Gene therapy no longer needs to prove it can treat disease. With multiple approvals across rare genetic disorders, the field has crossed its long-anticipated proof-of-concept threshold. The more difficult challenge now is how to turn those early successes into therapies that work for many more patients.
Manufacturing bottlenecks, delivery constraints, and eye-watering costs still limit who can benefit from these advanced treatments. Solving the next phase of gene therapy will require platforms that are easier to tailor, scale, and deploy, shifting the field from bespoke, one-off cures toward treatments that can realistically reach patients beyond the rarest of rare diseases.
This shift is pushing start-ups to rethink foundational assumptions — particularly around vector choice, immune engineering, and manufacturing — and to design therapies around patient needs and biological reality rather than historical precedent.
Two European companies, Genespire and AAVantgarde Bio, illustrate how the field is branching into more specialized, purpose-built approaches.
Designing gene therapy for growing patients
Genespire’s platform is designed around a problem that early gene therapies largely sidestepped: how to treat very young children with diseases that require durable, lifelong correction.
Many of the first approved liver-directed gene therapies use adeno-associated viral (AAV) vectors, which deliver therapeutic genes that remain episomal rather than integrating into the genome. This approach can produce strong early efficacy, but it comes with a trade-off. As liver cells divide and the organ grows, the therapeutic DNA can be progressively diluted, potentially eroding gene expression over time. For pediatric patients, whose livers are still rapidly expanding, this raises fundamental questions about durability, redosing, and whether one-time gene therapies can truly provide permanent benefit.
We’ve generated extensive durability data in animal models, including dogs and non-human primates. In these models, we see stable transgene expression maintained over the lifetime of the animal, even in growing organs.
—Lucia Faccio, Genespire
Genespire has instead centered its platform on lentiviral vectors, which integrate into the genome of target cells and can maintain stable expression as tissues grow. “We’ve generated extensive durability data in animal models, including dogs and non-human primates. In these models, we see stable transgene expression maintained over the lifetime of the animal, even in growing organs,” Lucia Faccio, CEO of Genespire, told DDN.
Genespire’s lead program, GENE202, targets methylmalonic acidemia (MMA), a rare and severe metabolic disorder that prevents the proper breakdown of certain amino acids and fats.
“Children with MMA are diagnosed very early, often shortly after birth, because they experience severe metabolic crises. The disease causes toxic metabolite accumulation that damages the liver and kidneys,” said Faccio.
Today, the only effective long-term treatment is liver or liver–kidney transplantation — an approach that requires lifelong immunosuppression. “Our goal is to intervene early, before irreversible damage occurs, and allow the liver to produce the missing enzyme itself,” Faccio noted. In recognition of this unmet need, GENE202 has recently been granted orphan drug designation by both the FDA and the European Commission.
At the same time, the company has focused on engineering its vectors to be immune-shielded, tackling one of gene therapy’s most persistent challenges. “Our immune-shielded lentiviral vectors are engineered to avoid triggering the immune system. We remove surface molecules, such as MHC proteins, that normally signal ‘foreign body’ to immune cells, and we overexpress CD47, a natural ‘don’t eat me’ signal that prevents clearance by macrophages,” Faccio explained.
The aim is to enable systemic delivery while minimizing inflammation and avoiding the immune barriers that have complicated some first-generation gene therapies. But for Genespire, solving the biological challenges is only part of the equation.
“The biggest challenge for gene therapy now is not efficacy — that has already been demonstrated — but accessibility. Manufacturing costs, pricing, and reimbursement models need to evolve.”
That focus on accessibility has also shaped how the therapy is delivered. “Because our therapy is off the shelf and administered intravenously, it avoids the complexity of ex vivo cell manipulation. Once safety and efficacy are established, this could make treatment much more accessible within hospital settings.”
“Just as monoclonal antibodies took time to become scalable and affordable, gene therapy will require innovation in manufacturing and new business models to reach patients sustainably,” Faccio emphasized.
Pushing AAV beyond its size limits
While Genespire is rethinking durability, AAVantgarde Bio is tackling a different long-standing constraint: transgene size.
AAV vectors are the most widely used delivery vehicles in gene therapy, particularly in the eye, where they have demonstrated strong safety and long-term expression. However, AAVs have a limited genome packaging capacity of between 4.7 and 5kb, restricting the size of the genes that they can carry.
AAVantgarde is working to expand what AAV gene therapy can deliver by developing dual-AAV strategies, which split large genes across two vectors. The company is testing this approach in two programs. One, AAVB-039, uses a protein splicing method to rebuild the 6.8 kb ABCA4 gene for Stargardt disease. The other, AAVB-081, uses a dual recombination system to deliver the 6.7 kb MYO7A gene for Usher syndrome type 1B. Each strategy is designed to fit the biology of its target gene and disease.
Both approaches begin by splitting the gene into two halves, each packaged into its own AAV vector. Once inside retinal cells, the two halves are reassembled into a functional gene. In the dual recombination approach, the halves are stitched together at the DNA level, which is then transcribed and translated into a functional protein. In protein-splicing, each vector produces mRNA for a fragment of the protein. These fragments are translated and then self-assembled into the full protein with the help of special intein sequences.
The company selected which approach to use based on the reconstitution efficiency in animal models. “Because patients are born deaf and gradually lose their sight – meaning they become double-disabled – the unmet need is huge for Usher 1B,” Natalia Misciattelli, CEO of AAVantgarde, told DDN. “We found our DNA-splicing approach was most effective for treating Usher 1B. For Stargardt disease, protein splicing via inteins proved far more efficient. It’s essentially choosing the right tool for the job — efficacy drives everything we do.”
Preclinical data show that co-transduction — ensuring both halves of the dual-AAV system enter the same cell — occurs in 76–99 percent of target cells, reducing the risk of mis-recombination or incomplete protein assembly.
Patients are gaining letters of sight on standard BCVA tests. Clinicians report meaningful improvements in daily functioning and quality of life.
—Natalia Misciattelli, AAVantgarde
“We’ve measured this extensively in non-human primates,” Misciattelli said. “And our safety data are clean: long-term studies in mice and primates show no bioaccumulation or deterioration over time, and inflammation in treated eyes resolves quickly with a steroid regimen.”
In January 2026, AAVantgarde completed enrollment in LUCE-1, a Phase 1/2 first-in-human trial evaluating AAVB-081 in adults with Usher syndrome type 1B–associated retinitis pigmentosa. The multicenter, open-label study is assessing the safety, tolerability, and preliminary efficacy of a single subretinal administration of the dual-AAV therapy. With enrollment complete and dosing finished, the company expects the dataset to mature over the course of 2026, alongside continued recruitment in its CELESTE study for Stargardt disease.
“We’ve treated all the patients in our phase 1/ 2 LUCE study and have data for some of them stretching up to one year where we are seeing not only a halt in disease progression, but improvements in vision,” Misciattelli said. “Patients are gaining letters of sight on standard BCVA tests. Clinicians report meaningful improvements in daily functioning and quality of life.”
From rare cases to broader impact
By designing therapies that account for growing organs, complex genes, and early intervention, these start-ups are transforming one-off experimental treatments into strategies that could reach more patients and offer lasting benefit. The combination of innovative vector engineering, tailored delivery approaches, and careful attention to safety and efficacy is helping gene therapy become scalable, sustainable, and meaningful for patients’ lives.
