Overcoming barriers to commercially pre-viable gene and cell therapies for rare and ultra-rare diseases

Abstract

Gene and cell therapies offer transformative potential for patients with rare and ultra-rare diseases. However, many treatments stall despite demonstration of safety and efficacy in pre-clinical studies and early-stage clinical trials. This market failure creates a barrier where otherwise successful therapies are unable to reach patients due to commercial non-viability. In March 2025, ASGCT held a workshop, “Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases,” focusing on developing actionable paths forward to ensure that successful gene therapies reach patients regardless of commercial viability. The field faces ongoing and deep-seated challenges; addressing them will require coordinated action across private companies, regulatory agencies, and non-profit organizations to explore non-traditional business models. During the workshop and described here, ASGCT reviewed a matrix of solutions encompassing regulatory innovations, manufacturing efficiencies, financial modeling, and patient-focused frameworks to ensure that efficacious gene and cell therapies reach the patients who need them. Strategies included the creation of a temporary repository for deprioritized gene and cell therapy programs offering support while working to identify new sponsors to continue clinical trials and the creation of a consortium of developers focused on accelerating timelines and reducing costs.

Graphical abstract

Gene and cell therapies offer transformative potential for patients with rare and ultra-rare diseases. However, many treatments stall despite demonstration of safety and efficacy in clinical trials. This market failure creates a barrier where otherwise successful therapies are unable to reach patients due to commercial non-viability. ASGCT held a workshop, “Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases,” focusing on developing actionable paths forward to ensure gene therapies reach patients regardless of commercial viability.

Introduction and recommendations

Gene and cell therapies offer transformative potential for patients with rare and ultra-rare diseases.^1,2,3 However, many treatments stall despite demonstration of safety and efficacy in pre-clinical studies and early-stage clinical trials. This market failure creates a barrier where otherwise successful therapies are unable to reach patients due to commercial non-viability. This paper serves as a summary of a workshop hosted by the American Society of Gene and Cell Therapy (ASGCT) in March 2025, “Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases.” This workshop focused on developing actionable paths forward to ensure that successful gene therapies reach patients regardless of commercial viability.

Multiple gene therapy programs that have recently been halted after significant investment and/or receiving market approval were discussed at this workshop. These discontinuations have occurred despite producing promising results in patients as companies struggle with the economic challenges of returning value on large investments into developing therapies for extremely small and most often pediatric patient populations. The sudden end of investigational therapies that have been successfully translated into the clinic can leave patients with few or no treatment options, and may diminish investor confidence in the field.

In short, the field faces ongoing and deep-seated challenges; addressing them will require coordinated action across private companies, regulatory agencies, and non-profit organizations to explore non-traditional business models (see Table 1). This paper reviews a matrix of solutions described at the workshop encompassing regulatory innovations, manufacturing efficiencies, financial modeling, and patient-focused frameworks to ensure that efficacious gene and cell therapies reach the patients who need them.

Table 1.

Matrix of solutions: A multi-faceted approach

	Regulatory solutions	Manufacturing innovations	Financial and business models	Patient access and support
Private companies	•platform master files •standardized vector approaches •real-world evidence generation	•scalable GMP facilities •automated vector production •quality-by-design approaches •multi-product platform tech	•PBC corporate structures •platform technology cost distribution •alternative funding models •value-based pricing agreements	•patient identification tech •digital engagement tools •long-term outcome tracking •patient support programs
Regulatory bodies	•accelerated approval pathways •flexible trial designs •platform IND/DMF approaches •START Pilot program •CoGenT harmonization initiative	•risk-commensurate standards •non-GMP materials guidance •accelerated CMC review •streamlined comparability protocols	•outcome-based reimbursement •value assessment frameworks •government infrastructure subsidies •federal safe harbor models	•cross-border treatment coordination •clinical trial networks •data sharing mandates •patient registry integration
Non-profits and advocacy organizations	•natural history studies •biomarker development •registry-based evidence •patient-reported outcomes	•open-source manufacturing protocols •academic GMP initiatives •IP management for discontinued therapies	•translational research funding •“valley of death” bridge grants •patient assistance programs •charitable access programs	•disease registries •patient identification networks •educational resources •advocacy for coverage
Public-private partnerships	•global regulatory harmonization •master protocol initiatives •coordinated ethics reviews •data standards development	•shared GMP manufacturing •technology transfer programs •process standardization •quality control networks	•collaborative financing mechanisms •joint risk mitigation •subscription pricing models •mission capital integration	•cross-border patient identification •centralized treatment coordination •multi-stakeholder patient support •global access initiatives

ASGCT has resolved to act on the ethical imperative of making transformative gene and cell therapies more accessible for all patients who could benefit from them. The next step in this effort is to develop and implement strategies to establish two complementary models addressing different aspects of the commercially pre-viable (CPV) gene therapy challenge.

Strategy 1: Maintaining and placing discontinued programs

The first strategy is to develop a temporary repository for intellectual property (IP), physical materials, and data from discontinued gene and cell therapy programs. This model may take any one of many forms, but would be most efficient as a 501(c)3 non-profit entity capable of accepting donated IP through ownership transfer or licensing agreements, along with physical property such as master cell banks, vector materials, and patient data from companies discontinuing development. It would maintain active patents, preserve physical materials according to US Food and Drug Administration (FDA)-compliant standards, and securely store clinical trial records while evaluating each program’s potential value, remaining gaps, manufacturing complexity, and available patient population. In doing so, it would maintain the integrity of programs while seeking to identify potential sponsors, whether public, corporate, academic, or non-profit, capable of continuing clinical development.

