Genetic renaissance: a cross-regional analysis of the approval landscape of authorised gene therapeutics in paediatrics, challenges and future prospects

Abstract

Gene therapies are proven to be a milestone in the treatment of genetic disorders, especially in children who bear a disproportionately high burden of rare and hereditary diseases. Clinical evaluation of gene therapy (GT) in paediatrics is a significant challenge for every regulatory body. This study examined the available data on GT products that have been authorised for use by children in Japan, Europe, and the United States. We systematically analysed publicly available regulatory databases from USFDA, EMA, and PMDA to track GT approvals. Therapies were categorized based on their intended patient population (adults, paediatrics, or both), approval trends, and regulatory designations such as Orphan Drug Designation (ODD), Fast Track Designation (FTD), Breakthrough Therapy Designation (BTD), and Rare Paediatric Disease Designation (RPDD). As of April 2024, a total of 75 GTs were approved across these three regions for adults, paediatrics, and both populations combined. 37 in the US, 18 in Europe, and 20 in Japan. Among them, 41 were for adults, 13 for paediatrics, and 21 for both age groups. Of the 13 paediatric approvals the USFDA leads in paediatric GT approvals with 7 therapies, followed by the EMA with 5 (of which 2 were later withdrawn due to commercial reasons), and the PMDA with 1 therapy. Gene therapies hold immense promise for paediatric patients, offering life-changing treatments where few or no options exist. However, high costs, complex clinical trial requirements, and long-term safety concerns continue to limit their widespread adoption. This study underscores the urgent need for global regulatory harmonization and policy initiatives to improve access to paediatric GTs. While regulatory frameworks have enabled faster approvals, sustained efforts are required to ensure affordability, long-term safety, and equitable access for children worldwide.

Introduction

Background

Many severe diseases in childhood have a genetic etiology. The knowledge on Gene Therapies (GTs) has significantly expanded, leading to advancements in diagnosis and treatment. Moreover, the chances of completely treating genetic disorders in paediatrics are higher than in adults if the treatment starts before irreparable damage has occurred (Wright et al. 2018). The process of treating any disease by altering the gene is considered as GT. GTs are a type of biological medicinal product that utilize nucleic acids as their active components, which are responsible for carrying genetic information. These therapies are employed to modify, correct, replace, insert, or delete specific sequences of nucleic acids. Their therapeutic, preventive, or diagnostic effects are directly tied to the recombinant nucleic acid sequences they incorporate or the products derived from these genetic sequences (Institute 2025). In the early 1970 s, Theodore Friedmann and Richard Roblin first introduced the idea of using “good” DNA to rectify flawed genetic information behind hereditary illnesses (Ma et al. 2020). Recent advancements in GTs have led to the approval of several groundbreaking treatments, including Onasemnogene abeparvovec (Zolgensma™) for spinal muscular atrophy (SMA), Voretigene neparvovec (Luxturna™) for inherited retinal diseases caused by RPE65 mutations, and Tisagenlecleucel (Kymriah™) and Axicabtagene ciloleucel (Yescarta™) for certain types of blood cancers like B-cell lymphomas and acute lymphoblastic leukemia (ALL). Additionally, Etranacogene dezaparvovec (Hemgenix™) has been approved for hemophilia B, offering a one-time treatment to address the genetic deficiency (Therapy 2024). Worldwide, millions of children are impacted by paediatric genetic diseases (PGDs), of which 2–3% of live births are thought to be affected by an estimated 7,000 distinct abnormalities (Koh and Jamuar 2023). PGDs are considered a global health issue, and to deal with this issue, every country focuses on the development of GTs. The term GT is specifically used by the United States Food and Drug Administration (USFDA), the US regulatory body (USFDA 2018a, b, c, d, e). In Japan, the GT is known as a regenerative medical product by the Pharmaceuticals and Medical Devices Agency (PMDA 2024a, b).

The PMDA is the regulatory authority in Japan responsible for the review, approval, and post-market surveillance of pharmaceuticals, medical devices, and regenerative medicine products. Moreover, in Europe, GT comes under the category of Advanced Therapy Medicinal Products (ATMPs) (EMA 2024a, b, c, d, e).

ATMPs are innovative medicines regulated by the European Medicines Agency (EMA) under the Committee for Advanced Therapies (CAT). These products are based on genes, cells, or tissues and offer ground breaking treatments for various diseases, including rare and life-threatening conditions. ATMPs are classified into three main types, i.e. Tissue Engineered Products (TEPs), Cell Therapy Medicinal Products (CTMPs), and Gene-Therapy Medicinal Products (GTMPs).

