being selected in the clinic will provide benefit and avoid the risk of harm. 

Therapeutic intervention not possible after symptom development 

Many times, the therapy being developed is the first attempt to treat the disease. As such, screening efforts in newborns may not have been developed or implemented broadly. In addition, there may be limited understanding of how the disease will progress for a patient. Therefore, the patients who might enter the trial may have already progressed past a point where gene correction could help.  

This is especially true for target genes where there is a narrow treatment time window due to loss of the affected neurons or other irreversible brain and neuronal damage that can’t be restored from cellular and tissue-level compensation. This is a difficult scenario for drug development teams and for families of trial participants. Gene therapy trials are often quite small in size because the hope is that the magnitude of benefit will be so large that you can see a benefit in a small number of patients. However, in diseases with a narrow treatment time window, in families with multiple affected members, one of the siblings may be too advanced to participate in the trial. And if benefit is truly not possible past a certain point, then enrolling both siblings may result in a dilution of any efficacy signal from the overall study. This is even further complicated for diseases that have a variable progression. In those cases, it becomes even tougher to know whether the lack of progression in a patient who was able to be treated earlier in the course of their disease reflects a true benefit, or just a case where the disease was slower to progress in that particular patient. 


In the case of monogenic epilepsy gene therapy development programs, each of these considerations come to bear. And while it is true that we’ve seen gene replacement benefit seizure activity in rodents (e.g. CLN2, SCN1A)7, we don’t yet know whether there will be a therapeutic window and/or treatment time window that will allow us to reach the right percent of cells or right cell types in the clinic. Or whether our ability to correct the gene’s function in rodents will predict success for that gene in humans. And should we see clinical success for one epilepsy, it is still unknown whether that would predict success for other gene targets.   

Despite these obstacles and unknowns, there is much promise for AAV gene therapies in the treatment of syndromic and non-syndromic monogenic epilepsies. As an industry, our road ahead is clear, even if the ultimate answers are not. What is clear is that we will need to keep diligently seeking to understand the answers to these questions for every program and acknowledge that for some programs the data may not support continued development at this time. All the while, we will need to ensure transparency to patients, and their caregivers, who are considering enrolling in our studies, as they are our partners in these endeavors. The “one and done” promise of these therapies still cuts both ways until we have solutions for re-dosing patients.   

In parallel, we can also continue to work on solutions to some of the technological challenges limiting candidate therapies in the past. The list is long: novel immunosuppressant prophylaxis to reduce side effects or allow re-dosing, capsids with improved tropism/transduction efficiency or therapeutic windows, improved promoters, novel gene control elements, better manufacturing methods, better phenotypic measures of success, and much more. With all this effort, there is hope that there may be successes in many monogenic epilepsies in the near-term, but if not, technological advances in this parallel track may allow us to re-open efforts to address diseases where a door has been temporarily closed.

Emily Walsh Martin is a volunteer crew member for Sail For Epilepsy’s Atlantic crossing on the vessel Ingwe. When she’s not sailing, she is a consultant for gene and cell therapy companies and investors who are seeking to advance novel therapies in the clinic.

Read the Series

Part 4: Key Elements for Selecting a Proper Clinical Dose

Part 3: How Would Gene Therapy Work to Address Monogenic Epilepsies?

Part 2: An Overview of Syndromic and Monogenic Non-syndromic Epilepsies

Part 1: A Worthy Excuse for Missing the ASGCT Annual Meeting