About

Lindsey A. George, M.D., is an Assistant Professor of Pediatrics at the University of Pennsylvania and the Director of Clinical In Vivo Gene Therapy at the Children's Hospital of Philadelphia. Her laboratory focuses on developing gene-based therapies for coagulation disorders, with particular emphasis on factor VIII biology and hemophilia A. Her research has led to the development of a next-generation gene therapy approach for hemophilia A, which is currently being evaluated in a phase 2b clinical trial. Dr. George's work also investigates the immunologic and molecular basis of unexplained clinical observations from adeno-associated virus (AAV) gene therapy trials, aiming to improve their safety and efficacy. In addition to her laboratory research, she founded and directs the Clinical In Vivo Gene Therapy group at the Children's Hospital of Philadelphia, providing regulatory support for investigator-initiated studies, operational management of a portfolio of in vivo gene addition and editing trials, and clinical infrastructure to facilitate the safe and efficient implementation of commercial in vivo gene therapies.

Research topics

• Biochemistry
• Medicine
• Internal medicine
• Chemistry
• Biology
• Chromatography
• Molecular biology

Selected publications

• Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery

  New England Journal of Medicine · 2026-05-13 · 1 citations

  articleSenior author

  and expression of a chimeric AAV-PLAG1 transcript.

  PublisherDOI

• Safety, efficacy, and patient-reported outcomes 6 years after fidanacogene elaparvovec in adults with hemophilia B

  Blood Advances · 2026-02-24 · 1 citations

  articleOpen access

  ABSTRACT: Fidanacogene elaparvovec is a single-dose gene therapy designed to express the high-activity factor IX (FIX) variant FIX-R338L. Participants (N = 15) with FIX activity of ≤2% were dosed with 5 × 1011 vector genomes per kilogram infusion of fidanacogene elaparvovec and completed the 1-year dosing trial. After the initial 52 weeks, participants could enroll in long-term follow-up (LTFU) for 5 additional years. This report includes final safety and efficacy data of the LTFU trial through 6 years after gene therapy, with additional patient-reported outcomes (PROs). Of 14 participants enrolled in the LTFU, 11 completed 6 years of follow-up. During years 2 to 6, 9 serious adverse events were reported in 4 participants (28.6%); none were considered treatment-related or resulted in study discontinuation or death. Eight participants had increased alanine aminotransferase levels, and 3 of 8 also had increased aspartate aminotransferase levels; none received corticosteroids. No liver masses, malignancies, thrombotic events, or FIX inhibitors were reported. FIX activity was maintained, with a mean FIX activity of 24.7% at year 2 (n = 14) and 26.1% at year 6 (n = 11). Mean treated annualized bleeding rates remained lower than 1.0 (median, 0.0) during each year of follow-up. Ten participants (71%) had no treated bleeding events. None of the 14 enrolled participants resumed FIX prophylaxis. Improvements relative to before gene therapy in PROs and target joints were observed over the duration of follow-up. Overall, fidanacogene elaparvovec exhibited a favorable safety profile, sustained efficacy, and improved PROs for up to 6 years. This trial is registered at www.clinicaltrials.gov as NCT03307980.