Regulatory landscape and regulatory challenges

Although regulatory authorities have published comprehensive guidelines to promote the development and evaluation of GTs—including safety documents like the FDA’s "Long Term Follow-Up After Administration of Human Gene Therapy Products” (USFDA 2020a, b) which emphasizes the critical need for long-term safety monitoring to address risks such as insertional mutagenesis and persistent biological activity, and the EMA’s "Guideline on Safety and Efficacy Follow-Up and Risk Management of Advanced Therapy Medicinal Products” which underscores the importance of risk management plans and post-authorization safety studies—significant challenges remain, particularly in the context of paediatric genetic disorders. Despite these efforts, there are still few or no therapeutic options available for many of these illnesses, which continue to cause considerable morbidity, disability, and mortality in children. The FDA and EMA require rigorous preclinical safety assessments, as outlined in the FDA’s "Preclinical Assessment of Investigational Cellular and Gene Therapy Products” (USFDA 2019a, b, c) and the EMA’s "Guideline on the Quality, Non-Clinical and Clinical Aspects of Gene Therapy Medicinal Products” (EMA 2021) to evaluate toxicity, immunogenicity, and tumorigenicity, ensuring patient safety before clinical trials. Furthermore, both agencies mandate robust clinical evidence to demonstrate efficacy, as highlighted in the FDA’s "Human Gene Therapy for Rare Diseases” (USFDA 2020a, b) and the EMA’s guidelines, which call for well-controlled trials with clinically meaningful endpoints. However, the development of gene therapies for paediatric genetic disorders is often hindered by the rarity of these conditions, the challenges of conducting trials in small populations, and the need for long-term follow-up to assess delayed adverse effects (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). GT are a life-saving treatment option for paediatric patients by treating the root genetic causes of these debilitating illnesses. Over the past few decades, substantial progress has been achieved in the development. These advanced treatments have shown incredible promise, starting with the first approved GT for adenosine deaminase deficiency in 1990 (Blaese 1993) and continuing with the latest wave of approvals for diseases, including SMA (USFDA 2025) and retinal dystrophy (USFDA 2018a, b, c, d, e). Nevertheless, the market’s acceptance of GTs for paediatric patients has progressed at a slower pace compared to adult indications, a trend that can be partially attributed to historical challenges and safety concerns within the field. A pivotal example is the early GT trials for Severe Combined Immunodeficiency (SCID), which initially demonstrated remarkable success in restoring immune function in affected children. However, the subsequent development of leukemia in some patients, resulting from insertional mutagenesis caused by the retroviral vectors used in the therapy, underscored significant safety risks and raised critical questions about the long-term implications of gene-editing technologies. This adverse outcome not only highlighted the inherent complexities of GT but also led to a temporary slowdown in clinical development and regulatory approvals (Domingues et al. 2023, Sandamini, et al. 2025). While earlier research has looked at the regulatory environment for adult populations or nations, there is currently a dearth of thorough studies on licenced paediatric GT medicines in the major pharmaceutical markets. This understanding gap is crucial since children frequently struggle to participate in scientific trials and develop new treatments (EMA 2025b, a). By assessing the status of licenced gene treatments for paediatric indications in the United States, Europe, and Japan—three key regulatory jurisdictions which collectively represent the primary members of the International Council for Harmonisation (ICH). The ICH establishes globally recognized standards for pharmaceutical development, promoting regulatory convergence while allowing for regional adaptations in the evaluation of advanced therapies (ICH 2025).—the current study seeks to close this distance. Through the examination of data supplied by various regulatory bodies, our objectives were to ascertain the number of licensed goods, their uses, and the regulatory routes employed to promote the creation of these innovative therapies for hereditary illnesses affecting children. Notably, therapeutics development for the paediatric population has unique hurdles, such as complex trial designs, ethical constraints, and possible long-term safety and effectiveness problems (Unguru 2015). To tackle these obstacles and hasten the process of developing therapies for uncommon and grave illnesses that impact children, regulatory bodies have instituted many accelerated routes and designations i.e., Orphan Drug Designation (ODD), Priority Review (PR), Breakthrough Therapy Designation (BTD), Regenerative Medicine Advanced Therapy (RMAT) Designation, Rare Paediatric Disease Designation (RPDD), Fast Track Designation (FTD), Prime Designation (PD) and Sakigake Designation (USFDA 2023a, b, c; EMA 2025b, a; PMDA 2025).

Accelerating peadiatric gene therapies

Among these, ODD is for drugs and biologics meant to treat uncommon illnesses or ailments that impact fewer than 200,000 persons in the US (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o) and fewer than 5 in 10,000 people in the EU are given this classification (EMA 2025b, a). The prevalence threshold in Japan is 50,000 patients or less (PMDA 2021). Sponsors who receive ODD are eligible for several benefits, including prolonged marketing exclusivity (7-year) periods, tax credits, and fee exemptions (USFDA 2022). Moreover, PR is given for medications that have the potential to significantly improve treatment or fill the gap in the absence of effective therapy. The objective of finishing the evaluation in six months instead of the usual ten seeks to expedite the FDA's review procedure (USFDA 2018a, b, c, d, e). Furthermore, the BTD accelerated program is meant for medications that, according to preliminary clinical data, show a significant improvement over current treatment. It enables more comprehensive FDA advice and speeds up the development and evaluation process (USFDA 2018a, b, c, d, e). In the case of RMAT designation, the focus is more on research and approval of regenerative medicine, including GTs that aim to cure serious or life-threatening illnesses and have promising clinical data suggesting they may be able to meet unmet medical needs, it can proceed more quickly with the creation and evaluation procedure (USFDA 2023a, b, c). For rare paediatric diseases, the United States has RPDD, which pertains to severe or fatal illnesses that mostly impact children who are 18 years of age or less and have a prevalence of less than 200,000 individuals in the United States (USFDA 2019a, b, c; USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o), Sponsors of items that are identified, as permitted are given a priority review voucher, which they can use to expedite the evaluation of another product in the future (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). Furthermore, FTD is meant to speed up the evaluation of medications used to treat severe or critical illnesses that show promise in meeting unmet medical requirements. It enables to meet and converse with the FDA regularly while the project is under development (USFDA 2018a, b, c, d, e). Similar to PR in the US, as mentioned above, Europe has PD; with this programme, aspires to support drugs that might assist patients without access to treatment choices or give a significant therapeutic edge over current therapies early and with improved scientific and regulatory support (EMA 2025b, a). The objective is to enhance the development plans and expedite the assessment procedure (EMA 2024a, b, c, d, e). Likewise, the Japanese regulatory body (PMDA) has granted Sakigake designation exclusively to novel products in regenerative medicine, such as GT, that have the potential to provide noteworthy therapeutic benefits over current treatments. Shorter review periods, priority regulatory support, and limited authorisation based on preliminary clinical evidence are all made possible by it. With uncommon and debilitating diseases that frequently disproportionately affect paediatric populations, these regulatory routes and rewards seek to expedite the approval process, offer monetary benefits, and stimulate investment in the discovery of medicines addressing these illnesses (PMDA 2024a, b). Through this study, the authors try to identify the hurdles and challenges pharmaceutical companies face in marketing paediatrics GTs. The ultimate goal of the study is to promote GTs in paediatrics.