Strategy 2: Supporting existing developers of gene and cell therapies for ultra-rare diseases

The second strategy is to support existing and future developers of gene and cell therapies for ultra-rare diseases by forming a consortium focused on creating economies of scale by pooling resources, standardizing processes, and negotiating programs. This consortium would limit membership to organizations developing therapies for ultra-rare conditions, open to non-profit, academic, or corporate entities. It would facilitate sharing of Drug Master Files for FDA filings, enabling cross-referencing to reduce regulatory burden and share pre-clinical data through standardized formats to accelerate development timelines.

Background: The crisis of dropped gene and cell therapy trials

Overview of the workshop “Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases”

On March 6–7, 2025, the ASGCT convened a workshop in Washington, DC, titled “Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases.” The event brought together experts from the FDA, National Institutes of Health (NIH), academia, biotechnology companies, and patient advocacy organizations (see Table 2) to address the issue of CPV gene and cell therapies—treatments that show strong clinical promise, but face development barriers because they do not align with traditional profit-driven business models.

Table 2.

Attendees of the March 2025 ASGCT workshop, “Establishing and Maintaining Access to Gene and Cell Therapy for Rare and Ultrarare Diseases”

Jennifer Adair	Fred Hutchinson Cancer Center
Paul Ayoub	Rarity PBC
David Barrett	ASGCT
Vladimir Bermudez	Columbia University
Claire Booth	UCL Great Ormond Street Institute of Child Health
Derek Brand	St. Jude Children’s Research Hospital
P.J. Brooks	NIH/NCATS
Wilson Bryan	Wilson W. Bryan Consulting, LLC
Paula Cannon	University of Southern California
Brian Doehle	The Gates Foundation
Boro Dropulic	Caring Cross
Maria Ester-Bernardo	Vita-Salute San Raffaele University Medical School
Terence Flotte	UMass Chan Medical School
Javier Garcia	Columbus Ventures
James Geraghty	–
Sarah Glass	n-Lorem Foundation
Joseph Glorioso	University of Pittsburgh
Eric Hoffman	Binghamton University
Rich Horgan	Cure Rare Diseases
Alicia Kemble	Foundation Fighting Blindness
Donald Kohn	University of California, Los Angeles
Mimi Lee	ARPA-H
Crystal Mackall	Stanford University
Sunitha Malepati	Buffalo Initiative Inc.
Punam Malik	Cincinnati Children’s Hospital Medical Center
Peter Marks	Food and Drug Administration
Oralea Marquardt	National Tay-Sachs & Allied Diseases Associations Inc.
Caitlin McCombs	ASGCT
Rachel McMinn	Neurogene
Kamal Menghrajani	White House Office of Science and Technology Policy
Federico Mingozzi	Nava Therapeutics
Špela Miroševič	CTNNB1 Foundation
Edward Nielan	NORD
Paul Orchard	University of Minnesota
Kirsten Pier	TKD Solutions LLC
Terry Pirovolakis	Elpida Therapeutics SPC
Matthew Porteus	Stanford University
Leslie Powell	Cystic Fibrosis Foundation
Isabelle Rivière	Takeda
Rachel Salzman	Armatus Bio
Darshak Sanghavi	Advanced Research Projects Agency for Health
Celeste Scotti	Fondazione Telethon
Miguel Sena Esteves	UMass Chan Medical School
Courtney Silverthorn	FNIH
Kevin Strauss	Clinic for Special Children
Julie Tierney	Food and Drug Administration
Fyodor Urnov	University of California, Berkeley
Margarita Valdez Martinez	ASGCT
Nicole Verdun	Food and Drug Administration
Jen Wellman	Akouos
Beth White	Orphan Therapeutics Accelerator
Timothy Yu	Boston Children’s Hospital
Manar Zaghlula	Innovative Genomics Institute

This CPV w° focused on developing actionable frameworks to ensure gene and cell therapies for rare diseases can reach patients regardless of commercial constraints. Rather than viewing these treatments as commercially non-viable, participants emphasized their pre-viable status to recognize that, with appropriate regulatory, manufacturing, and financial innovations, many could achieve sustainability through non-traditional development pathways that prioritize patient access while returning reasonable economic value.^4,5,6

Scientific and medical promise of gene and cell therapies

Gene and cell therapies represent a paradigm shift in medicine, offering the potential to address the genetic root causes of previously untreatable diseases. Unlike conventional treatments that manage symptoms, gene therapies add or modify DNA to correct or compensate for genetic abnormalities, potentially providing long-term or permanent therapeutic benefits from a single administration. These treatments have shown remarkable efficacy in clinical trials for various rare diseases, offering hope to patients who previously had limited or no treatment options.⁷

Scientific advances in gene and cell therapy technologies, including viral vectors such as adeno-associated viruses (AAVs) and lentiviruses, gene editing approaches such as CRISPR, and ex vivo cell modification techniques, have created unprecedented opportunities to develop treatments for thousands of genetic disorders.⁸ Early successes in conditions such as spinal muscular atrophy (SMA), inherited retinal diseases, and blood cancers have demonstrated the transformative potential of these therapies. Since then, the pipeline of gene and cell therapies in clinical development has grown exponentially, now including over 4,400 gene, cell, and RNA therapies that are in development from the pre-clinical stage to pre-registration with the regulatory bodies.⁹

