Skysona (elivaldogene tavalentivec) / Genetix Biotherapeutics - LARVOL DELTA

Disease severity and rate of progression impact ex-vivo gene therapy for Childhood Cerebral Adrenoleukodystrophy and Metachromatic Leukodystrophy: a review of the literature (ASGCT 2026) - P1/2, P2, P2/3, P3 | "For both disorders the FDA has approved ex-vivo lentiviral gene therapy: elivaldogene autotemcel (eli-cel; lentiviral vector carrying ABCD1 cDNA under a MNDU3 promoter-enhancer) and atidarsagene autotemcel (arsa-cel; lentiviral vector carrying ARSA cDNA under PGK promoter)...Results Adrenoleukodystrophy In the eli-cel trials 67 CCALD patients were treated (32 in ALD-102 with cyclophosphamide/busulfan conditioning and 35 in ALD-104 with fludarabine/busulfan conditioning)...As hematological malignancies were seen with eli-cel but not arsa-cel, treatment with eli-cel should be limited to CCALD patients who do not have a suitably matched donor available for allogeneic HSCT. AEs related to conditioning and disease were important contributors to overall safety in both trials."

Gene therapy • Preclinical • Review • Acute Myelogenous Leukemia • Alzheimer's Disease • Bone Marrow Transplantation • CNS Disorders • Cognitive Disorders • Developmental Disorders • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Malignancies • Immunology • Infectious Disease • Leukemia • Metabolic Disorders • Myelodysplastic Syndrome

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P2/3 | N=64 | Active, not recruiting | Sponsor: bluebird bio | Phase classification: P ➔ P2/3

Phase classification • Genetic Disorders

ULTRA-RAPID CD3/CD45RA-DEPLETED HAPLOIDENTICAL HSCT FOR PEDIATRIC CEREBRAL ALD: FEASIBILITY, ENGRAFTMENT KINETICS, CHIMERISM BEHAVIOR, AND EARLY NEUROLOGIC OUTCOMES IN THREE CASES (EBMT 2026) - "In parallel, lentiviral gene therapy (elivaldogene autotemcel) is an option for select early-stage patients, but eligibility, access, and time-to-treatment constraints frequently limit real-world use relative to the pace of inflammatory progression...Conditioning comprised ALC-based Thymoglobuline, model-based Fludarabine and Busulfan, Rituximab, and IVIG; GVHD prophylaxis included Tacrolimus... A standardized CD3/CD45RA-depleted haploidentical platform enabled rapid time-to-transplant, ultra-fast engraftment, and low GVHD in pediatric cALD. The recurrent observation of mixed/declining chimerism in early-stage patients—despite robust initial engraftment—highlights a potentially stage- and platform-specific behavior that may benefit from protocolized monitoring and timely DLI. These data support haploidentical HSCT as a timely, feasible option for cALD for multicenter evaluation to refine conditioning intensity, graft composition, and DLI strategies to optimize durable..."

Clinical • Acute Graft versus Host Disease • Bone Marrow Transplantation • Chronic Graft versus Host Disease • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Immunology • Infectious Disease • Metabolic Disorders • Mucositis • Pediatrics

852370: When the Trial Ends Early: Perspectives on Premature Clinical Trial Closures in Rare Disease Therapeutics (ACMG 2026) - "Medical genetics has entered a new therapeutic era, with increasing FDA approvals for rare disease treatments such as pegvaliase, vosoritide, and Skysona. Dr. Melinda Peters will offer a regulatory view on the complex aftermath of abruptly halted trials.Together, these perspectives highlight the need for sustainable, ethical frameworks to advance therapeutics in rare disease care.Learning Objectives:• Describe the evolution of therapeutic development in medical genetics and its impact on rare disease management.• Identify the regulatory, ethical, and practical challenges posed by premature clinical trial terminations.• Discuss the psychological and clinical consequences of early trial closure on affected patients and families.• Evaluate potential strategies for maintaining patient care continuity when investigational therapies are halted."

Clinical • Cognitive Disorders • Rare Diseases

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P=N/A | N=50 | Enrolling by invitation | Sponsor: bluebird bio | N=25 ➔ 50 | Trial completion date: Nov 2033 ➔ Mar 2036 | Trial primary completion date: Nov 2033 ➔ Mar 2036

Enrollment change • Trial completion date • Trial primary completion date

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P=N/A | N=25 | Enrolling by invitation | Sponsor: bluebird bio | N=17 ➔ 25

Enrollment change • Genetic Disorders

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P=N/A | N=17 | Enrolling by invitation | Sponsor: bluebird bio

New trial • Genetic Disorders

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P=N/A | N=64 | Active, not recruiting | Sponsor: bluebird bio | Trial completion date: May 2037 ➔ Aug 2038 | Trial primary completion date: May 2037 ➔ Aug 2038