Materials and methods

Study design and data source

The purpose of this study was to conduct a thorough examination of GT products that have been authorised for use in paediatrics in the three main regulatory regions—Japan, Europe, and the United States. Each country has regulatory authorities that publish and update data on authorised GT. USFDA publishes and updates information on GT in the United States region (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). Similarly, EMA updates the same in Europe, whereas PMDA updates in Japan (EMA 2024a, b, c, d, e; PMDA 2024a, b). The data available enabled the classification of GT products into various categories, including their use across different age populations. Furthermore, these products were grouped according to the regulatory designations they received, facilitating their faster availability to the public. This comprehensive categorization illustrated the current status of GT across these three regions.

Data collection and organization

The procedure for gathering data entailed methodically accessing the databases of relevant regulatory bodies to get details on licenced GTs. In the USA, the FDA has provided information on a webpage, “Approved cellular and Gene Therapy products”, where enlisting of products is done alphabetically; additionally, each product is provided with a package insert section. The package insert supplied many additional details on that specific product and an overview of the rationale for the regulatory action. In Europe, “The Committee for Advanced Therapies” (CAT) of the EMA produced a paper titled “Quarterly Highlights and Approved ATMPs” that served as a complete list of approved gene treatments in the European area. In a similar vein, the statistics for Japan were taken from the PMDA's website, the “Regenerative medical products” section, and the “list of approved products” contains details about approved gene treatments.

A Microsoft Excel spreadsheet was used to carefully arrange the gathered data, with distinct pages for each of the three regulatory zones. The data that was gathered was classified according to whether it was intended for use in adults, children, or both. For every approved gene therapy product, the name of the product and its indication were noted. These were then further sub-categorised into special designations or expedited review pathways that had been granted by the relevant regulatory body. ODD, PR, BTD, and RPDD were among the classifications used in the US. PD and ODD were the designations that were taken into consideration in Europe. The Sakigake designation and the ODD applied to Japan. The approval dates and years for each gene therapy product were also documented to facilitate chronological examination of the approvals.

Data analysis

The quantity of GT products authorised for use in children throughout the three regulatory areas was broken down by nation after the gathered data was reviewed. An in-depth comprehension of the therapeutic regions targeted by these medications was made possible by the full table stratification of the data based on their indications, special designations, and approval periods. The split up of approved gene therapies across their special designations and the total number of approved therapies were shown using visual aids like graphs and pie charts. We also discussed the mechanisms of action of each gene therapy that is intended for use in paediatrics to enable a much better understanding.

Results

Examining the approval history, regulatory trends, and current status in the market, each country had varied results. A total of 75 GTs were approved in these markets for the treatment of various disorders across all age groups, many of which were supported by expedited regulatory designations to facilitate their development and approval process. While the majority of these therapies remain commercially available and actively in use, a small number have been withdrawn from the market due to various reasons, including safety concerns, commercial viability, or the emergence of more effective treatment alternatives. Overall, GTs for adults across the three regions was found to be 41; for paediatrics, it was found to be 13; and for both adults and paediatrics, it was found to be 21. The maximum GTs approval for paediatrics was observed in USFDA, followed by EMA and then PMDA. The total number of GTs that were approved across the three regions till April 2024 is represented in Fig. 1.

Fig. 1.

Number of approved Gene Therapies in United States Food and Drug Administration (USFDA), Pharmaceutical and Medical Device Agency (PMDA) and European Medicines Agency (EMA)

Landscape of gene therapy approvals in the united states

As per the database provided by the USFDA, a total of 37 GTs were approved till April 2024 spanning all age ranges and are regulated under CBER (Centre for Biologics Evaluation and Research). Out of these 37 approved therapies, seven (18.9%) were specifically approved for use in paediatrics.13 (35.1%) were approved to be used in both adults and paediatrics, and the remaining 17 (46%) were approved to be used in adults only.

The seven approved therapies for paediatrics identified as Onasemnogene abeparvovec (ZOLGENSMA™) a by Novartis Gene Therapies which is used to treat spinal muscular atrophy (SMA), a genetic disorder that affects motor neurons and muscle strength (USFDA 2023a, b, c). Exagamglogene autotemcel (CASGEVY™) by Vertex Pharmaceuticals Incorporated approved for the treatment of sickle cell disease and transfusion-dependent beta thalassemia, targeting the underlying genetic cause of these blood disorders (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). RETHYMIC™ by Enzyvant Therapeutics GmbH is a issue-based therapy used to treat congenital athymia, a rare immune disorder where infants are born without a thymus, by providing functional thymic tissue (USFDA 2021a, b). Delandistrogene moxeparvovec (ELEVIDYS™) by Sarepta Therapeutics, Inc. was approved for the treatment of Duchenne muscular dystrophy (DMD), targeting the genetic mutation responsible for muscle degeneration (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). Lovotibeglogene autotemcel (LYFGENIA™) by Bluebird Bio, Inc was approved to treat sickle cell disease by modifying hematopoietic stem cells to produce functional hemoglobin (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). Elivaldogene autotemcel (SKYSONA™) by Bluebird Bio, Inc is used for the treatment of cerebral adrenoleukodystrophy (CALD), a severe neurodegenerative disorder caused by mutations in the ABCD1 gene (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). Atidarsagene autotemcel (LENMELDY™) by Orchard Therapeutics was approved to treat metachromatic leukodystrophy (MLD), a rare genetic disorder affecting the nervous system (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). LENMELDY™ was the most recent approval on 18 March 2024.