Market failures despite efficacy

Despite scientific and clinical successes, a growing number of gene and cell therapy programs have been abandoned at the pre-clinical stage or after phase 1/2 trials due to financial constraints rather than because of efficacy concerns.¹⁰ The traditional biotechnology business model is focused on maximizing shareholder value and struggles with the economics of and return-on-investment for rare disease treatments. Clinical trials for gene therapies differ significantly from those for traditional small-molecule drugs due to the therapies’ targeted and often transformative mechanisms of action. Unlike conventional drugs, which typically require large patient cohorts to detect modest treatment effects, gene therapies can show dramatic clinical benefit with far fewer participants, particularly in rare or severe diseases. This is partly because gene therapies often address the root cause of a condition at the molecular level, resulting in more pronounced and measurable outcomes. As a result, early-phase trials—especially phase 1 and 2—are frequently combined, focusing on safety as well as preliminary efficacy and durable response. This adaptive, streamlined approach is both scientifically justified and ethically appropriate given the urgent unmet needs and limited patient populations involved.

The standard development pathway for these therapies involves an average cost of $2.5 billion to bring a treatment to market, with success rates (defined as a sponsor securing a licensing authorization from a global regulatory body) under 10%. While gene and cell therapies are three times more likely to be approved by regulators than traditional drugs, the financial calculus for sponsors remains challenging due to the small patient populations involved. One mechanism that has provided some additional financial incentive and reward for pursuing such therapies is the Pediatric Priority Review Voucher (PRV) program, which awards a voucher at the time of approval of a Biologics Licensing Application (BLA) for therapies treating rare pediatric disorders. Such a voucher is highly valuable. The awardee of a PRV will typically sell it at auction for prices in the $100–$150 million range. However, the PRV is only awarded at the end of a process that can take many years and only for products that successfully reach the market.

Case studies of discontinued gene and cell therapy programs

Companies do not make decisions to discontinue their development programs lightly, especially once they have reached the late clinical stage. These gene and cell therapies represent monumental investments of time and resources, including from patient communities which often provide financial and operational support for the development of therapies. Biotechnology and large pharmaceutical companies are, however, profit-making enterprises, so they continually reassess which elements of their development portfolio show commercial promise.

For companies with developing or commercially approved gene and cell therapies, that has increasingly meant the discontinuation of programs that have either progressed to late-stage clinical development or have already been granted marketing authorization by one or more global regulatory bodies.

Here, we share a representative sample of halted gene and cell therapy trials and commercialized products in the last 5 years. This is not a comprehensive list, nor is it meant to indicate that these companies are acting in bad faith. By exploring the challenges they faced, our goal is to illuminate common elements of their experiences.

• •Editas Medicine/Reni-Cel: Editas Medicine halted development of Reni-Cel (EDIT-101), its CRISPR-based therapy for Leber congenital amaurosis type 10 in 2024, despite promising early efficacy data in clinical trials. The discontinuation resulted from financial constraints requiring the company to focus their resources on programs with clearer commercial potential, given the limited patient population of approximately 300–400 individuals in the US. Editas stated it would complete ongoing trials and seek collaboration partners to continue the program's development.
• •Audentes Therapeutics/XLMTM: Audentes Therapeutics suspended development of AT132 for X-linked myotubular myopathy after patient deaths between 2020 and 2021 in high-dose cohorts led to multiple FDA clinical holds. While showing initial promise in restoring muscle function, the program faced ongoing challenges balancing efficacy and safety. After Astellas Gene Therapy acquired Audentes Therapeutics portfolio reassessment and commercial viability considerations for this ultra-rare condition led to the program's deprioritization.
• •Lysogene/GM1: Lysogene presented data on its discontinued gene therapy for GM1 gangliosidosis in 2024, which was halted after preliminary results failed to demonstrate clear clinical benefit. The program faced multiple challenges including an extremely small patient population, high manufacturing costs, and financial constraints at the company. The abrupt discontinuation left participating families with limited communication about transition plans, highlighting the emotional impact on patient communities when trials are terminated.
• •Pfizer/Beqvez: Pfizer discontinued Beqvez, its FDA-approved gene therapy for hemophilia B, less than a year after approval in early 2025 due to limited uptake and strategic portfolio reprioritization. Despite demonstrating clinical efficacy, the therapy faced competition from other treatments and significant reimbursement challenges. This decision was part of Pfize's, broader retreat from the gene therapy field, although the company committed to ensuring ongoing care for patients who had already received treatment.
• •bluebird bio/Zynteglo: bluebird bio withdrew Zynteglo from the European market in 2021 despite European Medicines Agency (EMA) approval for transfusion-dependent beta-thalassemia 2 years earlier. The company cited inability to secure adequate reimbursement in major markets and prohibitive infrastructure costs, resulting in an average 531 days to reimbursement for innovative treatments across the EU. By the time of withdrawal, only a handful of patients had been treated with the commercial product despite years of availability, highlighting the gap between regulatory success and commercial viability.
• •Orchard Therapeutics/Strimvelis: Strimvelis, an ex vivo stem cell gene therapy for adenosine deaminase severe combined immunodeficiency (ADA-SCID), was deprioritized by Orchard Therapeutics in early 2022 as part of a strategic shift toward more common indications. The therapy faced commercial challenges due to its ultra-rare target population and the requirement for treatment at a single center in Milan, Italy. The University of California Los Angeles (UCLA), where researchers were involved in the original development, reclaimed the therapy’s IP rights and the San Rafael Telethon Institute became the market authorization holder, operating the program at break-even returns rather than targeting profits.
• •SIO Gene Therapies/GM2 and GM1 gangliosidosis: scientists at the University of Massachusetts (UMass) Chan Medical School developed AAV-based gene therapies for both GM2 gangliosidosis (one therapy that would treat both Tay-Sachs and Sandhoff variants) and GM1 gangliosidosis. UMass then conducted an initial expanded access use of the gene therapy for GM2, while National Human Genome Research Institute investigators initiated a phase 1/2 trial of the GM1 therapy. SIO Gene Therapies licensed the technology from UMass and became the investigational new drug (IND) sponsor for a phase 1/2 trial of GM2 at UMass and the financial sponsor of the GM gene therapies. In April 2022, in the midst of the phase 1/2 trial, SIO abruptly announced they were discontinuing funding of both GM1 and GM2 development efforts, despite the dose escalation study not being completed. This decision was driven by market analysis rather than efficacy concerns. UMass chose to continue the GM2 trial at UMass with a combination of institutional and foundation funds to support the completion of the GM1 trial at the NIH Clinical Center, allowing them to complete the dose escalation studies of both products and capture critical dose-response data that otherwise would have been lost.