  PublisherDOI

• Coagulation and Fibrinolysis Pathways

  2026-01-01

  book-chapter1st authorCorresponding
  PublisherDOI

• Fidanacogene Elaparvovec for Hemophilia B — A Multiyear Follow-up Study

  New England Journal of Medicine · 2025-04-16 · 18 citations

  articleOpen access

  BACKGROUND: Treatment with fidanacogene elaparvovec, a recombinant adeno-associated virus (AAV) vector developed for the treatment of hemophilia B, led to sustained expression of the high-activity factor IX variant (FIX-R338L, or FIX-Padua) in a phase 1-2a study. The long-term safety and efficacy of this treatment are not known. METHODS: vector genomes (vg) per kilogram of body weight; thereafter, participants could enroll in a 5-year follow-up study. Safety end points included adverse events and changes in laboratory measures. Efficacy end points included the annualized rate of treated bleeding events (annualized bleeding rate) and factor IX activity. RESULTS: A total of 14 participants provided consent and completed at least 3 years of follow-up (median, 5.5; range 3 to 6); participation was ongoing among 8 at the data cutoff. None of the participants reported treatment-related adverse events after year 1. Throughout follow-up, nine serious adverse events were noted in 4 participants; none were thrombotic or treatment-related. No factor IX inhibitors were detected. Throughout follow-up, mean factor IX activity was in the mild hemophilia range; the mean annualized bleeding rate was less than 1, and 10 participants had no treated bleeding episodes. Surveillance liver ultrasounds obtained from year 1 onward showed no evidence of cancer but showed steatosis in 4 participants who had weight gain and elevated aminotransferase levels (maximum alanine aminotransferase level, 77 U per liter). One participant with a history of hepatitis C, hepatitis B, human immunodeficiency virus infection, and an elevated body-mass index had progression of underlying advanced liver fibrosis. A total of 13 surgical procedures were performed in 8 participants; exogenous factor IX was administered for 10 procedures, and no associated unexpected bleeding complications occurred. CONCLUSIONS: vg per kilogram, one of the lowest intravenous doses of AAV used for any indication. (Funded by Pfizer; ClinicalTrials.gov number, NCT03307980.).

  PublisherOA PDFDOI

• HTRS2025.P2.95 FVIII Thrombotic Risk is a Function of FVIII Potency and the Means of FVIIIa Inactivation

  Research and Practice in Thrombosis and Haemostasis · 2025-11-01

  articleOpen accessSenior author
  PublisherDOI

• Patient-Specific In Vivo Gene Editing to Treat a Rare Genetic Disease

  New England Journal of Medicine · 2025-05-15 · 254 citations

  articleOpen access

  Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle-delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.).

  PublisherOA PDFDOI

• Real-world outcomes of delandistrogene moxeparvovec gene therapy: Motor outcomes and emerging safety concerns

  Molecular Therapy · 2025-10-05 · 3 citations

  articleOpen accessSenior author
  PublisherOA PDFDOI

• Platelets stabilize factor VIIIa against loss of activity through subunit dissociation