Hematopoietic progenitor cells (HPC), cord blood was the first ever therapy used for hematopoietic reconstitution in paediatrics and adults in 2011 (USFDA 2019a, b, c). Fast forwarding Onasemnogene abeparvovec (ZOLGENSMA™) became the first ever GT to be used in paediatrics for the treatment of SMA, SMA is a group of inherited neuromuscular disorders caused by the loss of lower motor neurons in the spinal cord, which transmit signals from the brain to muscles. This loss leads to progressive muscle weakness, atrophy, and low muscle tone, (NORD 2024). but it comes with a high price of USD 2.1 million (17 crore INR) (Thielen et al. 2022). Since the approval of Onasemnogene abeparvovec in 2019 the landscape also started focusing more towards paediatrics, the result being that now the USA has the most no. of GTs available for children (Hospital 2025).

Since GTs are meant to treat rare, orphan and unmet medical needs, they often receive certain designations, making them available for human use as early as possible. In our study, we looked into designations received by GT, and we found out that 25% were granted ODD, 15% FTD, 19% PR, 14% BTD, 10% RMAT, and 17% RPDD, which is observable in Fig. 2.

Fig. 2.

Designations granted by the United States food and drug administration (USFDA) to gene therapies

Landscape of gene therapy approvals in Europe

According to the database available on EMA, there were a total of 26 ATMPs approved for all ages in the EU market as per February—April 2024 quarterly highlights (EMA 2024a, b, c, d, e). Of the 26 approved ATMPs, there were four TEPs (15%), four CTMPs (15%), and 18 GTMPs (70%). Out of 18 GTMPs, five (28%) were specifically approved for use in paediatrics. Four (22%) were to be used in both adults and paediatrics and remaining nine (50%) were to be used in adults only. Among the five approved therapies three therapies, identified as Onasemnogene abeparvovec (ZOLGENSMA™), atidarsagene autotemcel (LIBMELDY™) (sold under the brand name LENMELDY™ in the USA) and Exagamglogene autotemcel (CASGEVY™) were still commercially available in the EU market however two other therapies namely Elivaldogene autotemcel (SKYSONA™) and betibeglogene autotemcel (ZYNTEGLO™) which were approved by EMA for use in paediatrics were withdrawn from the European market by Bluebird Bio. in Nov 2021 and early 2022 due to challenges in achieving appropriate value recognition and market access for these ATMPs further decreasing the potential hope for children to treat their medical conditions (EMA 2024a, b, c, d, e). Exagamglogene autotemcel received a “conditional authorisation” on 14 December 2023 and full marketing authorisation on 9 February 2024 (EMA 2024a, b, c, d, e). In terms of designation granted by EMA, 64% of the approved therapies received ODD, and 36% received PD, which has been represented in Fig. 3.

Fig. 3.

Designations granted by the European Medicines Agency (EMA) to gene therapies

Landscape of gene therapy approvals in Japan

In accordance with data available on PMDA`s website, Japan had the least number of approved therapies as only one, i.e. Onasemnogene abeparvovec by Novartis, was approved to be used in paediatrics out of 20 total approved GTs (regenerative medicines), and four were meant to be used in both adult and paediatrics. In terms of designations received, Onasemnogene abeparvovec and (STEMIRAC™) received the Sakigake designation (33%), while 50% were granted ODD, and 17% were non-orphan products (Fig. 4).

Fig. 4.

Designations granted by the Pharmaceutical and Medical Devices Agency (PMDA) to Gene Therapies (Regenerative Medicines)

Global regulatory pathways for GT approvals demonstrate distinct regional patterns, with analysis of approval timelines revealing important trends. The United States has emerged as a leader in paediatric GT, evidenced by its approval of five paediatric-specific treatments in 2023 alone—representing a clear strategic focus on addressing childhood diseases. Meanwhile, Europe's approval pace has slowed significantly since authorizing just two therapies collectively in 2018 and 2020, suggesting potential challenges in its GT landscape. In contrast, Japan's approval of two GTs in 2023 signals growing momentum in its market, with this recent activity pointing toward likely expansion in future approvals. These divergent trajectories highlight how major regulatory regions are developing specialized approaches to advancing gene therapies, with the US particularly prioritizing paediatric applications while other markets follow different evolutionary paths. A complete set of information regarding the country-wise approved GT have been given in Table 1.

Table 1.

