Smarter design through targeted delivery and human-relevant testing can save the industry from costly safety failures.
After a combined 55 years developing cardiac gene therapies, we have witnessed remarkable breakthroughs—and watched how safety setbacks can derail entire programs. Recent industry challenges have underscored a fundamental truth we’ve learned: Safety is always a moral imperative, but in gene therapy, it is also a primary driver that will determine which companies succeed.
After a series of deaths and clinical holds hit gene therapy makers earlier this year, investor confidence dampened. The field’s high visibility means one company’s misfortune affects perceptions of the entire sector, making capital harder to raise across gene therapy.
We co-founded Medera a decade ago, prioritizing safety and effectiveness. Having seen too many promising therapies stumble due to preventable safety issues, we built our entire approach around human-relevant preclinical testing models and targeted delivery. We have a vested interest in this perspective, but the industry-wide data speaks for itself.
It is important to emphasize that this discussion does not serve to single out or denounce any particular vector or therapeutic approach. Rather, the purpose is to critically evaluate strategies based on safety and economic sustainability, ensuring that the entire field can move forward with lessons learned and collective improvement in mind.
Just as we don’t blame an entire drug class when someone overdoses on a painkiller, we need balanced, evidence-based analysis of what is driving these recurring problems. In our view, the issue often lies not with the therapeutic agent itself but with how it is being delivered. We maintain that delivering genetic materials directly to their target locations can significantly enhance the safety profile of these therapies, thereby supporting the advancement of gene therapy.
When Safety Failures Hit the Bottom Line
Unlike small-molecule drugs where adverse events might prompt dosing adjustments, a single safety incident in gene therapy triggers cascading outcomes that can potentially destroy commercial viability.
Regulatory delays can add years to drug development timelines and tens of millions in additional expenses. When companies face clinical holds, investors don’t just question that asset, they look at other programs that use the same vector. Sarepta’s vector-related challenges illustrate this point: when a patient on an investigational gene therapy for limb-girdle muscular dystrophy died following two reported deaths of boys taking approved Duchenne muscular dystrophy treatment Elevidys. Even more broadly, investors might review or question the common practice of using high-dose systemic approaches.
In addition to investment woes, gene therapy makers face payer resistance when safety profiles threaten to shift risk-benefit ratios. Payers are increasingly sophisticated—they know that today’s adverse event could become tomorrow’s black box warning.
It is thus clear that we need to prioritize safety. At the heart of gene therapy’s safety problems is systemic delivery of massive doses, requiring immunosuppression, leading to off-target toxicity, particularly liver damage, and triggering harmful immune responses. Take it as a warning: Every liver toxicity signal in your Phase II trial is a potential FDA hold and a regulatory nightmare that can add years to your timeline.
High doses can also mean unsustainable manufacturing demands and costs. When each patient needs hundreds of thousands of dollars’ worth of viral vectors, your commercial model breaks before you even reach the market. Add into that calculation the exponentially higher clinical complexity of systemic delivery—extended hospital stays, intensive monitoring, immunosuppression protocols—and your therapy becomes economically uncompetitive.
While systemic delivery may look convenient in early development because it is a known quantity in the healthcare system, it becomes a costly liability from a commercial standpoint that can sink your entire program.
The Path to Safe and Successful Outcomes
For diseases involving multiple organs, systemic delivery makes practical sense. It is the appropriate tool when broad biodistribution is required. But for diseases affecting a single organ, targeted delivery isn’t just scientifically elegant—it’s economically essential.
When you deliver therapeutic vectors directly to affected tissue, you unlock multiple cost advantages, most immediately: dramatic dose reduction. In our cardiac programs at Medera, we have achieved therapeutic efficacy with approximately 100-fold less vector than IV approaches require, directly translating to improved safety. Medera’s intracoronary delivery is being deployed in three FDA-cleared trials with no gene therapy-related serious adverse events across all studies.
Simplified clinical trial protocols also become possible when you eliminate systemic exposure. Patients in our clinical trials go home after an overnight stay versus the extended monitoring required for patients who are receiving high-dose systemic delivery.
Finally, manufacturing scalability improves significantly. Lower doses mean your production capacity can treat more patients, and your cost per patient can drop to commercially viable levels.
Medera is not alone in recognizing the value of organ-specific delivery. In ophthalmology, Luxturna demonstrated durable visual improvements with subretinal injection, while Atsena Therapeutics and Regenxbio have both reported encouraging Phase I/II readouts with favorable safety profiles. Beyond these, inhaled CFTR gene therapy for cystic fibrosis has entered clinical testing, and Children’s Hospital of Philadelphia recently restored partial hearing in a child with OTOF-related deafness through cochlear gene therapy. Together, these examples show that when delivery methods are matched to disease biology, therapies become both safer and more economically viable.
But innovation in delivery alone isn’t enough. The other critical piece is robust preclinical validation using human-relevant models. Traditional animal models often miss human-specific safety and efficacy signals, leading to expensive clinical failures. Indeed, the FDA is actively reshaping the preclinical landscape by moving away from mandatory animal testing. In April 2025, the agency announced plans to phase out animal requirements for monoclonal antibodies and other drugs, endorsing New Approach Methodologies (NAMs) such as human cell-based systems that reduce translational risk and accelerate timelines. At a July workshop, FDA leaders stated clearly that the goal is for animal studies to become the exception rather than the rule in preclinical safety testing.
At Medera, our patient-derived mini-Heart platform exemplifies this shift. Unlike rodent or large-animal models, it faithfully mimics human cardiac physiology, enabling us to identify safety signals and optimize dosing in a human context before trials ever begin. More broadly, new platforms involving other organ systems are proliferating across the industry. These innovations, now recognized and encouraged by regulators, are rapidly becoming essential tools for companies that want to build therapies that are both safe and commercially viable.
The future leaders in gene therapy will be those who recognize that safety, manufacturability and regulatory credibility must be integrated from discovery through commercialization. This isn’t aspirational—it’s already happening among a small but rapidly growing group of next-generation biotechs that are pioneering fundamentally different approaches.
From Hype to Sustainable Value Creation
Gene therapy’s future cannot hinge on excitement and speculation alone. Sustainable success requires a fundamental shift in how we approach development.
For patients, this means therapies with better risk-benefit profiles and broader access as costs decrease. For payers, it means treatments with justifiable economics and predictable safety profiles. For investors, it means programs with lower risk profiles and clearer paths to commercial returns. For regulators, it means confidence in rational design backed by relevant human evidence.
The companies that embrace organ-specific delivery, human-relevant models and holistic safety design won’t just survive—they’ll define the next generation of gene therapy. Those that continue pursuing mismatched delivery approaches will likely find themselves explaining safety holds and manufacturing delays to increasingly skeptical investors and regulators.
The original vision of gene therapy—curing the incurable—remains as compelling today as it was decades ago. Achieving that vision, however, requires learning from recent setbacks and treating safety as foundational rather than optional. The economics are clear: smart design isn’t justbetter science—it’s better business.