Consequences of trial discontinuation

The deprioritization of promising gene and cell therapy programs due to commercial constraints, rather than clinical shortcomings, carries profound consequences for the rare disease ecosystem. When trials are discontinued, patients with rare conditions—who often have few or no therapeutic alternatives—are left behind. For patients, family members, and caregivers who may have spent years working toward a gene and cell therapy, news of a clinical trial or commercial product discontinuation can have a significant emotional impact. As a patient advocate emphasized during the CPV workshop, industry withdrawals such as the UMass gene therapy study collapse can severely erode patient trust in the research process, creating lasting damage to the relationship between patient communities and therapeutic developers. Such breakdowns may make it more challenging to recruit participants for future clinical trials, further hampering research progress.

Moreover, when a therapy is discontinued, the associated IP often remains under the control of the original developer, effectively blocking it from potential repurposing or continuation by other entities. The inability to access or license existing IP means that patients and advocacy groups are often left without viable alternatives to advance the therapy independently, creating stagnation in treatment development for these conditions. Beyond the immediate patient impact, these discontinuations can create a negative feedback loop that diminishes investor confidence, making it increasingly difficult to secure funding for similar rare disease programs in the future.

Regulatory innovations: Reducing barriers while ensuring safety

Regulatory barriers impacting commercialization

CPV workshop participants discussed the significant regulatory challenges that can impact commercial viability for gene and cell therapies. They include.

• (1)Stringent CMC requirements: FDA’s Chemistry, Manufacturing, and Controls (CMC) standards for gene and cell therapies require extensive documentation of product consistency, potency, purity, and manufacturing processes. Strong CMC standards are an important element of protecting patient safety and product quality, but it can create a disproportionate burden for academic centers and small biotechnology companies. These requirements demand specialized analytics expertise, which often necessitates expensive outsourcing and consumes significant quantities of limited product material for testing. The extensive validation protocols and documentation requirements may encompass thousands of pages, requiring multiple regulatory interactions and specialized expertise that smaller organizations struggle to maintain internally. These comprehensive requirements are largely applied universally regardless of whether a therapy is intended to treat dozens or millions of individuals, creating fundamental economic misalignment and disparities.
• (2)High clinical trial costs: rare disease gene and cell therapy trials face particular cost challenges due to geographically dispersed patient populations, often requiring multiple international clinical sites. That can dramatically increase coordination complexity and per-site costs. Extensive site training for specialized administration techniques (e.g., intrathecal delivery or retinal injections) must be conducted regardless of enrollment numbers, creating high fixed costs that cannot be distributed across large patient populations. Patient identification also represents a major expense, as many rare disease patients remain undiagnosed or misdiagnosed, requiring investment in disease awareness and diagnostic capabilities. Long-term follow-up requirements—typically 5–15 years for gene and cell therapies—create sustained monitoring expenses that extend far beyond the standard for small-molecule and biologics drug programs.
• (3)Differing international standards: regulatory agencies maintain distinct requirements for gene and cell therapy product characterization, with FDA, EMA, and Japan’s Pharmaceutical and Medicines Devices Agency emphasizing different aspects of CMC documentation, validation methods, and reference standards. Manufacturing facility inspections lack mutual recognition between regulatory authorities, necessitating multiple visits and duplicative qualification efforts for essentially identical processes. Pharmacovigilance frameworks and risk management requirements also vary significantly across jurisdictions, requiring separate monitoring protocols, safety reporting systems, and registry structures. These differences require sponsors to maintain parallel regulatory strategies and documentation packages—multiplying costs for therapies that already face economic challenges due to small patient populations.

