Scaling In Vivo Gene Therapy: From Promise to Practice
What will it take to make in vivo gene therapies truly scalable, safe, and commercially viable?
Dr. Natalia Elizalde discusses some of the key technical and manufacturing challenges that need to be overcome to realize the potential of in vivo gene therapies. Credit: IBTV x Technology Networks.
Gene therapy has the potential to change the treatment landscape for many genetic disorders, cancers, and inherited diseases from symptom management to one-time interventions. Ex vivo gene therapies, such as CAR T-cell treatments, benefited from earlier regulatory acceptance; today, however, advances in delivery science and regulatory confidence have led to growing interest in in vivo approaches alongside ex vivo approaches.
In vivo approaches have the potential to overcome the often complex and expensive logistical and manufacturing challenges associated with ex vivo therapies. Many drug developers envision a future where in vivo gene therapies could be offered as a one-time, off-the-shelf treatment produced at scale, distributed globally, and administered in a single visit. This could not only make gene therapies more commercially viable but also help bring these therapies to larger patient populations.
Dr. Natalia Elizalde, chief business development officer at VIVEbiotech, explored what it will take to make this vision a reality in a recent IBTV x Technology Networks Expert Perspectives episode. Drawing on VIVEbiotech’s experience developing and manufacturing ex vivo and in vivo lentiviral vectors, Elizalde shared her perspective on what is needed for in vivo gene therapies to succeed.
In vivo vs ex vivo gene therapy
In vivo gene therapy involves delivering the therapeutic payload directly into the patient’s body, enabling cells to be modified in situ. On the other hand, ex vivo gene therapy involves modifying cells outside the body and then reinfusing them into the patient.
What does manufacturing readiness really mean for in vivo gene therapies?
The manufacture of in vivo gene therapies is rapidly maturing, driven by the need to bridge the gap between promising science and real‑world application. According to Elizalde, scalability comes down to three key factors:
- Purity
- Cost-effectiveness
- Raw material quality
Purity is a critical quality attribute in in vivo gene therapy that is not only crucial for regulatory acceptance but also directly affects the safety, potency, and immunogenicity of the therapy. Cost-effectiveness is vital to ensuring that the therapy is commercially viable, and the “quality of the raw materials should be demonstrated to be of the highest standard from the very early clinical trials,” said Elizalde.
While production processes have come a long way, manufacturing constraints continue to shape therapeutic design as much as biology. Manufacturing can no longer be treated as a downstream concern, but instead as a strategic early-stage consideration.
“Production processes, even though they are giving good results… still need to be continuously optimized,” explained Elizalde.
Optimizations include the need to produce high viral titers. This ensures that sufficient functional particles reach the target cells, reducing the amount of vector needed and increasing safety.
Elizalde also highlighted the importance of developing new serotypes and cell-targeting approaches to target specific sites in the body more effectively. One strategy is the design of decorated vectors to improve immune evasion. For example, researchers have engineered biomimetic artificial enveloped adeno-associated virus (AEV) inspired by natural enveloped viruses. In mice, the AEVs demonstrated superior transduction efficiency and minimal immune activation compared with adeno-associated virus.
Smarter vectors can not only improve the efficiency and safety of gene therapies but also reduce manufacturing burden by improving efficiency per dose.
Incorporating regulatory strategy from day one
Alongside manufacturing readiness, having a clear regulatory strategy from the start is key to a successful in vivo gene therapy, Elizalde stated. This includes defining the potency assay and validating it in early clinical trials. Additionally, clear impurity profiles and an understanding of what in-process controls are required throughout the manufacturing process are critical.
Early conversations with regulators are also key in a field where regulatory requirements are rapidly evolving. On January 11, 2026, the US Food and Drug Administration announced information about the agency’s flexible approach to overseeing chemistry, manufacturing, and control requirements for cell and gene therapies. This highlights one of many shifts towards more flexible, risk-based frameworks.
Regulatory planning can reduce downstream risk and delays, and Elizalde emphasizes that ongoing conversations and partnerships with regulators are essential to ensuring the success of any gene therapy.
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Bridging science and real-world impact
Several key technological developments are set to accelerate the development and commercialization of safe and effective in vivo gene therapies. One of the key hurdles that in vivo gene therapies face is the efficient transport of genetic cargo into specific target cells while avoiding off-target effects. Researchers are now developing and fine-tuning tissue-specific promoters and new delivery systems to enhance therapy outcomes.
Different strategies for ensuring the batch-to-batch consistency of therapies are also emerging. “For instance, in our case, we are now also developing a stable cell line that could demonstrate this reproducibility from batch to batch,” said Elizalde.
AI and machine learning are playing an increasing role across the entire gene therapy lifecycle, from discovery to manufacturing, clinical translation, and regulatory applications. In manufacturing, digital twins—virtual replicas of manufacturing processes—can model product behavior under varying conditions. This allows developers to optimize their processes before production begins. Predictive models can also help identify process parameters and anticipate failures based on manufacturing data.
“I think that it [AI] will help to make the process more efficient and therefore diminish the costs,” said Elizalde.
Both in vivo and ex vivo gene therapies represent a path towards treating conditions previously considered incurable. The scalability and broad applicability of in vivo therapies make them promising targets. But success in this landscape will hinge on scientific innovation and the integration of biology, manufacturing, and regulation.
About the interviewee:
Dr. Natalia Elizalde is the chief business development officer at VIVEbiotech. Elizalde holds a PhD in pharmacology from the University of Navarra, where her thesis focused on the long-term effects of chronic mild stress over behavior and neurobiological markers. After her PhD, Elizalde specialized in business development in the biotech sector, working for various drug discovery companies and CDMOs.
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