Gene therapy is no longer an approach for the future. It's a technique used now.
As of January 2020, the FDA has approved four gene therapies for use in the United States and has received more than 900 investigational new drug (IND) applications for clinical studies. At present, more than 3,400 active gene therapy trials are taking place worldwide, according to ClinicalTrials.gov.
None of these trials would have launched without valid preclinical research. One of the key requirements during preclinical research is selection of the appropriate animal model.
Selecting animal models that reflect the population studied and reproduce the target disease state increases the likelihood that studies will meet strict regulatory expectations. Further, strong preclinical research, with accurate data and clinically relevant biomarkers, helps ensure that clinical trials get to the finish line on time and on budget.
"If you choose a too simplistic model or a model that does not accurately recapitulate the disease state you're trying to address, your preclinical data doesn't amount to much," said Anjli Venkateswaran, PhD, spokesperson for Biomere, a preclinical CRO based in Worcester, Massachusetts. "Selection becomes even more important in gene therapy research, and it's something scientists grapple with daily."
Animal Model Evolution
Gene therapy researchers rely on animal models to assess variables such as safety, efficacy, dosage and localization of transgene expression. Traditional inbred and outbred mice — the most common laboratory mice — are suitable for most pharmaceutical research. However, when the goal is to alter a human genetic defect, scientists need to test their approach in models that contain the human target sequences. This led to the development of genetically engineered mouse models (GEMMs) — of which there are many.
"Any mouse that is genetically changed or altered to be an appropriate model for disease falls under this umbrella," Dr. Venkateswaran said. "These models express the gene target and recapitulate some, if not all, of the disease pathophysiology."
As animal model providers gain access to next-generation sequencing, genome-engineering tools and other technology, they can develop more customized models. "Older technology was based on homologous recombination," said Tom Pack, PhD, senior scientist for Axovant, a New York City-based clinical-stage gene therapy company. "Now we've moved into an era of CRISPR-Cas9, where you have more efficient and sophisticated technology for manipulating DNA, and you can more closely mimic human mutations. You can also focus on specific organs or tissue types with DNA recombinase-based and intersectional genetics approaches to design more targeted therapies more rapidly."
For all the technological advances, certain studies may require a different type of model. "There are limitations as to how much you can humanize mice," Dr. Venkateswaran said. "Also, mice behave very differently physiologically from humans, and they have a different blood-brain barrier, which can result in differences in gene therapy delivery to the brain. Because of their anatomical differences, large-animal models are emerging in gene therapy."
Large-animal models, including nonhuman primates, may suit certain studies more specifically than humanized mice. For example, pig models have been used effectively in cystic fibrosis studies because their respiratory is more similar to humans than mouse models.¹
However, large-animal models have limitations. They are more expensive than mouse models and require specialized scientists and technicians and adequate lab space. That's why Dr. Venkateswaran recommends that, generally, researchers should start small and move up.
"You need to get some confidence in your gene therapy's performance," she said. "When data looks good in in vitro models and in mouse models, then, depending on the therapy, consider testing in relevant large animal models."
Axovant has two pediatric rare-disease studies in the pipeline: both fatal diseases with no other treatment options available. These delicate situations require Axovant to be especially thoughtful about model selection.
"You not only want to mimic the genetic condition, you want to be able to practice the same surgical techniques you would use to deliver the therapy as well as look at some of the same clinical biomarkers," Dr. Pack said. "With a larger-animal model, you can optimize everything clinically before you start clinical trials."
Scientific and Practical Considerations
To determine the appropriate animal model(s) for preclinical gene therapy studies, researchers must weigh both scientific and practical considerations.
Scientific considerations include:
- Which model best recapitulates disease physiology?
- Which model best works for the targeted gene(s)?
- Which model will best allow the therapy to cross the blood-brain barrier?
- Which model has the appropriate anatomy and physiology to test the therapy?
Practical considerations include:
- Can the study be performed in the lab or would it need to be outsourced?
- How soon can the data be available?
- Does the model's life cycle suit the timeline?
- Is the scientific expertise available to test on this animal model?
A Model Solution
Gene therapy researchers have a lot to consider when designing preclinical research. Appropriate animal model selection is one of the first and most important steps to help move that research into clinical trials.
Fortunately, a select group of CROs have preclinical research expertise to help expedite the process. That includes access to complex genetically modified mouse models and other animal models, as well as scientific experts that understand the biology of these models. Many CROs, including Biomere, also have housing and breeding programs and experience with testing multiple types of therapies (CRISPR-mediated gene editing, AAV and other viruses, RNA therapeutics (RNAi andmiRNA), ceDNA, antisense oligos etc.).
"When you get it right in preclinical studies, you improve the success rate in the clinic," Dr. Venkateswaran said. "A more thoughtful approach will lead to more robust therapies, which ultimately leads to more patient lives saved." To learn more about model selection for gene therapy studies, download Biomere's white paper.
Need a preclinical partner for a gene therapy study? Visit Biomere.com to contact one of its scientists about your preclinical study today.
¹ Meyerholz DK. Lessons learned from the cystic fibrosis pig. Theriogenology. 2016;86(1):427-432. doi:10.1016/j.theriogenology.2016.04.057