List of approved gene therapies to be used in paediatrics

Administration	Proprietary name	Patient	Year of authorisation	Indication	Applicant	Designations
USFDA	Hemacord (HPC, cord blood)	Both paediatrics and adults	2011	Hematopoietic reconstitution	New York Blood Center	-
	Ducord (HPC,cord blood)	Both paediatrics and adults	2012		Duke university school of medicine
	HPC, cord blood (HPC, cord blood)	Both paediatrics and adults	2012		Clinimmune labs, university of colorado cord blood bank
	Allocord (HPC, cord blood)	Both paediatrics and adults	2013		Ssm cardinal glennon children's medical center
	HPC, cord blood—lifesouth (HPC, cord blood)	Both paediatrics and adults	2013		Lifesouth community blood centers, inc
	HPC, cord blood—bloodworks (hpc, cord blood)	Both paediatrics and adults	2016		Bloodworks
	Clevecord (HPC, cord blood)	Both paediatrics and adults	2016		Cleveland cord blood center
	Kymriah (tisagenlecleucel)	Both paediatrics and adults	2017	B-cell acute lymphoblastic leukemia (ALL), follicular lymphoma (FL)	Novartis pharmaceuticals corporation	ODD, BTD, RPDD
	Luxturna (voretigeneneparvovec-rzyl)	Both paediatrics and adults	2017	Retinal dystrophy	Spark therapeutics, inc	PR, ODD, BTD, RPDD
	HPC, cord blood—md andersoncord blood bank (HPC, cord blood)	Both paediatrics and adults	2018	Hematopoietic reconstitution	MD Anderson cord blood bank	-
	Zolgensma(onasemnogeneabeparvovec-xioi)	Paediatrics	2019	Spinal muscular atrophy (SMA)	Novartis gene therapies, inc	ODD, BTD, FTD, RPDD
	Rethymic (allogeneic processed thymus tissue–agdc)	Paediatrics	2021	congenital athymia	Enzyvant therapeutics gmbh	PR, ODD, BTD, FTD, RMAT, RPDD
	Zynteglo (betibeglogeneautotemcel)	Both paediatrics and adults	2022	ß-thalassemia	Bluebird Bio Inc	PR, ODD, BTD, FTD, RPDD
	Skysona (elivaldogeneautotemcel)	Paediatrics	2022	Cerebral adrenoleukodystrophy (CALD)	Bluebird Bio Inc	PR, ODD, BTD, RPDD
	Omisirge (omidubicel-onlv)	Both paediatrics and adults	2023	Hematologic malignancies	GamidaCell Ltd	PR, ODD, BTD
	Vyjuvek (beremagenegeperpavec)	Both paediatrics and adults	2023	Dystrophic epidermolysis bullosa (DEB)	Krystal biotech, inc	PR, ODD, FTD, RMAT
	Elevidys (delandistrogenemoxeparvovec-rokl)	Paediatrics	2023	Duchenne muscular dystrophy (DMD)	Sarepta therapeutics, inc	PR, ODD, FTD
	Casgevy (exagamglogeneautotemcel (exa-cel))	Paediatrics	2023	Sickle cell disease (SCD), transfusion-dependent ß-thalassemia (TDT)	Vertex pharmaceuticals incorporated	PR, ODD, FTD, RMAT
	Lyfgenia(lovotibeglogeneautotemcel (lovo-cel))	Paediatrics	2023	Sickle cell disease (SCD)	Bluebird Bio, Inc	PR, ODD, FTD, RMAT, RPDD
	Lenmeldy (atidarsageneautotemcel)	Paediatrics	2024	Metachromatic leukodystrophy (MLD)	orchard therapeutics (europe) limited	ODD, RMAT, RPDD
EMA	Strimvelis (autologous cd34 + enriched cell fraction that contains cd34 + cells transduced with retroviral vector that encodes for the human adacdna sequence)	Both paediatrics and adults	2016	Immunodeficiency due to adenosine deaminase deficiency (ADA-SCID)	Fondazione telethon ets	ODD
	Kymriah(tisagenlecleucel)	Both paediatrics and adults	2018	B-cell acute lymphoblastic leukemia (ALL), follicular lymphoma (FL)	Novartis europharm limited	ODD, PD
	Luxturna(voretigeneneparvovec)	Both paediatrics and adults	2018	Biallelicrpe65 mutation-associated retinal dystrophy	Spark therapeutics, inc	ODD
	Zynteglo(betibeglogeneautotemcel)	Both paediatrics and adults	2019	ß-thalassemia	Bluebird Bio Inc	ODD, PD
	Zolgensma (onasemnogeneabeparvovec-xioi)	Paediatrics	2020	Spinal muscular atrophy (SMA)	Novartis europharm limited	ODD, PD
	Libmeldy (atidarsageneautotemcel)	Paediatrics	2020	Metachromatic leukodystrophy (MLD)	orchard therapeutics	ODD
	Skysona (elivaldogeneautotemcel)	Paediatrics	2021	Cerebral adrenoleukodystrophy (CALD)	Bluebird Bio Inc	ODD, PD
	Upstaza (eladocageneexuparvovec)	Both paediatrics and adults	2022	Aromatic l amino acid decarboxylase (AADC) deficiency	PtcTherapeutics International Limited	ODD
	Casgevy (exagamglogeneautotemcel (exa-cel))	Paediatrics	2024	Sickle cell disease (SCD), transfusion-dependent ß-thalassemia (TDT)	Vertex pharmaceuticals incorporated	ODD, PD
PMDA	Stemirac(human (autologous) bone marrow-derived mesenchymal stem cells)	Both paediatrics and adults	2018	Spinal cord injury	Nipro corporation	SAKIGAKE
	Zolgensma (onasemnogeneabeparvovec-xioi)	Paediatrics	2020	Spinal muscular atrophy (SMA)	Novartis europharm limited	ODD, SAKIGAKE
	Kymriah (tisagenlecleucel)	Both paediatrics and adults	2022	B-cellacute lymphoblastic leukemia(ALL), follicular lymphoma (FL)	Novartis europharm limited	ODD
	Jacemin(melanocyte-maintaining human (autologous) epidermis-derived cell sheet)	Both paediatrics and adults	2023	Vitiligo	Japan tissue engineering co., ltd	-
	Luxturna (voretigeneneparvovec)	Both paediatrics and adults	2023	Biallelicrpe65mutation-associated retinal dystrophy	Spark therapeutics, inc	ODD

