Cell and gene therapy advances in pediatrics

Dordaviprone (Modeyso), approved August 2025, for diffuse midline glioma in patients with H3 K27M-mutation.⁵

• Indication: First FDA-approved systemic treatment for adult and pediatric patients 1 year of age or older with H3 K27M-mutant diffuse midline glioma, a rare pediatric brain tumor.
• Mechanism: Works to exert its therapeutic effect through a dual mechanism:⁶
  • Activating the mitochondrial caseinolytic protease P, which leads to mitochondrial stress and triggers apoptosis in tumor cells
  • It also inhibits the dopamine D₂ receptor, contributing to anti-tumor activity in H3 K27M mutant diffuse midline glioma
• Cost/billing hasn’t been published at the time of this report.
• Impact:
  • Current standard treatment is use of radiotherapy alone
  • Dordaviprone (Modeyso) addresses the genetic mutation driving this aggressive cancer
  • May extend survival and improve quality of life in affected children and young adults⁵
  • Marks a paradigm shift from palliative to potentially disease-modifying treatment

Elamipretide (Forzinity; MTP-131), approved in September 2025, is a mitochondrial cardiolipin binder to improve muscle strength in adult and pediatric patients with Barth Syndrome weighing at least 30kg.⁷

• Indication: Barth syndrome is a rare, X-linked mitochondrial disorder affecting heart and skeletal muscle caused by mutations in the TAZ gene leading to defective cardiolipin metabolism, a crucial lipid for mitochondrial energy production.
• Mechanism: works as a mitochondrial cardiolipin-binding compound that selectively localizes to the inner mitochondrial membrane stabilizing the lipid-protein interactions essential for proper energy production.
• WAC: $4,360.27/mL ($795,750/year)
• Billing codes: Unclassified J3490, C9399; NDC 727507-0800-04
• Impact:
  • A mitochondria-targeted peptide that binds to cardiolipin, stabilizing mitochondrial membranes
  • Could significantly improve cardiac function and energy metabolism in affected children

Pipeline therapies with transformative potential

Sodium Dichloroacetate (SL-1009), an oral solution, is under FDA review for treatment of pyruvate dehydrogenase complex deficiency (PDCD) received a complete response letter from the FDA on 9/8/2025. Saol Therapeutics remains confident they can work with the FDA for a resolution. In the interim, SL-1009 remains available as investigational drug.⁸

• Developers: Saol Therapeutics
• Designations: Priority review
• Condition: PDCD is a rare mitochondrial disorder caused by mutations in genes affecting the pyruvate dehydrogenase complex. It impairs the body’s ability to convert carbohydrates into usable energy, particularly affecting the brain.
• Impact:
  • Offers non-invasive, metabolic therapy
  • May address the neurological and systemic impacts of impaired energy metabolism
  • Current treatment is supportive treatment targeting respiratory, seizure activity and metabolic management through diet and nutritional supplements

Rebisufligene Etisparvovec (UX111) Rebisufligene Etisparvovec (UX111) for mucopolysaccharidosis IIIA (sanfilippo syndrome) (MPS IIIA) is under FDA review.⁹

• Developers: Ultragenyx and Abeona Therapeutics
• Condition: MPS IIIA is a devastating pediatric neurodegenerative disorder.
• Modality: Adeno-associated virus based gene therapy to deliver N-sulfoglucosamine sulfohydrolase gene directly to CNS.
• Goal: Restore enzyme activity to slow or prevent neurological decline
• Impact:
  • Aims to alter the natural course of a fatal disorder
  • Represents potential for curative gene therapy for MPS IIIA
  • Current treatment is primarily supportive and palliative as current enzyme replacement therapy is limited due to lack of access to the central nervous system

Apitegromab (SRK015) is a monoclonal antibody targeting myostatin in patients with spinal muscular atrophy (SMA) that is under FDA review as adjunctive treatment received a CRL related to observations identified during inspection of the third-party fill-finish facility. Scholar Rock is working closely with the facility and the FDA for a resolution by the end of 2025.¹⁰

• Developers: Scholar Rock
• Designation: Priority review
• Condition: SMA is a genetic neuromuscular disorder caused by mutations in the SMN1 gene, leading to muscle weakness, atrophy and loss of motor function.
• Impact:
  • The first muscle-targeted add-on therapy for SMA patients who continue to experience motor function decline despite receiving SMN-targeted treatments
  • Approval could include patients ages 2 to 21 with SMA type 2 or 3 that didn’t receive onasemnogene abeparvovec-xioi (Zolgensma)¹⁰

Onasemnogene abeparvovec-xioi (Zolgensma, OAV101 IT) is under FDA review for intrathecal (IT) administration for spinal muscular atrophy (SMA) with potential for biologic license application by the end of 2025.¹¹

• Developer: Novartis
• Condition: Adeno-associated virus (AAV) vector-based gene therapy to treat SMA patients ages 2 and older that weren’t eligible for intravenous (IV) treatment.
• Impact:
  • IT administration provides an efficient route and allows for a lower fixed dose to be used due to the greater viral load necessary to treat older and larger patients, which has raised safety concerns and has essentially made the use of Zolgensma IV prohibitive for patients ages 2 and older
  • Could be marketed as a different name due to different dosing and administration

Doxecitine/Doxribtimine is under FDA review for safety and efficacy for treatment of thymidine kinase 2 deficiency (TK2d) with a potential for submission by the end of 2025.¹²

• Developers: UCB
• Designations: Priority review, breakthrough therapy, orphan drug and RPD
• Condition: TK2d is an ultra-rare mitochondrial disease that causes progressive muscle weakness, respiratory failure, feeding difficulties and often leads to early death without intervention.
• Impact:
  • Targets a life-threatening cause of progressive muscle weakness
  • Represents a major advancement in mitochondrial medicine for infants and children

The wave of innovation in pediatric cell and gene therapies isn’t just reshaping the standard of care, it’s creating it. With each approval and clinical milestone, we edge closer to a world where rare genetic disorders are no longer a life sentence, but a treatable condition. For clinicians, researchers and patient families, cell and gene therapy represents a beacon of possibility and progress in pediatric medicine.

Abbreviations: WAC = whole acquisition cost