Overcoming Toxicity Challenges in Gene Therapy
With several trials halted after patient deaths, dosing concerns are troubling the gene therapy space.
Gene therapy is reaching a tipping point.
Despite achieving several high-profile successes, with the US Food and Drug Administration (FDA) having approved gene therapies for sickle cell disease, hemophilia A, certain leukemias and several other serious conditions, the field faces many challenges. Chief among these is the need for very high doses, which carry a higher risk for serious adverse events.
In recent months, several fatalities have been reported in relation to gene therapy trials. In May, the FDA ordered a clinical hold on Rocket Pharmaceuticals’ Phase II trial of gene therapy for Danon disease following the death of a patient who suffered a serious adverse event. In September, Capsida Biotherapeutics chose to pause its Phase 1/2a trial on child patients with syntaxin-binding protein 1 (STXBP1) encephalopathy, after the death of the first child dosed in the study. Following three patient deaths, Sarepta Therapeutics also recently suspended its gene therapy treatment for Duchenne muscular dystrophy (DMD), after initially resisting a request from the FDA to pull the drug from the market.
Erik Wiklund, PhD, chief executive officer at Circio, believes that these events could have a long-term impact on the perception of the gene therapy space and on how the FDA and other regulators view gene therapeutics.
Wiklund was an author on the first study to describe a functional human circular RNA (circRNA) before leaving the world of academia to pursue a business career. Circio’s “circVec” technology for in situ circRNA production in cells is now being investigated to improve the potency of gene therapies, potentially avoiding this dosing issue.
Technology Networks spoke with Wiklund to learn more about the challenges facing gene therapy, Circio’s circVec system and what advances in gene therapy delivery systems could mean for patients.
What are the major challenges that come with developing gene therapy for treating rare diseases?
Erik Digman Wiklund, PhD (EDW):
The major challenges for gene therapy development in 2025 relate to the shortcomings of available vector technology and negative investor sentiment, drying up available capital.
The adeno-associated virus (AAV) vector is the workhorse of gene therapy today, with several examples of clinical and commercial success. However, AAVs cannot be repeat-dosed and generally require very high dosages, especially when administered systemically. The dosage issue has created problems because it can lead to severe toxicity – in some cases, fatal – and it drives up cost. For these reasons, most approved AAV gene therapies have struggled to become commercially viable.
The negative publicity around toxicity and commercial viability has led to venture capital fleeing out of the gene therapy field, with investments dropping by over 80% since the peak of the COVID-related biotech fundraising surge. Consequently, new gene therapy programs are increasingly difficult to finance, [meaning] that many promising approaches are being delayed or completely shelved.
Ultimately, patients with devastating genetic disorders that lack adequate therapeutic options are the ones who will suffer most. New technologies that can make gene therapy more efficient, safer and lower cost are sorely needed to shift the momentum in the field, regain investor confidence in the sector and ensure safer deliveries of therapies to the patients who desperately need them.
AB:
Sadly, 2025 has seen multiple deaths of patients involved in Phase 1 and Phase 2 gene therapy clinical trials, with another gene therapy for DMD being suspended following three patient deaths. In the wake of these tragedies, do you anticipate there may be a lasting effect on how gene therapies are viewed by the public and by regulators?
EDW:
As I see it, the major lasting negative effect is likely to be the consequences of biotech investors and biopharma pulling out of gene therapy. This will severely slow down development and send broader signals that gene therapy is not clinically and commercially viable. In turn, this will lead to less research and development and fewer biotech start-ups attempting to fix the problems.
Regulators have an important role to play here by clearly signaling that the development of novel therapies for rare diseases will be streamlined and prioritized, especially when the medical need is high and no satisfactory treatment alternatives exist. Advocacy groups and the public also have a role to play here to bring focus on the problem and demand action to put appropriate incentive structures in place.
AB:
These patient deaths have come from gene therapy trials that use high doses of AVV as a delivery vehicle. Why are very high doses often used? What risks does this bring?
EDW:
AAV gene therapy requires high dosages, especially when delivered systemically. This is to ensure that enough AAV vectors reach their target tissue and cells and that the genetic payload is expressed at a sufficient level to achieve meaningful clinical benefit. Unfortunately, the high dosage can cause severe hepatotoxicity as the liver attempts to clear the virus. Immunological over-reactions to the sudden high viral load can cause additional problems and usually require the co-administration of immunosuppressive medications that may cause further complications on top of the liver toxicity.
New technologies that can enable more efficient uptake in target cells and drive enhanced gene expression from the AAV vector once delivered will be essential to fix this problem. Circio´s circVec circular RNA-based expression system represents such technology, with the ability to boost AAV protein expression by up to 40-fold in target tissues.
AB:
Can you tell us more about how Circio’s AAV-circVec technology works and what this could mean for patients?
EDW:
The circVec technology triggers circularization of the RNA molecule transcribed by the AAV vector inside the host cell. This is a major advantage because circular RNA has a 75-fold increased half-life compared to linear mRNA. The longer half-life enables the RNA to reach a higher intracellular steady-state concentration, which in turn leads to increased protein expression.
In animal models, Circio has demonstrated that circVec can increase AAV gene expression by 40-fold in the heart and 15-fold in the eye compared to conventional mRNA-based AAVs. Switching to circVec-based expression can therefore enable substantial dose reduction, which would be expected to lead to improved safety for patients and lower treatment cost. This could completely transform the clinical and commercial viability of AAV therapy as we know it today and establish circVec as a novel gold-standard gene expression system.
AB:
What more can scientists, biotechnology companies and others working in this field do to provide reassurance and improve confidence in the gene therapy sector?
EDW:
Success stories need to be highlighted to counterbalance the negative impact of recent gene therapy fatalities and commercial failures. Zolgensma® has been a big breakthrough for spinal muscular atrophy patients and quickly reached blockbuster sales revenues. Experimental gene therapies are giving patients with terminal genetic disorders new hope in areas such as Danon and Huntington´s disease and muscular dystrophies. These positive stories need to be told.
Science is also progressing to solve many of the AAV issues. New capsids and genetic design are enabling better tissue targeting. Companies such as Circio are developing technology to enhance expression and increase the potency of AAVs. When such advances are validated clinically and eventually combined into the same construct, a new generation of optimized and targeted AAVs with significantly improved clinical and commercial viability will emerge.
In parallel, the quest to develop synthetic non-viral gene therapies is continuing, with the promise of low-cost, repeat-doseable genetic medicines in the future. But the path and time required to get there will be substantially slower and more complicated if the current negative sentiment toward the gene therapy field as a whole is allowed to persist for much longer.