Proposed regulatory solutions

Global regulatory alignment

The Collaboration on Gene Therapies (CoGenT) Pilot represents a promising initiative for international regulatory collaboration. As described by Dr. Nicole Verdun, Former Director of FDA’s Office of Therapeutic Products, at ASGCT’s 2024 Policy Summit, this program aims to facilitate simultaneous regulatory decisions across multiple global agencies to streamline approval processes. Coordination under this pilot would reduce redundancy in submissions and accelerate patient access across jurisdictions. By working toward a single application, which is reviewed collaboratively to produce near-simultaneous decisions, the program would address the challenge that some therapies fail to achieve commercial viability when the cost of market entry in multiple regions becomes prohibitive. Simultaneous approval would help companies access patient populations that may be extremely small in a single jurisdiction, but larger and more economically viable across multiple countries or regions.

Accelerated approval and flexibility for rare diseases

Biomarker-driven approvals can expedite therapies for rare conditions where traditional endpoints might be impractical due to small patient populations or heterogeneous disease progression within a population. Accelerated approval is a regulatory pathway established by the FDA to expedite the approval of drugs that treat serious conditions and fill an unmet medical need. Under this program, drugs can be approved based on a surrogate endpoint—a marker that is not a direct measure of clinical benefit but is reasonably likely to predict clinical benefit.

Compared with small-molecule and biologics drugs, gene and cell therapies are often well suited to surrogate endpoint use due to their direct action on the genetic root cause of disease. Unlike small molecules that may affect multiple pathways, gene and cell therapies have a more defined mechanism, creating a clearer relationship between biological modification (e.g., enzyme production or protein expression) and clinical benefit. This mechanistic directness allows measurement of biological consequences—such as factor VIII levels in hemophilia or survival motor neuron protein in SMA—that, when validated, can predict clinical improvement before symptoms visibly change. Additionally, the durable nature of gene and cell therapy effects makes these early biomarker changes particularly valuable for predicting long-term outcomes without waiting years to observe full clinical benefits.

Enhanced regulatory communication

The FDA’s support for Clinical Trials Advancing Rare disease Therapeutics (START) Pilot program increases communication between selected sponsors and FDA regulators through initial review meetings and additional ad hoc written communication. This enhanced communication can accelerate rare disease therapy development for products “intended to address an unmet medical need as a treatment for a serious rare disease or condition, which is likely to lead to significant disability or death within the first decade of life.” In the first round of the program, which was announced June 2024, seven products were selected to participate. Programs such as the START Pilot offer the opportunity for companies to develop rare disease therapies more efficiently, but expanding the program would require additional FDA resources and staff.

Regulatory frameworks for platform technologies

Standardized regulatory pathways for platform technologies such as CRISPR-, mRNA-, and AAV-based therapies could significantly reduce review burden on agencies while providing clearer guidance to developers. NIH’s Platform Vector Gene Therapy initiative provides valuable gene therapy regulatory guidance for rare diseases, publishing interactions with regulators to help others navigate the approval process. The NIH, through its Division of Rare Diseases Research Innovation (DRDRI) at the National Center for Advancing Translational Sciences (NCATS), is actively promoting the “bundling” of gene therapies to accelerate treatment development for rare diseases. Recognizing that many rare diseases share common molecular etiologies, DRDRI supports basket trials that evaluate a single therapeutic approach across multiple rare conditions.

In tandem, a provision in the 2023 Food and Drug Omnibus Reform Act created the Platform Technology Designation Program, offering a potential pathway for manufacturers to streamline cell and gene therapy (CGT) development by adopting standardized platforms for multiple products. Platform technologies, such as viral vectors or nucleic acid sequences, allow manufacturers to leverage existing data across multiple products, reducing the regulatory burden and speeding patient access to transformative therapies. This program would allow those who are granted the designation to receive additional assistance from the FDA, similar to what is available for Breakthrough Therapies. At this time, the program cannot be utilized across multiple INDs. Looking to the future, technologies such as CRISPR and mRNA platforms could benefit from streamlined development pathways that recognize their shared characteristics across different disease applications.

Manufacturing innovations: Reducing cost and expanding access

Barriers to scalable gene and cell therapy manufacturing

Manufacturing challenges significantly impact gene and cell therapies’ prospects for commercialization

The cost of producing viral vectors and sourcing raw materials remains a major hurdle, with cytokines representing the largest consumable cost, followed by RNA synthesis. While prices per unit decrease with increased scale, the initial manufacturing investment remains substantial. Building and operating facilities under Good Manufacturing Practices (GMP) require significant capital investment, while maintaining consistency across small production runs presents technical challenges.

A significant difference exists between “GMP-certified” and “GMP-like” materials in terms of cost per patient. Workshop participants discussed whether fully GMP materials are necessary for phase 1 trials, as FDA guidance states manufacturers “should” follow GMP in phase 1, suggesting that flexibility might be possible for rare disease trials. However, a challenge in using less-expensive reagents is that there are often requirements to demonstrate comparability to higher-grade materials, necessitating additional costly analyses.

Potential manufacturing solutions

Government-supported GMP manufacturing

Public infrastructure investment could dramatically reduce manufacturing barriers, for which the California Institute of Regenerative Medicine (CIRM) provides a useful example. CIRM established a “California CGT Manufacturing Network” to fund dedicated GMP manufacturing facilities at academic institutions across the state. These facilities enable the production of clinical-grade viral vectors, and gene and cell therapy products at lower costs than commercial contract manufacturing organizations while maintaining necessary quality standards for patient safety. Ongoing discussions at the NIH and the Advanced Research Projects Agency for Health (ARPA-H) are exploring parameters for establishing similar manufacturing hubs in the country. The NIH Ultra-Rare Gene-based Therapy Network represents a step in this direction, although expanded support would be needed to create a truly comprehensive national solution.