Orphan Drug Designation (ODD), Priority Review (PR), Breakthrough Therapy Designation (BTD), Regenerative Medicine Advanced Therapy (RMAT) Designation, Rare Paediatric Disease Designation (RPDD), Fast Track Designation (FTD), Prime Designation (PD)and Sakigake Designation

Since GT offers treatment for a variety of disorders, it is essential to understand how its mechanism works. We discussed the Mechanism of Action (MOA) of seven GTs available for treatment in paediatrics to better understand its pharmacological activity. MOA was provided by the USFDA in the respective “package insert” sections of each and every GT.

In Exagamglogene autotemcelthe modified CD34 + cells are engrafted in the bone marrow following injection and develop into erythroid lineage cells with decreased BCL11A expression. Erythroid cells generate more HbF protein and express γ-globin when BCL11 A expression is reduced. HbF expression lowers the concentration of intracellular haemoglobin S (HbS) in sickle cell disease patients. This keeps red blood cells from sickling and treats the illness's root cause, which eliminates Vaso-Occlusive Crises (VOCs) (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). The diagrammatic MOA is explained in Fig. 5.

Fig. 5.

Mechanism of action for Exagamglogene autotemcel. Here, BCL11A: B-Cell Lymphoma/Leukemia 11 A; CD34 + : Cluster of Differentiation 34 Positive

As for the Delandistrogene moxeparvovec the cassette has two components: 1) a DNA transgene that codes for the modified ELEVIDYS micro-dystrophin protein, and 2) a Muscle Creatine Kinase 7 (MHCK7) gene regulatory component that consists of an α-myosin heavy chain enhancer and a creatine kinase seven promoters. Transgene: A mutation in the DMD gene that prevents the dystrophin protein from functioning is the underlying cause of DMD. A transgene producing a micro-dystrophin protein, which is composed of specific dystrophin domains produced in normal muscle cells, is carried by the ELEVIDYS virus. It is known that ELEVIDYS micro-dystrophin localises to the sarcolemma. The therapeutic process begins with the delivery of a viral vector carrying a functional micro-dystrophin transgene to the patient's muscle cells. Once inside the target cells, the vector transports the therapeutic gene to the nucleus, where it integrates into the host genome or persists as episomal DNA. The nucleus then utilizes this new genetic material to transcribe and translate the micro-dystrophin mRNA, producing a truncated but functional dystrophin protein. This functional protein is incorporated into the muscle fiber sarcolemma, where it stabilizes the dystrophin-glycoprotein complex and restores critical structural and signaling functions in muscle cells. Over time, the presence of the functional micro-dystrophin protein mitigates the degenerative processes characteristic of dystrophinopathies, leading to improved muscle integrity, reduced fibrosis, and enhanced muscle function. Figure 6 represents the MOA flow diagram for ELEVIDYS (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o).

Fig. 6.

Mechanism of action for Delandistrogene moxeparvovec

In the case of Atidarsagene autotemcelby transduction of autologous CD34 + cells with aryl sulfatase, a lentiviral vector (ARSA LVV), it introduces one or more functional variants of the human ARSA complementary deoxyribonucleic acid (cDNA) into the patient's HSCs. Transduced CD34 + HSCs generate the ARSA enzyme when they engraft in bone marrow following LENMELDY™ infusion and regenerate the hematopoietic compartment. A functional ARSA enzyme can break down sulfatides or stop them from building up dangerously (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). The MOA is represented in Fig. 7

Fig. 7.

Mechanism of action for LENMELDY™. Here, ARSA: Arylsulfatse A (ARSA gene)

Furthermore, in Lovotibeglogene autotemcel (LYFGENIA™) by transduction of autologous CD34 + cells with BB305 LVV, it introduces functional copies of a variant βA-globin gene (threonine [T] substituted with glutamine [Q] at position 87, T87Q or βA-T87Q-globin) into patients'hematopoietic stem cells (HSCs). Transduced CD34 + HSCs that have received Atidarsagene autotemcel infusion engraft in the bone marrow and develop to form red blood cells with physiologically active βA-T87Q-globin. These cells will then mix with α-globin to produce functional Hb that contains βA-T87Q-globin (HbAT87Q). βA-T87Q-globin may be identified using reverse-phase high-performance liquid chromatography (RP-HPLC) or ultra-high performance liquid chromatography (UPLC) from both wildtype βA-globin and βS-globin. In addition to lowering intracellular and total haemoglobin S (HbS) levels and having an oxygen-binding affinity and oxygen haemoglobin dissociation curve identical to wild-type HbA,

HbAT87Q is engineered to prevent HbS polymerisation sterically, hence minimising the premature death of red blood cells (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). The flow diagram of MOA is presented in Fig. 8

Fig. 8.

