The gene therapy landscape is rapidly evolving with 32 approved products globally that alter gene expression, and seven more expected to receive regulatory approval by the end of 2024. However, despite significant investment from major pharmaceutical companies and over $3.2 billion raised from private equity investors between January 2023 and March 2024, these potentially life-changing treatments continue to face substantial challenges in safety, efficacy, and commercial viability.
According to Citeline data, as of April 2024, 2,093 gene and cell therapies are in development globally, with 30 products currently in phase 3 clinical trials. Major pharmaceutical companies including AstraZeneca, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Novo Nordisk, Roche, and Sanofi have all made significant investments in this therapeutic area.
Mixed Clinical Results and Commercialization Challenges
Gene therapies have shown promising results for certain rare diseases, including Duchenne muscular dystrophy, hemophilia A and B, sickle cell anemia, and spinal muscular atrophy. However, many programs have failed either due to lack of efficacy, such as Novartis' OTQ923, or unexpected side effects, as seen with Pfizer's fordadistrogene movaparvovec and BioMarin's BMN307.
Even successfully approved therapies have faced significant commercialization hurdles. UniQure's Glybera (alipogene tiparvovec) was withdrawn from the European market just five years after approval for familial lipoprotein lipase deficiency. More recently, Bluebird Bio's Zynteglo (betibeglogene autotemcel) for transfusion-dependent beta-thalassemia has struggled to gain market traction.
Dr. Erik Wiklund, CEO of Circio, explains: "Gene therapies have been available for more than 30 years, and there are now AAV-based and HSV-based approaches available. However, these therapies are technologically suboptimal, and we need to move away from viral delivery systems towards nucleic acid systems to enable repeat dosing."
Advancing Beyond CRISPR-Cas9
The approval of Vertex Pharma/CRISPR Therapeutics' Casgevy (exagamglogene autotemcel) in late 2023 marked a significant milestone as the first FDA-approved ex vivo CRISPR-based therapeutic for sickle cell disease and beta-thalassemia. This breakthrough has accelerated development of in-vivo CRISPR therapies, such as Intellia Therapeutics' phase I LNP-delivered CRISPR drug NTLA-2002 for hereditary angioedema.
However, the industry is already moving beyond traditional CRISPR-Cas9 toward more refined gene editing technologies. These include CRISPR interference (CRISPRi), CRISPR activation (CRISPRa), Base Editors (BE), Prime Editors (PE), Programmable Addition via Site-specific Targeting Elements (PASTE), and CRISPR-associated transposase (CAST) technologies.
Interest in Base Editors and Prime Editors is growing particularly rapidly as these tools can correct large genes (>4 kb) without creating double-strand breaks in DNA, thereby reducing unwanted modifications and off-target effects. In April 2024, Prime Medicine received FDA clearance to initiate a phase I/2 trial with PM359, an ex vivo Prime Editing-based gene therapy for chronic granulomatous disease (CGD). The therapy has received both rare pediatric drug designation and orphan drug designation from the FDA.
Revolutionary Delivery Systems
A major focus in the industry is developing alternatives to traditional viral vectors, which are costly to manufacture and may trigger immune responses that prevent repeat dosing. Companies are advancing both viral and non-viral delivery systems to overcome these limitations.
Non-viral delivery platforms under development include:
- Conjugate-based platforms
- Exosomes
- Lipid nanoparticles (LNPs)
- Non-lipid hydrophilic nanoparticles (HNPs)
In January 2024, GenEdit partnered with Roche's Genentech to utilize its non-lipid hydrophilic nanoparticle NanoGalaxy platform for targeted delivery of nucleic acid-based medicines to treat autoimmunity. The company previously partnered with Sarepta Therapeutics to focus on neuromuscular diseases.
Viral delivery innovations include:
- Next-generation AAV capsids
- Herpes simplex virus vectors
- Virus-like particles (VLPs)
Regeneron recently demonstrated that DB-OTO, which uses a dual adeno-associated virus (AAV) modality to deliver the otoferlin gene in two parts, can restore hearing in patients born with otoferlin gene mutations. However, the high manufacturing costs and dosing limitations of viral vectors continue to drive the search for alternatives.
Exosomes: A Promising Alternative
Exosome-based delivery systems are emerging as particularly promising alternatives to viral vectors. Companies including Excellio Labs, EV Therapeutics, Exo Biologics, and ReNeuron are developing exosome-based therapies that may provide biocompatible, cost-effective alternatives.
Kasia Maj, co-founder and CEO of Excellio Labs, highlights the advantages: "Exosomes offer several compelling advantages over traditional and other novel delivery systems. Exosomes are naturally occurring biocompatible, low immunogenic nanovesicles that can deliver genetic material with high specificity to target tissues. In addition, exosomes can be seamlessly integrated into the cellular machinery, to offer precise and efficient delivery of therapeutic genes."
In June 2024, Belgium-based EXO Biologics completed dosing the first cohort of its phase 1/2 EVENEW study to assess the safety and efficacy of EXOB-001, an exosome-based therapy administered intratracheally for the prevention of bronchopulmonary dysplasia in pre-term babies.
Romain de Rauville, CBO of EXO Biologics, notes: "EVs are inherently safe and, unlike AAVs, there is no need to remove toxic empty capsids."
Payer Concerns and Future Outlook
The evolving gene therapy landscape presents significant challenges for healthcare payers. While traditional one-time gene therapies allow payers to accept high upfront costs by eliminating long-term treatment expenses, newer approaches requiring repeat administration create uncertainty about long-term financial impact.
Maria Lowe, Pharm.D., BCPS, associate vice president of Pharmaceutical Intelligence at the Institute for Clinical and Economic Review (ICER), highlighted this concern at the AMCP 2025 annual meeting: "I think the main challenge is we're talking about a much more significant expense, or the potential for a more significant expense over time. Instead of having a price for a treatment that you expect to be delivered once, and that's it, it's difficult to know how many rounds of treatment patients might require with these agents and for what period of time throughout their life."
Lowe also noted that more than half of the 23 emerging gene therapy products she highlighted are already under FDA review with decisions expected this year, particularly in areas including epidermolysis bullosa, Fanconi anemia, and neurological conditions.
As the field advances, the focus remains on developing gene therapies that are not only clinically effective but also financially sustainable for healthcare systems. The shift toward non-viral delivery systems and more precise gene editing technologies represents a promising path toward achieving these goals, potentially making these revolutionary treatments accessible to more patients worldwide.
