Over the past 30 years, gene therapy has evolved from a speculative concept to a viable treatment modality for a growing number of rare and complex diseases. Groundbreaking discoveries in viral vector engineering, gene editing, and nonviral delivery systems have fueled this transformation. Regulatory approvals have steadily increased, and advanced technologies such as CRISPR are expanding the therapeutic horizon. Despite early safety setbacks and ongoing manufacturing and regulatory challenges, the field has made extraordinary strides. As industrialization efforts progress and regulatory frameworks mature, gene therapy is poised to play a central role in the future of precision medicine.
Laying the Groundwork: Foundational Discoveries in Genetics
The first step toward gene therapy occurred in the 19th century when Gregor Mendel identified the heritable units we refer to as genes today.1 In the early 20th century, American geneticist Thomas Hunt Morgan built on Mendel’s work by demonstrating that genes are carried on chromosomes — a discovery that earned him the Nobel Prize and advanced understanding of genetic inheritance.2 The concept of gene therapy was first proposed on the late 1920s, and the modification of traits by adding DNA to cells was demonstrated in the 1940s. The 1950s saw the structure of DNA described by Watson and Crick (with invaluable contributions from Franklin and Wilkins) and the first use of a virus to treat cancer. In the 1960s, researchers showed that genetic information delivered to cells using natural and genetically modified viruses results in expression of heritable traits.
Significant advances were made in the 1970s and 1980s, starting with clearly defined proposal and rationale for gene therapy.2 The first hint that injecting DNA into human cells could affect cell function was demonstrated in 1971 in a laboratory using human fibroblast cells extracted from patients with galactosemia.3 The concept of delivering a gene therapy to live patients was broached shortly thereafter.4
Other events in the 1970s and 1980s included development of adenovirus (AdV), retrovirus (RV), and adeno-associated virus (AAV) vectors, new methods for DNA transfection, the first demonstrations of successful mammalian cell genetic modification and diseases correction using viral vectors, launching of the first gene therapy company (Genetic Therapy Inc.), use of lipids as non-viral delivery vehicles, and the first mention of chimeric antigen receptor (CAR)-T cells.2
1990s: The First Gene Therapy Trials and More Discoveries
The 1990s marked a pivotal turning point for gene therapy, as the field moved from concept and laboratory research to clinical application. The decade began with the first human gene transfer study — a landmark moment in medical history. In this trial, a four-year-old girl with severe combined immunodeficiency (SCID) caused by a deficiency of the enzyme adenosine deaminase (ADA) was treated with her own (autologous) tumor-infiltrating lymphocytes. These cells were extracted, genetically modified in the laboratory using a retrovirus carrying the corrective ADA gene, and then reintroduced into her body.² This procedure demonstrated that gene therapy could be applied in living patients to address genetic disease at its source.
This early success accelerated progress in the field, leading to a wave of innovations throughout the decade. Researchers refined methods for in vivo gene transfer — delivering therapeutic genes directly into patients — and made significant advances in viral vector engineering to improve the safety and efficiency of gene delivery. The 1990s also saw the development of DNA vaccines and the introduction of lentiviral vectors (LVVs), which offered new options for stable gene integration and long-term expression.
Additional gene therapy trials targeting ADA deficiency followed, further validating the potential of gene therapy as a transformative approach to treating inherited genetic disorders.²
Safety Issues Raise Concerns
Despite early breakthroughs, the 1990s ended with serious setbacks that cast a shadow over the future of gene therapy. In 1999, 18-year-old Jesse Gelsinger died while participating in a clinical trial testing a gene therapy for ornithine transcarbamylase (OTC) deficiency, a rare metabolic disorder. His death — the result of a severe immune reaction to the adenoviral vector used to deliver the therapeutic gene — was a tragic reminder of the risks inherent in emerging medical technologies. Gelsinger’s case became the most widely known, but in total, three patients in gene therapy trials died during this period due to uncontrolled immune responses triggered by the treatment.⁵,⁶
Compounding these concerns were reports that several children treated in the late 1980s for ADA deficiency — using their own white blood cells modified with a murine-based retrovirus — later developed forms of leukemia. This was traced to insertional mutagenesis, a phenomenon in which the inserted genetic material disrupted normal cellular function, contributing to cancer development.
These events prompted widespread scrutiny from regulatory agencies. The U.S. Food and Drug Administration (FDA) launched investigations into gene therapy clinical trials, uncovering questionable study practices and significant safety concerns, particularly related to the viral vectors then in use.⁵⁻⁷ As a result, gene therapy research in the United States entered a prolonged period of stagnation, with many clinical trials paused or halted for nearly a decade as the field worked to rebuild trust and address fundamental safety challenges.