Decentralized production models

Decentralized (i.e., point-of-care) manufacturing also has a role to play in expanding gene and cell therapy access for small patient populations. Caring Cross has been a leader in that space. The organization’s mobile GMP units enable local production at hospitals with just 5–6 trained staff to produce over 750 therapies annually. That model has successfully facilitated technology transfer to countries including Turkey and Brazil, providing significant cost advantages through local labor utilization. These point-of-care manufacturing units include both manufacturing space and quality control facilities within the same unit, which is key to maintaining consistency.

Caring Cross’s experience shows that, by using identical devices, materials, and release reagents across locations, highly similar products can be produced consistently in different settings. Similarly, Spain’s national point-of-care manufacturing model has demonstrated successful nationwide comparability, enabling standardized production across multiple sites with national reimbursement. Broader adoption would require clear regulatory pathways that recognize the validity of decentralized models, robust data sharing frameworks to ensure transparency and consistency, and investment in workforce training to maintain technical standards across all sites.

Non-profit-led vector production

Patient foundations are increasingly funding Contract Drug Manufacturing Organization partnerships to ensure manufacturing capacity for their target diseases. For example, the Buffalo Initiative employs a patient-led non-profit model that blends philanthropic funding with investment capital to support AAV vector production for rare diseases, directly funding early-stage manufacturing infrastructure while ensuring equitable access for academic programs. Meanwhile, Italy’s San Raffaele Telethon Institute for Gene Therapy combines translational research with in-house GMP manufacturing under a non-profit framework, maintaining control over timelines and costs while prioritizing patient access. Both organizations demonstrate how patient foundations can transform manufacturing from a commercial barrier into a strategic tool for advancing therapeutic access.

Academic institutions such as UMass have also demonstrated that non-GMP materials can be used for phase 1/2 trials with appropriate quality control testing, reducing costs to approximately 25% of those charged by contract manufacturers while maintaining necessary quality standards for patient safety. At the CPV workshop, a representative from the university described how academic laboratories have proven they could meet commercial GMP standards, successfully advancing programs for conditions such as Cockayne syndrome and UBA5 deficiency.

The FDA has not, however, provided specific guidance that would help other laboratories replicate that success. This lack of clarity can leave academic centers uncertain about how to scale their efforts or when certain regulatory milestones—such as Process Performance Qualification studies for critical starting materials—are required, to pursue non-traditional commercialization of CGTs. Clearer FDA guidance on risk-based approaches, including how non-commercial entities can meet expectations for safety and efficacy without duplicative or cost-prohibitive studies, could empower more academic programs to pursue clinical development. Providing specific case examples, aligning with EMA standards, and formalizing expectations around quality definitions for vendors would not only help academic labs but also promote broader innovation across rare and ultra-rare CGT pipelines.

Financial and business model innovations

Funding bottlenecks for CGTs

Gene and cell therapy development faces several financial challenges. For one, traditional investors rarely focus on ultra-rare diseases due to limited return-on-investment potential. The standard profit-maximizing approach often drives biotechnology companies to prioritize more common conditions over rare diseases. Additionally, high clinical trial costs coupled with uncertain reimbursement create significant financial risk.

As CPV workshop participants discussed, three major funding sources exist for rare disease therapies: industry (which typically avoids ultra-rare diseases), government (which supports research but not commercialization), and philanthropy (often the only source available for ultra-rare diseases).

Alternative financial models

Outcome-based agreements

Payment structures tied to long-term patient outcomes can address payer concerns about upfront costs and uncertainties about durability. The Center for Medicare and Medicaid Innovation’s Cell and Gene Therapy Access Model for sickle cell disease (SCD) gene therapies represents a pioneering approach, with upfront payments followed by 5-year outcome tracking and potential rebates based on therapeutic performance.¹¹ The model focuses on the approximately 100,000 SCD patients in the US, 60% of whom are on Medicaid, representing an annual cost to the healthcare system of approximately $3 billion. By enabling federal government negotiation on behalf of states to establish outcomes-based arrangements, the model aims to ensure more equitable access while managing costs. Key outcomes tracked include continued blood transfusions, reduction in vaso-occlusive crises, and patient-reported outcomes.

Recent regulatory developments have helped enable these models. Notably, the Centers for Medicare & Medicaid Services (CMS) finalized the Multiple Best Price rule in 2022, clarifying that manufacturers participating in Medicaid can offer outcomes-based contracts to commercial payers without jeopardizing their “best price” obligations under Medicaid, as long as multiple price points are reported. This update removes a long-standing disincentive for manufacturers to enter value-based agreements, particularly for high-cost therapies such as those for rare and ultra-rare diseases.

In Congress, the 2023 Medicaid VBPs for Patients (MVP) Act was introduced to further facilitate value-based purchasing (VBP) in Medicaid. The bill sought to create a legal and operational framework for VBP contracts by allowing state Medicaid programs to enter into outcomes-based agreements without running the risk of violating federal anti-kickback or Medicaid rebate rules. Although it was not passed in the 118th Congress, and at the time of publishing has not been reintroduced in the 119th, the MVP Act illustrates growing bipartisan interest in making high-cost, durable therapies more accessible through innovative payment structures.