Mechanism of action for LYFGENIA

The goal of RETHYMIC™ is to help athymic patients rebuild their immunity. The transfer of recipient T cell progenitors from the bone marrow to the embedded rethymic slices, where they mature into naïve immunocompetent recipient T cells, is the suggested mechanism of action. The emergence of naïve T cells in the peripheral circulation is indicative of thymic activity; this is unlikely to be seen until 6–12 months following rethymic therapy. The therapeutic approach begins with the surgical implantation of allogeneic processed thymus tissue into the patient. Following implantation, T-cell progenitors originating from the recipient's bone marrow migrate to the implanted thymic tissue. Within this specialized microenvironment, the progenitor cells undergo thymic education and maturation processes, including positive and negative selection, ultimately developing into naive, immunocompetent T cells. This process effectively restores functional T-cell immunity in the recipient by providing a platform for the generation of a diverse and self-tolerant T-cell repertoire. The implanted thymus tissue thus serves as a biological scaffold that supports the complete differentiation and maturation of host-derived T-cell precursors, addressing conditions characterized by T-cell immunodeficiency or thymic dysfunction (USFDA 2021a, b). The below-mentioned MOA is shown in Fig. 9.

Fig. 9.

Mechanism of action of RETHYMIC™

The therapeutic process involving Elivaldogene autotemcel with ABCD1 cDNA begins with the introduction of functional ABCD1 cDNA to correct the genetic defect. Once administered, the genetically modified hematopoietic stem cells (HSCs) engraft in the bone marrow, establishing a stable population of these corrected cells. These HSCs then differentiate into monocytes, which carry the functional ABCD1 gene and possess the ability to migrate to affected tissues. The monocytes travel from the bone marrow into the brain, crossing the blood–brain barrier to reach the central nervous system. Upon arrival, they further differentiate into macrophages and cerebral microglia, cell types essential for maintaining brain health and function. By expressing the functional ABCD1 gene, these cells help stabilize the disease course, addressing the underlying metabolic dysfunction characteristic of conditions such as adrenoleukodystrophy. This approach leverages the body’s natural cellular mechanisms to deliver targeted genetic correction, offering potential long-term therapeutic benefits (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). The mechanism is shown in Fig. 10.

Fig. 10.

Mechanism of action of SKYSONA. Here, ABCD1: ATP binding cassette subfamily D member 1; HSC: Hematopoietic stem cells; ALDP: Adrenoleukodystrophy protein; VLCFA: Very long chain fatty acids

Onasemnogene abeparvovec is aAAV9-based recombinant GT and is intended to transfer a copy of the gene that codes for the human survival motor neuron (SMN) protein. A bi-allelic mutation in the SMN1 gene leads to inadequate production of the SMN protein, which is the origin of SMA. Two human case studies have shown that intravenous treatment of Onasemnogene abeparvovec causes cell transduction and production of the SMN protein (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). The therapeutic process begins when the AAV9 vector, carrying the survival motor neuron (SMN) gene, targets and enters motor neuron cells. This serotype is specifically chosen for its ability to cross the blood–brain barrier and efficiently transduce neurons. Once inside the target cell, the vector delivers its payload to the nucleus, where the self-complementary recombinant SMN DNA is released. Due to its unique design, the single-stranded DNA rapidly forms a double-stranded circular episome through base-pairing of its self-complementary ends, bypassing the need for host-cell-mediated second-strand synthesis. This episomal DNA remains separate from the patient's genomic DNA but is stably maintained in the nucleus. The nucleus then transcribes the SMN gene into mRNA, which is translated into functional SMN protein. This protein is essential for motor neuron survival and function, particularly in spinal muscular atrophy (SMA). The episomal configuration enables rapid and sustained expression of the SMN protein, compensating for the deficient endogenous SMN production characteristic of SMA. Over time, the restored SMN protein levels prevent further motor neuron degeneration, improve neuromuscular function, and halt disease progression (USFDA 2024a, b, c, d, e, f, g, h, i, j, k, l, m, n, o). The diagrammatic representation of the described MOA is given in Fig. 11.

Fig. 11.

Mechanism of action Onasemnogene abeparvovec. Here, AAV: Adeno- associated virus; SMN: Survival motor neuron; DNA: Deoxyribonucleic acid

In summary for paediatric GT, we conclude that every GT was associated with a different gene. A major variation was also seen in the disease treatment in the case of paediatrics. Exagamglogene autotemcel and Lovotibeglogene autotemcel two GTs were associated with sickle cell anaemia (28.57%), Delandistrogene moxeparvovec used in the treatment of muscle dystrophy (14.28%), Atidarsagene autotemcel was related in the treatment of early juvenile phase (14.28%), RETHYMIC™ were associated with immunity building (14.28%), Elivaldogene autotemcel used for neurological dysfunction (14.28%) and Onasemnogene abeparvovec related to spinal dysfunction (14.28%).

Discussions

Exploring the field of GT provides an overview of the current state of paediatric GT for various types of indications. The results from the study revealed a significant difference between the landscape of GT for paediatric patients and that of adult patients. In Europe, only three (16.6%) therapies were specifically present for paediatrics out of the 18 therapies approved. It was also observed that, due to cost concerns, market authorisation holder Bluebird Bio, a biotechnology company, discontinued its 2 GTs, namely Betibeglogene autotemcel and Elivaldogene autotemcel, which were also used in paediatrics. Elivaldogene autotemcel was approved in July 2021 and was withdrawn just after four months in November 2021, leading to missed opportunities for children to treat their genetic disorders. Betibeglogene autotemcel and Elivaldogene autotemcel are still available in the US market.