Trial completion date • Trial primary completion date • Genetic Disorders

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P=N/A | N=64 | Active, not recruiting | Sponsor: bluebird bio | Enrolling by invitation ➔ Active, not recruiting

Enrollment closed • Genetic Disorders

LTF-304: Long-term Follow-up of Participants With Cerebral Adrenoleukodystrophy Who Were Treated With Lenti-D Drug Product (clinicaltrials.gov) - P=N/A | N=50 | Enrolling by invitation | Sponsor: bluebird bio | Trial completion date: Mar 2036 ➔ May 2037 | Trial primary completion date: Mar 2036 ➔ May 2037

Trial completion date • Trial primary completion date

Orsini Now Distributing Gene Therapies LYFGENIA, ZYNTEGLO, SKYSONA (PRNewswire)

Commercial • Beta-Thalassemia • CNS Disorders • Genetic Disorders • Sickle Cell Disease

CRISPR-Cas editing technologies for viral-mediated gene therapies of human diseases: Mechanisms, progress, and challenges. (PubMed, Mol Ther Nucleic Acids) - "Since then, the US FDA has approved nearly 30 new viral gene therapy programs, with notable examples including Zolgensma, Spinraza, Hemgenix, Zynteglo, Lyfgenia, Kymriah, Skysona, and Tecelra...In this review, we examine the range of these therapeutics and their viral carriers, focusing primarily on LVs and AAVs. We provide a snapshot of the current status of the field and highlight some of the current challenges in the clinical application of gene therapy, with particular emphasis on viral CRISPR-Cas-based technologies and their future potential."

Journal • Review • Gene Therapies • Genetic Disorders

Risk and Benefit Assessment of Gene Therapy with Lentiviral Vectors and Hematopoietic Stem Cells: The Skysona Case. (PubMed, Hum Gene Ther) - "With event rates <0.6/100 patient-years, lower than those after autologous HSCT, the therapeutic index of approved LV-HSPC advanced therapy medicinal products remains favorable. Ongoing optimization of vector design, conditioning, and long-term surveillance, together with emerging genome-editing platforms, is expected to further mitigate residual risk."

Journal • Bone Marrow Transplantation • Gene Therapies • Hematological Disorders • Hematological Malignancies • Oncology

Maximizing Safety and Efficacy in Hematopoietic Stem Cell Gene Therapy (ASGCT 2025) - "Although new treatments for hematopoietic stem cell (HSC) gene therapy have been recently approved for several diseases such as beta-thalassemia (Zynteglo), sickle cell disease (Lyfgenia and Casgevy), and adrenoleukodystrophy (Skysona), a certain number of challenges still remain such as the high costs and scalability associated with these therapies, as well as the increased safety concerns regarding the related leukemic events. Experiments to investigate the mechanisms involved in better performance of LV transduction on the automated platform, including detailed molecular analysis of gene expression pathways by Next Generation Sequencing (NGS), are ongoing. Disease Focus of Abstract:Other Other: Rare diseases of the blood such as (but not limited to) hemoglobinopathies"

Clinical • Gene therapy • Beta-Thalassemia • Gene Therapies • Genetic Disorders • Hematological Disorders • Rare Diseases • Sickle Cell Disease • CD34 • FLT3

Integrating Emerging Gene Therapies into CIBMTR Data Reporting Using Skysona As a Model (TCT-ASTCT-CIBMTR 2025) - "With proper preparation and collaboration among the data management team, our center was able to seamlessly report new Skysona data requirements to the CIBMTR. Over the following months, we will monitor new form completion as well as ask questions of clinical staff and submit tickets to CIBMTR as issues arise. NEXT STEPS: As a center, we plan to implement new learnings into our job aids and adapt the lessons learned to any upcoming gene therapy products."

Gene therapy • Gene Therapies • Infectious Disease • Metabolic Disorders • Oncology

Maximizing Safety and Efficacy in Hematopoietic Stem Cell Gene Therapy (TCT-ASTCT-CIBMTR 2025) - "Hematopoietic stem cell (HSC) gene therapy has been recently been aproved for beta-thalassemia, sicklce cell disease, and adrenal leukodystrophy, specifcially Lyfgenia ™ ,Casgevy ™ , Skysona TM, . Based on these results, we propose a combined strategy of transduction enhancers and the use of Baboon envelope pseudotyped LV on the automated platform to achieve significantly higher transduction efficiency. Ongoing experiments to investigate the mechanisms involved in better performance of LV transduction on the automated platform, validating BaEV pseudotyped LV on the automated platform, including detailed molecular analysis of gene expression pathways by Next Generation Sequencing (NGS), are underway."