Public benefit corporations

Public benefit corporations (PBCs) are for-profit entities that include a public benefit mission in their charter and are legally obligated to uphold that mission while considering the impact on all stakeholders in society. Unlike traditional for-profit companies, PBCs are mandated to balance profit and public benefit, allowing companies to raise capital and grow while ensuring therapies reach patients. One example of the approach, Rarity PBC, demonstrates how that structure can be applied to rare disease development. The organization is supporting access to UCLA’s ADA-SCID program, along with CIRM, and attempting to advance their therapy through FDA approval.

This approach does have its own challenges, including the difficulty of attracting traditional investors who may prioritize higher shorter-term returns over long-term impact. PBCs must also navigate complex regulatory pathways and manufacturing logistics with fewer resources than large pharmaceutical companies. Additionally, while the legal structure mandates balancing public benefit and profit, it does not guarantee sufficient funding or operational success—particularly in a field as capital-intensive as gene and cell therapy. Nonetheless, PBCs such as Rarity offer a compelling model for sustaining development and access for therapies that might otherwise be abandoned due to commercial considerations.

Philanthropy-driven commercialization

Another option is for non-profit entities to manage development and commercialization through philanthropic rather than profit-driven entities. The Telethon Foundation, for example, has funded ongoing development of gene and cell therapies for metachromatic leukodystrophy and ADA-SCID after they were discontinued by industry sponsors. They have demonstrated success in advancing treatments through commercialization; when Orchard Therapeutics discontinued Strimvelis, the San Rafael Telethon Institute, supported by the Telethon Foundation, took over as the market authorization holder and maintained patient access.¹²

This model shows how non-profit organizations can develop therapies from vector production through pre-clinical development, clinical trials, and eventually license to industry partners better suited to pursue non-traditional commercialization. When commercial entities withdraw support, non-profits can sometimes reclaim these assets, as seen with Strimvelis, which continues to be offered at break-even pricing with pro bono treatment for patients from non-EU countries.

Philanthropic models, however, often require sustained donor commitment in lieu of profits, which can be unpredictable and difficult to scale across multiple programs. Philanthropy alone may not provide the consistent, long-term capital needed to fund expensive late-stage trials, navigate regulatory approval, and implement global distribution infrastructure. Non-profits may also lack in-house manufacturing capacity or regulatory expertise, requiring reliance on academic or contract partners who can overcome coordination and quality challenges. A further challenge is that the ability to reclaim and maintain access to discontinued therapies often hinges on favorable licensing terms or relationships with the original developers—conditions that are not always guaranteed.

Bundling rare disease programs

As discussed previously, gene and cell therapy platforms have the potential to address regulatory barriers to development. Distinct from the FDA’s Platform Technology Designation Program, however, a platform approach can also be useful for fundraising. Creating economies of scale by aggregating multiple rare diseases under platform approaches can distribute costs across larger patient populations (i.e., using the same vector to deliver therapeutic genes to a tissue that is affected by several genes). Bundling an umbrella of INDs for multiple gene therapies using similar constructs but different therapeutic genes represent one way that this strategy could be implemented.

Workshop participants discussed that, when approaching venture capital or philanthropic funding sources, pitching a platform technology rather than a single disease indication can increase investment interest by demonstrating broader impact potential. However, some participants cautioned that this approach must balance a platform focus with attention to disease-specific complexities.

Public-private partnerships: Collaborating for impact

Public-private partnerships offer crucial mechanisms to address market failures by combining the resources, expertise, and risk tolerance of different sectors.

• (1)Academia: contributes basic research and early clinical development.
• (2)Non-profit and patient organizations: provide patient connections and mission-driven funding.
• (3)Industry: supplies raw materials, technologies, services, manufacturing expertise, global regulatory expertise and global commercialization capabilities.
• (4)Government: offers regulatory support and infrastructure funding.

Key partnerships and initiatives

NIH Accelerating Medicines Partnership-Bespoke Gene Therapy Consortium

The Accelerating Medicines Partnership-Bespoke Gene Therapy Consortium (AMP-BGTC) represents a public-private initiative focused on improving translational pathways for AAV-based rare disease gene therapies.^13,14 As described at the CPV workshop by a representative from the NCATS, the consortium helps advance AAV-based gene therapies from proof-of-concept to dosing patients more efficiently, sharing learnings across member organizations to develop iterative solutions. The program has released a “playbook” for AAV development for rare diseases and continues to update this guidance with new insights.¹⁵ AMP-BGTC focuses on a single vector type, so it will not have direct utility for all gene therapy developers, but represents the kind of collaborative approach that is needed across the field.

The access to gene therapies for rare disease project

The access to gene therapies for rare disease (AGORA) project provides centralized gene therapy manufacturing and marketing authorization in Europe. The project brings together academic centers with GMP manufacturing capabilities, such as the Great Ormond Street Hospital, to coordinate the development and delivery of gene therapies across European borders. The model enables each participating center to become a center of excellence in specific indications, facilitating patient access to treatments and promoting economies of scale to overcome the “second valley of death” in gene therapy development. By ensuring access to advanced therapies, AGORA enhances the likelihood of successful commercialization, particularly for ultra-rare diseases such as inborn errors of immunity and metabolism, which are the initial focus of the program.¹⁶

One challenge for this approach is ensuring equitable healthcare access and coverage for patients across the European continent. The initiative is exploring cross-border payment mechanisms, including the S2 funding route which covers planned medical care (as opposed to emergency care) that is not available in their home country. Under the S2 system, the patient’s country of residence covers their treatment costs.

