An ASO Drug Provides Hope for Twin Girls with Batten Disease

A behind-the-scenes look at how ASOs are tested, and how years of research are expediting their development

What if you could treat a genetic disease by simply skipping over the mutations causing it? This is the science behind antisense oligonucleotides or ASOs, a strategy that has transformed the treatment of a number of rare diseases, especially ultra-rare diseases. As of July 2024, the US Food and Drug Administration has approved more than a dozen ASOs for clinical use. In addition, there have been customized ASOs developed for a single patient, including Milasen, a drug designed for Mila Makovec, a girl born with  an ultra-rare type of the ultra-rare disease known as Batten, a fatal disease that affects the nervous system Sadly, Mila did not survive but the pioneering science that contributed to her drug has informed the ASO research in significant ways.

Without a doubt scientists are making tremendous progress in their understanding of ASOs, and they are now a viable option for parents whose children are born with a rare genetic disease including the twin girls of David and Karen Kahn. Mackenzie and Amelia Kahn, featured in a recent episode of Eureka’s Sounds of Science, also have Batten disease, though their mutation is different from the one that afflicted Mila. After learning of their children’s diagnosis, which causes vision loss, seizures, and loss of speech and motor function, David and Karen did what so many other parents in their situation did—they explored every avenue to find a drug that could help their daughters.  Eventually they found their way to the ForeBatten Foundation, which was able to collaborate with the University of Michigan to develop an ASO drug for the girls based on their specific mutation.

Charles River Laboratories, which has tested dozens of rare disease drugs, performed preclinical studies in 2023 and 2024 on the ASO given to Mackenzie and Amelia last summer. Here to talk more about the impact ASOs are having on rare disease drug development are Shawna Jackman, PhD, Director of Toxicology at Charles River’s Shrewsbury, Mass., site, where much of the preclinical testing on the Kahn’s ASO took place, and Hanna Witwicka, PhD, a Research Scientist II and the Study Director for this project. The answers below have been editing for clarity and brevity.

Parents of children with rare diseases obviously want projects to move as quickly as possible. After all, these diseases are life-threatening, life-changing so the earlier you intervene the better. Is it now accepted and typical practice for ultra-rare disease projects, like the one that helped the Kahn twins, to move faster than a more conventional drug study?

Shawna: I would not say anything is typical for these case-by-case programs, but a path forward is beginning to take shape. The FDA provides useful guidance in the Guidance Documents for Rare Disease Drug Development | FDA that rare disease treatment developers can utilize to help them navigate the process and expectations. The FDA is very open to engaging with the Sponsors of these individual programs, and the agency is also open to reviewing data as quickly as it can to be able to make a decision on whether to move the project to the next stage. Without that engagement, this accelerated timeline wouldn't work.

What we do at Charles River is create and implement the strategic plan for collecting and providing reliable data as quickly as possible. The details of each program we have been involved in have been different, but the same approach is taken to do everything we can to figure out the way to get what's needed as fast as possible but also as safely as possible. How it happens is customized for each of the programs, and dependent on the study designs and necessary data outputs.

These ASO projects are complex and require different disciplines and expertise. How many different groups within Shrewsbury were involved in the Kahn study? 

Hanna: Definitely our Safety Assessment, along with all teams including the In Life, Surgery, Formulations, Animal Care, Clinical Pathology, Necropsy, Histology and Sample Management as well as our QA and Analytical Lab. The bioanalysis and biodistribution were performed in our Den Bosch site in the Netherlands. So, I would say most of our Safety Assessment Department was involved, which is typical for most of our toxicology studies.

Aside from Den Bosch and Shrewsbury, what other sites worked on this project?

Hanna: At Charles River we take advantage of our global network and expertise to maximize timeliness of the results. In this case, Mattawan and Reno also performed clinical pathology evaluations which helped greatly.

What types of preclinical studies did your lab at Shrewsbury do on the ASO drug given to Amelia and Makenzie Kahn?

Hanna: We did two separate toxicology studies in rats. One was a non-GLP pilot study followed by the GLP study. The GLP study was a regulatory one, which means it has to meet specific guidelines and regulations in order for the drug to be submitted to the Food and Drug Administration for approval. There was also a biodistribution component, which helps us to identify target organs and provide some safety and pharmacodynamic insight from the accumulation in different tissues.

Shawna: The purpose of the non-GLP dose-range finding pilot study was to establish the dosing regimen, and to make sure that the animals were able to tolerate the doses needed for the definitive [GLP] study. Since the [Sponsor]’s goal was to get this therapy approved by regulators as quickly as possible, the pilot study became an expanded dose range-finding study, where you can also  incorporate more toxicology endpoints, like pathology. This way you can start to get early readouts on the doses that were administered from even the preliminary pilot study.

These studies obviously need to be done in a condensed time period in order to expedite the drug development process. How hard is it for staff to conduct work on overlapping studies?

Hanna: Usually, we wait until we finish the tolerability study and have some results before we start the GLP study. But in this case, the studies overlapped.  We were able to do that because we had some data from the non-GLP pathology and there was no indication that the doses were going to result in any adverse effects in the animals. The key to the accelerated process was reporting—lots and lots of reporting. The provision of multiple stages of accurate data reports was necessary throughout the studies. 

Shawna: The time that it takes to prepare each of the reports and study updates cannot be overestimated. There are hundreds of things that have to come together for each report. It falls on the shoulders of the Study Director to deliver on the deadlines for each of the studies with the same intensity that they would have for a single report. While this is understandably a lot of work, it is nonetheless rewarding and excellent to be able to be a part of something that is so useful—to provide a report that is so imperative to the next step.

As experts in the safety testing of these molecules, what are we learning from these projects that is helping inform greater success with future projects?

Shawna: From our perspective, from the CRO perspective, we are very focused on the study design and making sure that that study design is as lean as it can be for us to get the data that we need. And again, to get that data as fast as possible to make informed decisions about patient health for receiving that drug. That's what we are focused on. That has not changed over time. Now that we've done a few of these, we're getting better at knowing where we can streamline programs and building our teams so that we can get data reviewed quickly and reported quickly. The ASOs themselves are evolving, the delivery is evolving, as is determining which patients are going to be most successful for it.

Hanna:  Also, the molecules are different. We know more about what is in the structure of the molecule that might cause undesired effects. We know more right now compared to five, six years ago.
Shawna: And all of that previous work has informed the designs of future ASO drugs. I have been involved in the periphery of earlier projects, and I would say the Kahn project was incredibly well-organized and well thought out. We had very strategic deliverables that were challenging to pull off, but we were able to do it.

How rewarding was it to work on this project?

Hanna: I’ve worked at Charles River for five years, and thus far none of the molecules have been approved by the FDA because developing a drug takes time. In this case, we started in the fall of 2023 and by the following summer the girls were dosed, and we know it’s working. That is rewarding.