Improved Vectors Make a Difference
In response to early safety setbacks, researchers turned their attention to understanding the underlying causes of adverse events and developing second-generation viral vectors designed to avoid the same issues. A major shift occurred in the field of in vivo gene therapy, with a growing emphasis on AAV vectors — initially AAV2 — and LVVs.⁶,⁸
AAV vectors quickly became the preferred choice for in vivo applications due to their favorable safety profile. They generally elicit minimal immune or inflammatory responses and can sustain transgene expression for the lifespan of the target cell without integrating into the host genome, reducing the risk of insertional mutagenesis. Over time, numerous wild-type AAV serotypes have been isolated and engineered to target specific tissues or cell types with greater precision. In addition, researchers have developed synthetic, non-natural AAV variants to further enhance performance and specificity.
For ex vivo gene therapies — in which patient cells are harvested, genetically modified outside the body, and then reintroduced — replication-incompetent lentiviral vectors, such as those based on herpes simplex virus, have become the vector of choice. In this setting, their ability to integrate into the host genome is a benefit, enabling long-term gene expression in cultured cells that are expanded and reinfused into patients.
Global Approvals and Breakthroughs Since 2000
The 2000s ushered in a new era of progress for gene therapy, driven by both scientific discovery and technical refinement. In addition to the development of new AAV serotypes with enhanced targeting capabilities, researchers gained a much deeper understanding of the mechanisms underlying insertional mutagenesis — and, crucially, how to avoid it.²
This period also marked the first regulatory approval of a gene therapy: Gendicine, authorized in China for the treatment of head and neck cancer. Clinical trial activity resumed in earnest late in the decade, including the first study of an AAV-based gene therapy in humans. Positive clinical results were also achieved using hematopoietic stem cell therapies employing retroviral and lentiviral vectors to treat X-linked severe combined immunodeficiency (SCID) and a neurodegenerative disease.
Momentum accelerated throughout the 2010s, as gene therapy research expanded globally and achieved a series of important firsts.² Clinical efficacy was demonstrated for an AAV8 gene therapy for hemophilia B. In 2012, the European Commission approved Glybera, its first gene therapy — although the product was later withdrawn from the market in 2017 due to commercial challenges. In 2016, the European Union granted its first approval for an ex vivo gene therapy, Strimvelis, to treat SCID.
Meanwhile, CAR-T cell therapies emerged as a groundbreaking approach to cancer treatment, showing high efficacy even against aggressive solid tumors. The first two CAR-T cell therapies — Kymriah and Yescarta — received FDA approval in 2017. That same year, the agency also approved its first gene therapy for a genetic disease, Luxturna, for the treatment of inherited retinal dystrophy.
During this period, the FDA also approved the first two antisense oligonucleotide (ASO) drugs and the first oncolytic virus therapy, Imlygic (talimogene laherparepvec), for melanoma. In parallel, the discovery of the CRISPR/Cas9 gene-editing system revolutionized the field, enabling precise, targeted modification of mammalian cells. The first clinical trial involving gene-edited cells — using zinc finger nucleases — was also launched.
Positive clinical results continued to accumulate for gene therapies targeting a range of severe diseases, including sickle cell disease, hemophilia A, spinal muscular atrophy, epidermolysis bullosa, and several other conditions, expanding both the potential and credibility of gene therapy worldwide.
Rising Rate of Approvals in the Early 2020s
The pace of gene and gene-modified cell therapy approvals has accelerated rapidly in the early 2020s, reflecting the field’s maturation and growing clinical success.⁹
FDA approvals began to climb steadily at the start of the decade, with a single approval in 2020 (Tecartus), followed by two in 2021 (Breyanzi and Abecma). The momentum continued to build, with four approvals in 2022, seven in 2023, and six more in 2024. As of early 2025, only one gene therapy — Encelto — has received FDA approval so far.
By the end of 2024, there were at least six gene therapy candidates in the preregistration phase in the United States, with an additional 35 therapies in phase III clinical trials globally.¹⁰ Several new approvals were anticipated in the United States for 2025; however, recent structural and leadership changes at the FDA, enacted under the Trump administration, have introduced considerable uncertainty about the agency’s capacity to maintain its prior pace of review and approval.
Increasing Role for Gene-Editing Technologies
Gene-editing technologies have dramatically expanded the therapeutic potential of gene therapy, enabling treatments for a much broader range of diseases.⁵ Unlike traditional gene therapies, which introduce a functional copy of a missing or defective gene, gene-editing tools allow for the direct removal, modification, or correction of aberrant genes within the patient’s own DNA.
Depending on the therapeutic strategy, gene-editing approaches may be designed to stop the production of a harmful protein (gene knockout), repair or replace a dysfunctional gene (gene correction), or initiate production of a new protein (gene insertion).¹¹
Early gene-editing efforts relied on transcription activator-like effector nucleases (TALENs) and zinc finger nucleases (ZFNs), but the advent of CRISPR/Cas9 technology — prized for its simplicity, precision, and versatility — has positioned it as the most promising platform to date. Perhaps most transformative is the potential for multiplex gene editing, which allows multiple genes to be edited simultaneously, opening new avenues for the treatment of complex polygenic disorders such as Alzheimer’s disease and diabetes.¹¹
However, gene-editing therapies carry significant risks, particularly the possibility of off-target editing that could lead to unintended genetic changes or serious complications. As a result, most clinical-stage gene-editing therapies to date have focused on severe, often fatal genetic diseases where the potential benefits far outweigh the risks.