Access4Kids

Access4Kids creates non-profit partnerships with academic pediatric centers to conduct pivotal trials, improve academic GMP standards, and reduce institutional liability while leveraging existing R&D efforts.¹⁷ This initiative focuses on pediatric cancer treatments that have experienced market failure for decades due to lack of industry investment, particularly given that high rates of Medicaid coverage among pediatric populations make traditional premium pricing models unsustainable.¹⁸ Formed following the meeting of academic, industry, and non-profit leaders, the effort seeks to provide the resources, infrastructure, and expertise needed to conduct registration trials, file BLAs, and conduct post-approval manufacturing and marketing. Its strategic vision is to build relationships within academia to access innovation, leverage accelerated approval and cost recovery regulatory pathways, and establish licensing practices that protect IP.

ASGCT's role in addressing CPV gene and cell therapy programs

The need for an intermediary

ASGCT is uniquely positioned to serve as a neutral, mission-driven intermediary that can bridge the gap between companies forced to abandon promising gene and cell therapies and organizations better equipped to continue their development. As a professional society representing individuals across academia, industry, regulatory and clinical sectors, and patient advocacy, ASGCT possesses the scientific credibility, cross-sector relationships, and technical expertise required to evaluate abandoned programs and identify appropriate partners for continued development. ASGCT’s broader focus on advancing cell and gene therapies allows it to address the systemic challenges facing multiple rare disease programs simultaneously, developing standardized processes that can benefit the entire field.

What is missing? The gaps that need addressing

IP management for discontinued therapies

When companies abandon promising gene and cell therapies, the IP often remains inaccessible to other entities that might continue development, and CPV workshop discussions highlighted the need for a formal mechanism to facilitate IP transfers. Industry representatives should consider establishing pathways to return IP even before launching programs, creating pre-determined contingency plans if commercial viability proves challenging.

Reimbursement and payer support

Current reimbursement systems in the US are not designed for high-cost, one-time curative therapies.

• (1)Medicaid challenges: for example, with approximately 60% of SCD patients covered by Medicaid, state programs cannot absorb the high upfront cost of gene and cell therapies without additional support.
• (2)Interstate barriers: single-case Medicaid agreements for out-of-state patients can take months to resolve, which is unacceptable for rapidly progressing diseases.

CMS must develop long-term financing strategies, potentially where the federal government supports upfront costs with states repaying as they realize healthcare savings over time. Workshop participants noted that states need to balance their budgets annually, making it difficult to absorb the cost of multi-million-dollar therapies, but would benefit from the healthcare savings provided by long-term curative therapies.

The role of academia

Academic institutions face unique challenges in advancing gene and cell therapies.

• (1)Perpetual IND model: some institutions maintain open INDs for continued therapy development, but this approach lacks direct reimbursement pathways.
• (2)Legal and indemnification issues: US state laws complicate indemnification for academic institutions managing clinical programs.

The field needs clear guidelines for transitioning gene and cell therapies from academic centers to commercialization, including risk management frameworks and shared competency models. CPV workshop participants suggested that a federal safe harbor policy, similar to the National Vaccine Injury Compensation Program, could provide a backstop for indemnification concerns, making it easier for academic centers to take on development responsibilities for ultra-rare conditions.

Conclusion and call to action

The crisis of CPV gene and cell therapies requires urgent, coordinated action across private industry, government, academia, and patient advocacy organizations. Without new approaches to development, manufacturing, financing, and regulation, promising therapies will continue to be abandoned, leaving patients without treatment options.

This paper outlines a wide variety of solutions that, implemented within a coordinated framework, could transform the landscape for rare and ultra-rare disease gene and cell therapies. We call on all stakeholders to commit to specific actions within their domains of influence.

Based on these considerations, the task force made a recommendation to the ASGCT Board of Directors to explore at least two options for future action by the society to facilitate the lowering of obstacles to access to CGTs for rare diseases: First, the creation of a consortium among those willing to share lower cost alternatives for manufacturing and regulatory advancement of CGTs along with appropriate data sharing on common platforms. Second, the ASGCT may also consider creating or partnering on a framework to “hold” or preserve regulatory and IP assets associated with CPV-CGTs that are no longer being pursued commercially so that they may be further developed and made available to patients in the future. The ASGCT Board has authorized the ASGCT staff to further develop proposals for action on the first of these ideas, establishing a consortium. The Board also authorized the staff to explore the potential risks and benefits of the second idea, creating an entity to preserve CPV-CGT assets until an interested party chooses to pursue them further.

By working together across these domains, we can ensure that scientific breakthroughs translate into accessible treatments for all patients with rare genetic diseases, regardless of the commercial considerations that have historically limited their development.

Acknowledgments

The authors wish to acknowledge Caitlin McCombs and Tom Gallagher for their assistance in preparing and editing this manuscript, Liz Hughes for her work to plan and execute the workshop logistics, as well as the members of the Society’s Commercially Pre-Viable Gene and Cell Therapy Taskforce who developed the workshop program.

Author contributions

All authors were involved in drafting and editing the manuscript. As elected officers and members of its Executive Committee, P.M.C., F.M., M.P., I.R., and T.R.F. approved the manuscript on behalf of ASGCT.

Declaration of interests

The authors declare no competing interests.