In the USA, only seven (18.9%) therapies were available for use in paediatrics, in contrast to 37 total therapies available. The most recently approved therapy for paediatric patients is Atidarsagene autotemcel by Orchard Therapeutics; it was the first ever GT to treat children who were suffering from MLD. This approval thus highlights the potential of GTs to treat catastrophic genetic disorders and to increase the quality of life in paediatrics.

Japan had the lowest number of GTs options available for paediatrics, with only one (5%) paediatric therapyout of 20 approved therapies. The only approved therapy was Onasemnogene abeparvovec (ZOLGENSMA™) by Novartis, which was also available in both the US and EU markets. Analysing the timeline and approval history, it was also interpreted that GT usually gets approval first in the USA, followed by Europe, and then in Japan. This reflects the rigorous and stringency followed by PMDA regarding safety towards children, but it can also be said that the USA is more favourable for any pharmaceutical and biotechnological company to launch their product considering the regulatory environment as well as a stronger focus on the development of GTs. With only a limited number of GTs available, there is a compelling need to treat significant unmet medical needs for this population. Paediatrics usually encounter difficulties in obtaining novel treatments because of worries about the safety, tolerability, and ethical implications of clinical trials, as well as their inherent weaknesses. Children represent a particularly vulnerable population in clinical research, requiring cautious evaluation to ensure both safety and efficacy when developing novel therapies. This study highlights a crucial gap in the availability of GTs for paediatric patients, despite the disproportionately high burden of genetic disorders in this age group. The limited number of approved GTs raises concerns about the challenges in clinical trial design, ethical considerations, and regulatory requirements that hinder paediatric drug development. While current GTs offer transformative potential, post-marketing safety monitoring remains a critical necessity, as paediatric patients may exhibit long-term or delayed adverse effects due to ongoing physiological development. Emerging regulatory initiatives, such as the FDA’s Rare Paediatrics Disease Priority Review Voucher Program and the EMA’s Paediatric regulation EC No.1901/2006), aim to encourage paediatric GT development. However, significant hurdles persist, including high costs, market withdrawals due to commercial non-viability, and the need for robust long-term follow-up studies. Looking forward, further integration of real-world evidence, adaptive trial designs, and global harmonization of regulatory frameworks could accelerate the availability of paediatric GTs, ensuring that children with rare and life-threatening genetic conditions have access to life-changing therapies. There is also an opportunity to tackle disorders at an early age for transformative and life-changing results in children. Achieving harmonization and fostering collaborative efforts require regulatory agencies, industry stakeholders, and academic researchers to establish standardized guidelines for paediatric GT clinical trials. Specifically, initiatives like joint regulatory workshops between the FDA, EMA, and PMDA, the creation of global paediatric GT registries, and the implementation of aligned post-marketing surveillance frameworks can enhance data sharing, optimize trial designs, and ensure consistent long-term safety monitoring. Additionally, incentivizing cross-border clinical trials and streamlining approval pathways through mechanisms such as mutual recognition agreements could accelerate access to life-saving GT for children worldwide. The long-term safety of these therapies remains a topic of debate among researchers, Concerns such as immune responses, unintended genetic modifications, and the potential impact on developmental processes highlight the need for careful monitoring. Additionally, the limited duration of follow-up in paediatric clinical trials often leaves gaps in understanding how these therapies behave over extended periods. Addressing these challenges requires robust post-marketing surveillance, long-term patient monitoring, and further research to ensure the safety and efficacy of GT in children, who represent a vulnerable and critical population for these advanced treatments.

Conclusion

An analysis of licensed GTs in the US, Europe and Japan highlights a promising but still emerging field of paediatric indication. Although there has been improvement, there are still not as many therapies available that are expressly designed for children as there are for adults. Currently, the United States leads the world in the sheer number of authorised paediatric gene treatments, followed by Europe and then Japan. Notwithstanding these obstacles, the approval of treatments such as Atidarsagene autotemcel, Exagamglogene autotemcel and Onasemnogene abeparvovec shows that GT could treat severe genetic abnormalities in children and provide hope for a better quality of life. However, problems like exorbitant prices and market exclusions show how important it is to keep working to guarantee the longevity and accessibility of these revolutionary medicines. To speed up the discovery of gene treatments for paediatric populations, solve safety issues and build strong clinical platforms for paediatrics, cooperation between regulatory bodies, healthcare providers, and researchers is essential going ahead. If GT can overcome these obstacles, it might revolutionise the way that uncommon and hereditary diseases are treated by children and provide a better future for people who suffer from these crippling illnesses.

Abbreviations

GT

Gene Therapy

SMA

Spinal Muscular Atrophy

PGD

Paediatric Genetic Diseases

ATMP

Advanced Therapy Medicinal Products

ODD

Orphan Drug Designation

USFDA

United States Food and Drug Administration

Author contributions

Aftab Ahmad: Conceptualization, Data curation, Methodology, Visualization, Writing -original draft; Simran Simran: Conceptualization, Methodology, Writing- original draft, Writing-review and editing; Vaishnavi Kalokhe: Data curation, Visualization; Fathima Musthafa: Visualization, Writing-review and editing; Vishal Sachin Gangawane: Visualization, Writing-review and editing; Khushboo Choudhary: Data curation, Writing- original draft; Rajeev Raghuvanshi: Methodology, Supervision; Saurabh Srivastava: Conceptualization, Methodology, Supervision, Writing-review.

Funding

None.

Data availability

The data was generated and analyzed during this study, including the information from the US FDA, EMA, and PMDA official websites. For detailed access to the data, please refer to the references provided in the manuscript.

Declarations

Ethical approval

None.

Competing interests

The authors declare no competing interests.