In late 2023, the FDA approved the first CRISPR-based gene-editing therapy, CASGEVY™ (exagamglogene autotemcel [exa-cel]), developed by CRISPR Therapeutics and Vertex Pharmaceuticals, for the treatment of sickle cell disease. In early 2024, the therapy also received approval for transfusion-dependent beta thalassemia (TDT).
Development of next-generation gene-editing technologies is ongoing, with a focus on improving tissue targeting, editing specificity, and safety.¹¹ As of March 2024, multiple gene-editing therapies were in clinical trials for a wide range of indications, including sickle cell disease, chronic bacterial infections, hereditary transthyretin amyloidosis (hATTR), hereditary angioedema (HAE), various ex vivo cancer therapies, cardiovascular disease, HIV/AIDS, diabetes, and autoimmune disorders.¹²
Growing Interest in Nonviral Delivery
While viral vectors have been the dominant platform for gene therapy delivery, their use continues to present several challenges — including immunogenicity, cytotoxicity, off-target gene insertions, complex manufacturing, and high costs.¹ To overcome these limitations, researchers have increasingly turned to nonviral delivery approaches designed to improve safety, flexibility, and scalability.
Leading nonviral delivery technologies include lipid-based solutions, such as lipid nanoparticles (LNPs) and liposomes, as well as polymer-based systems, including polymeric nanoparticles, exosomes, and DNA nanostructures.¹³ Physical delivery methods — such as electroporation, sonoporation, and gene guns — are also under active investigation.¹⁴ To date, LNPs and cationic polymeric systems have advanced the furthest, with several candidates entering clinical trials.¹
However, nonviral delivery methods face distinct technical hurdles. Chief among these is reduced transfection efficiency compared with viral vectors — a key factor limiting their effectiveness. Additional challenges include the risk of payload aggregation or degradation, unintended exposure and premature release of the genetic cargo, difficulties achieving tissue-specific delivery, and shorter durations of gene expression.¹⁵
Despite these obstacles, numerous companies are advancing innovative nonviral gene delivery platforms:
Eyevensys has developed a proprietary device that uses electroporation to deliver DNA plasmids directly to ciliary muscle cells within the eye.
Vesigen Therapeutics employs naturally occurring extracellular vesicles known as ARMMs (ARRDC1-mediated microvesicles) to package and deliver multiple gene-editing components within a single particle.
CyGenica has developed the GEENIE (Guided Efficient and Effortless Navigation) platform, which uses a negatively charged, cell-penetrating protein to transport gene-editing systems across cell membranes at high doses without causing cellular damage.¹⁶
Couragene, a company founded by Yale University researchers, is commercializing the STEP (Stimuli-responsive Traceless Engineering Platform) technology for the targeted delivery of genetic medicines — including CRISPR-based genome editing — to the brain for the treatment of neurogenetic diseases.¹⁷,¹⁸
Charting the Future: Industrialization, Regulation, and Investment
Despite the remarkable progress achieved over the past three decades, gene therapy remains in the early stages of its evolution, with much still to learn and many obstacles yet to overcome. Nearly 3,000 clinical trials have been conducted globally — with many still ongoing¹ — yet as of January 2025, only just over 30 cell and gene therapies have received regulatory approval worldwide.¹⁹
One of the greatest challenges facing the field today is the need to industrialize gene therapy development and manufacturing — creating scalable, efficient processes that can make these complex therapies more affordable and accessible to a broader patient population.
Regulatory considerations also remain a critical focus. In 2024, the U.S. Food and Drug Administration (FDA) established the Collaboration on Gene Therapies Global Pilot (CoGenT Global), an initiative aimed at fostering greater international harmonization and collaboration in gene therapy application reviews. As part of this effort, the agency also identified several key safety concerns requiring close attention, including liver toxicity, hematologic toxicity, infections, immune responses, reproductive toxicity and fertility effects, and off-target gene-editing effects.²⁰
Prior to the change in administration, the FDA’s Center for Biologics Evaluation and Research (CBER) had outlined plans to release up to 14 new guidance documents related to cell and gene therapies. These were expected to address a wide range of topics, including platform technologies for gene therapy products incorporating genome editing, and strategies to accelerate the approval of gene therapies targeting rare diseases.
This heightened regulatory focus reflects both the increasing complexity of gene therapies and the growing expectations for their impact on human health. There is much reason for optimism: from 2023 to 2024, the number of cell and gene therapy developers increased by 6%, while the number of clinical trials rose by 3%. Even amid a challenging funding environment, investment in the sector surged by 30%.²¹ Moreover, 13 of the world’s 15 largest pharmaceutical companies — by market capitalization — are now actively engaged in developing cell and gene therapy products, signaling strong industry commitment to advancing the field.
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