Why Ultra-Rare Gene Therapies Struggle to Reach Patients: Lessons From DBA at ASTCT

For patients with Diamond-Blackfan anemia (DBA), delays in developing gene therapy can mean more years of blood transfusions and continued exposure to iron overload. At the 2026 American Society for Transplantation and Cellular Therapy (ASTCT) Gene Therapy Summit in Boston, Nicholas Vita, co-founder and CEO of Apriligen, argued that overcoming scientific barriers is only part of bringing treatment to patients.

"It costs us time, and in this disease, time is measured in transfusions," Vita said, describing setbacks in the company's manufacturing plans.¹

The Burden Behind the Development Timeline

DBA is an inherited bone marrow failure disorder characterized by impaired red blood cell production. Some patients respond to corticosteroids; others require ongoing transfusions and iron chelation. Hematopoietic stem cell transplantation offers a potential hematologic cure but carries substantial risks.

International consensus recommendations emphasize early management of transfusion-associated iron overload and individualized transplant decisions. Monitoring may include MRI measurements of liver and cardiac iron; chelator selection depends on the burden of iron accumulation and drug tolerability.²

Vita described a child who had received approximately 250 transfusions by age 12, often enduring difficult intravenous access and hours in the hospital. He presented the account as an example of why conventional development timelines have consequences well beyond a company's financial projections.

"The biology was largely done a decade ago. It took 25 years because of the economics, because the economics didn't work. The operating model didn't exist," he said.¹

In May 2026, the Styrke Foundation convened an externally led patient-focused drug development meeting involving patients, caregivers, and FDA staff. Its published recap reports survey responses from 82 patients and caregivers across 9 countries.³ Vita said the feedback emphasized freedom from ongoing treatment, not simply improved control of anemia.

"That's not a wish list. That's a product specification," he said. "Patients told us and the FDA exactly what to build."¹

That distinction matters to pharmacists supporting transfusion-dependent patients. Even when transfusions preserve hemoglobin levels, chelation regimens require adherence support and monitoring for renal, hepatic, and other toxicities. Deferasirox (Exjade; Novartis), for example, requires renal and hepatic surveillance, while infused deferoxamine can impose its own treatment burden.² Successful new therapies would need to demonstrate meaningful benefits without overlooking these existing care burdens.

Rebuilding Manufacturing Around Small Populations

Vita described Apriligen's investigational APR-2020 program, which uses a patient's own CD34-positive hematopoietic stem cells modified with a lentiviral vector to supply functional RPS19. The phase 1, single-arm study (NCT07476183) is registered to assess safety and potential efficacy in transfusion-dependent patients with RPS19-deficient DBA. Its planned enrollment is 4 participants, and its measures include adverse events, hematologic response, and transfusion-related outcomes. No clinical efficacy is established by trial registration.⁴

Apriligen describes reduced-dose bone marrow conditioning before the modified cells are infused. That distinction matters: an autologous approach avoids a donor requirement and graft-versus-host disease but does not eliminate preparation-related risks.⁵

The company initially contracted with a commercial manufacturing organization, Vita explained, before moving production to an academic cell-processing facility after difficulties with that arrangement. He reported improved product quality and lower costs; those comparisons were company-reported, not independently established during the presentation.

"What it needs are 10 adequate doses for 10 patients," Vita said, contrasting ultra-rare production requirements with conventional large-scale operations.¹ The broader objective, he suggested, is to avoid rebuilding manufacturing infrastructure from scratch for every genetic condition.

"Design the first program so the second costs half as much," Vita advised.¹ Academic production may offer specialized expertise and suitable small-batch capabilities, although rigorous product comparability, release testing, and regulatory oversight remain essential. Vita acknowledged that regulatory updates forced revisions to release assays and delayed the timeline for treatment, illustrating the difficulty of combining speed with manufacturing consistency.¹

Patient Input Meets Regulatory Flexibility

Vita said patient advocacy helped Apriligen refine how it approaches development. "When the people who own the company are the people who need the drug, the incentive is very simple," he said.¹

He also described stepping away from a patient foundation to preserve its independence from commercial sponsors. "But combining advocacy with the business takes real discipline," he acknowledged.¹

The FDA's Rare Disease Evidence Principles (RDEP) process offers a potential route for certain treatments targeting known genetic defects in very small populations. The agency states that one adequate, well-controlled study, potentially single-arm, may be considered alongside strong confirmatory evidence. Participation does not waive safety and efficacy standards or guarantee approval.⁶ Vita advised developers to "treat the FDA as a design partner. Know which framework you're using before you knock, and ask precise questions."¹

Vita described the uncertainty of negotiating study design when eligible patients number only in the dozens, especially because he said the agency would not commit to a predetermined number of participants before seeing clinical data. His team also developed a company-reported computational approach to assess the biological effects of RPS19 correction.

"Did correcting the gene actually repair the disease biology? How far? In which direction," he asked, highlighting questions that remain separate from demonstrated clinical efficacy.¹

For pharmacy and cell therapy teams, such studies require careful coordination of stem cell collection, conditioning, product receipt, supportive medications, and longer-term monitoring. These operational demands are not erased by a smaller trial enrollment. The registered protocol also tracks changes in iron stores and chelation needs, outcomes directly relevant to supportive care.⁴

A Scientific Advance Still Needs a Delivery Model

Vita cautioned that favorable regulatory discussions do not resolve commercial uncertainty. "Frameworks have to outlast people who wrote them," he said, pointing to the vulnerability of development plans to changing policy. He also emphasized that "approval does not guarantee success."¹

Vita also raised the possibility that treatments could obtain authorization without becoming commercially available. His case for ultra-rare therapies remained grounded in a broader argument about how medical innovation is valued. "For decades, ultra rare has been treated as charity work at the edge of medicine. Too small, too hard, and too expensive, and I think that's exactly backwards. Ultra rare is where medicine learns to be precise," Vita said.¹

APR-2020 remains investigational, and its eventual clinical benefit, regulatory outcome, and access are unresolved.

"The rare disease lens is the lens, not the limit," he concluded.¹

REFERENCES

1. Vita N. DBA and the ultra-rare landscape: progress and perspective. Presented at: ASTCT Gene Therapy Summit; November 4, 2026; Boston, MA.

2. Wlodarski MW, Vlachos A, Farrar JE, et al. Diagnosis, treatment, and surveillance of Diamond-Blackfan anaemia syndrome: international consensus statement. Lancet Haematol. 2024;11(5):e368-e382. doi:10.1016/S2352-3026(24)00063-2

3. Styrke Foundation for Rare Disease Research and Treatment. Externally led patient-focused drug development meeting. Held May 1, 2026. el-pfdd-meeting

4. ClinicalTrials.gov. Assessing the safety, tolerability, and efficacy of APR-2020 in pediatric and adolescent subjects with RPS19 deficient Diamond-Blackfan anemia. NCT07476183. https://clinicaltrials.gov/study/NCT07476183

5. Apriligen. Our therapy and process. Accessed November 4, 2026. https://apriligen.com/therapy/

6. US Food and Drug Administration. CDER/CBER Rare Disease Evidence Principles (RDEP). cdercber-rare-disease-evidence-principles-rdep