Clinical • Gene therapy • Beta-Thalassemia • Gene Therapies • Hematological Disorders • Sickle Cell Disease • CD34

Elivaldogene autotemcel approved for treatment of cerebral adrenoleukodystrophy (CALD) in males: A therapeutics bulletin of the American College of Medical Genetics and Genomics (ACMG). (PubMed, Genet Med Open) - No abstract available

Journal • Gene Therapies • Genetic Disorders

FDA Investigating Serious Risk of Hematologic Malignancy Following Skysona (elivaldogene autotemcel) (FDA) - "FDA is investigating the known risk of hematologic malignancies with serious outcomes, including those such as hospitalization, the requirement for allogeneic hematopoietic stem cell transplantation, and death, and is evaluating the need for further regulatory action. Given the risk of hematologic malignancy, providers should carefully consider alternative therapies, including allogeneic hematopoietic stem cell transplant for patients who have a suitable, willing, and available human leukocyte antigen (HLA)-matched donor, prior to deciding to treat a child with Skysona."

FDA event • Gene Therapies

Blood Cancers Reported in Seven Children Dosed with SKYSONA™. (PubMed, Hum Gene Ther) - No abstract available

Journal • Hematological Malignancies • Oncology

Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy. (PubMed, N Engl J Med) - P, P2/3, P3 | "Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.)."

Gene therapy • Journal • Acute Myelogenous Leukemia • Bone Marrow Transplantation • Gene Therapies • Genetic Disorders • Graft versus Host Disease • Hematological Disorders • Hematological Malignancies • Immunology • Leukemia • Myelodysplastic Syndrome • Oncology • Transplantation • CD34 • CDKN2A • CDKN2B • KRAS • MECOM • NRAS • PRDM16 • RUNX1 • WT1

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy. (PubMed, N Engl J Med) - P, P2/3 | "At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.)."

Gene therapy • Journal • Bone Marrow Transplantation • CNS Disorders • Gene Therapies • Genetic Disorders • Hematological Malignancies • Inflammation • Myelodysplastic Syndrome • Oncology • Transplantation • CD34

Secondary failure of Lentiviral Vector Gene Therapy in a Cerebral Adrenoleukodystrophy Patient with an ABCD1 Whole-Gene Deletion. (PubMed, Mol Ther) - "He underwent hemopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel, elivaldogene autotemcel) as part of the ALD-104 clinical trial...The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient's whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy."

Gene therapy • Journal • Viral vector • Gene Therapies • Genetic Disorders • Transplantation • CD34

Association Between Potency Critical Quality Attributes and Clinical Efficacy Across Lentiviral Vector Cell and Gene Therapy Products (ASGCT 2024) - P1/2, P2/3, P3 | "Betibeglogene autotemcel (beti-cel), lovotibeglogene autotemcel (lovo-cel), and elivaldogene autotemcel (eli-cel) are distinct CGT products with differentiated safety and efficacy profiles that leverage lentiviral gene addition in CD34+ hematopoietic stem and progenitor cells for treatment of severe genetic diseases. Our findings indicate that all three products (beti-cel, lovo-cel, and eli-cel) share measures of transduction efficiency as the common potency-associated CQAs that highly correlate with product efficacy. These results highlight the value of transduction efficiency assays as surrogate potency measurements and can help guide the establishment of rigorous and meaningful product quality acceptance criteria for complex CGT products."

Clinical • Gene therapy • Viral vector • Beta-Thalassemia • Gene Therapies • Hematological Disorders • Hematological Malignancies • Myelodysplastic Syndrome • Oncology • Sickle Cell Disease • CD34

Stargazer: A Study of Participants With Cerebral Adrenoleukodystrophy (CALD) Treated With Elivaldogene Autotemcel (clinicaltrials.gov) - P=N/A | N=120 | Recruiting | Sponsor: bluebird bio | Not yet recruiting ➔ Recruiting

Enrollment open • Genetic Disorders

Viral Vectors in Gene Replacement Therapy. (PubMed, Biochemistry (Mosc)) - "Special attention is given to successful preclinical and clinical studies that have led to the approval of gene therapies: six AAV-based (Glybera® for lipoprotein lipase deficiency, Luxturna® for retinal dystrophy, Zolgensma® for spinal muscular atrophy, Upstaza® for AADC, Roctavian® for hemophilia A, and Hemgenix® for hemophilia B) and three LV-based (Libmeldy® for infantile metachromatic leukodystrophy, Zynteglo® for β-thalassemia, and Skysona® for ALD). The review also discusses the problems that arise in the development of gene therapy treatments, which, nevertheless, do not overshadow the successes of already developed gene therapies and the hope these treatments give to long-suffering patients and their families."

Journal • Review • Viral vector • Beta-Thalassemia • CNS Disorders • Gene Therapies • Genetic Disorders • Hematological Disorders • Hemophilia • Inherited Retinal Dystrophy • Metabolic Disorders • Movement Disorders • Muscular Atrophy • Muscular Dystrophy • Ophthalmology • Rare Diseases • LPL