  Blood · 2025-11-03

  articleOpen access

  Abstract Activated platelets have binding sites for factor VIII (FVIII) that include soluble fibrin bound to the αIIbβ3 integrin (Phillips et al 2004. J Thromb Haemost; Gilbert et al 2015. Blood). Platelets support FVIII activity at 100-fold lower concentrations than standard FVIII activity assays with phospholipid vesicles (PLV). The mechanism(s) through which platelet binding sites protect or increase FVIII activity have been only partially explored. Factor VIIIa is a semi-stable heterotrimer that can lose activity through dissociation of the A2 domain or through cleavage of scissile bonds susceptible to activated Protein C (APC) or other proteases. We wished to determine whether FVIII activity on platelet binding sites is enhanced by stabilization against A2 dissociation and/or protease cleavage. Like FVIII, the bispecific antibody emicizumab (Emi) serves as a cofactor that facilitates activation of FX by FIXa on either vesicles or platelets. Thus, Emi is an ideal control reagent to determine whether platelet binding sites act primarily through FVIII(a) vs. factor IXa or factor X. Site-directed mutagenesis of recombinant B-domain-deleted human factor VIII (FVIII-WT) replaced the primary APC cleavage sites R336/R562 with Q (FVIII-QQ) or stabilized the A2 domain against spontaneous dissociation by replacing D519/E665 with V (FVIII-VV) or both (FVIII-QQVV). Full-length recombinant factor VIII (octocog alfa (Antihemophilic Factor), Advate) was also used as a control (FVIII). Plasma clotting assays were performed using delipidated factor VIII-deficient plasma with corn trypsin inhibitor to inhibit contact pathway activation. FVIII was added to plasma in the presence of either PAR1/PAR4 activated cryopreserved platelets (apheresis platelets in 5% DMSO stored at -80C and then purified via density gradient, 3x107/mL) or 10 μM 20%PS PLV. Clotting was started by adding 5 mM Ca++ and 1 pM FXIa (intrinsic pathway) and clot time measured by change in turbidity. The impact of platelets vs. PLV on FVIII activity was compared to emicizumab activity. FVIII and Emi were also tested using a defined two-stage Xase assay with PLV or IIa-activated platelets. FIXa, FX, and Ca++ were added and FXa generated was measured using a chromogenic substrate. To test the dissociation of A2, FVIII with platelets or vesicles was preactivated with IIa and then incubated for 0-14 min before Xase assay start. Intrinsic pathway activated FVIII clotting was faster on platelets than on PLV. The relative platelet:PLV FVIII activity varied from approximately 40:1 to 2:1 with the highest ratios achieved with lower fVIII concentrations. In contrast, activity of Emi was similar on platelets and PLV. This indicated that FVIII binding sites primarily protect or enhance FVIII(a) rather than FIXa or FX. Experiments with protein C-deficient plasma demonstrated that the enhanced activity on platelets is not primarily due to preferential cleavage by APC on PLV vs. platelets. We tested FVIII mutants to determine whether platelets protect FVIIIa activity through cleavage of susceptible residues or by preventing dissociation of the A2 domain. FVIII-VV and FVIII-QQVV supported clotting equivalently on platelets and PLV. Whereas FVIII-QQ and FVIII-WT activity remained much greater on platelets vs. PLV. These data suggest that platelet binding sites may protect FVIIIa from spontaneous dissociation over the time course of clotting. In purified FXase assays, activated FVIII-WT activity decay was slower with platelets vs. PLV reaching 50% activity after 6.6 ± 0.3 min versus 3.7 ± 0.2 min. Similar results were seen using FVIII-QQ. Activity of FVIIIa derived from full-length FVIII decayed at the slower rate on both platelets and vesicles, suggesting that the B-domain acts to stabilize FVIIIa. We are currently investigating the effect of the reported slower IIa cleavage of full-length FVIII at residue 1689 as a possible explanation. Further experiments will probe the role(s) of FIXa and FX on decay of B domain deleted FVIII activity on platelets vs PLV.Our data shows that platelet binding sites provide enhanced factor VIII activity compared to phospholipid vesicles and suggests that stabilization of FVIIIa against dissociation contributes to the enhanced activity. These findings are relevant to assays of FVIII activity, particularly in the presence of inhibitory antibodies and to the relative activity of FVIII vs. FVIII mimetics that partially compensate for lack of FVIII activity.

  PublisherOA PDFDOI

• Clinical advances in gene, cell, and RNA therapies

  Molecular Therapy · 2025-05-20

  editorial
  PublisherDOI

• Current clinical applications of AAV-mediated gene therapy

  Molecular Therapy · 2025-05-05 · 62 citations

  reviewOpen accessSenior author

  Currently, there are an estimated 8,000 genetic disorders that cumulatively affect approximately 10% of the population. Even among the 5% of patients with genetic disease that have treatment options, these therapeutics rarely address the underlying cause of disease but rather focus on managing or modifying symptoms and typically require recurrent, lifelong therapy. A therapeutic approach to genetic disease that in vivo delivers a functional copy of the aberrant gene is an intuitive solution that has thus far taken 3 decades to reduce to clinical practice, predominantly using adeno-associated viral (AAV) vectors. Among available viral and non-viral gene delivery approaches, AAV vectors remain the most efficient means for in vivo delivery of DNA to the nucleus. AAV vectors now constitute a bone fide novel therapeutic drug class composed of seven US Food and Drug Administration-approved products with over 10-fold more in clinical development for an expanding number of disease indications and an identified list of problems to overcome for widespread clinical application. Here, we review current progress in clinical AAV gene therapy, including for neuromuscular disorders, hemophilia, primary cardiovascular disorders, or disorders with cardiovascular manifestations, lysosomal storage disorders, mucopolysaccharide disorders, primary central nervous systemic disorders, and ocular disorders.

  PublisherDOI

Recent grants

• Therapeutic Applications of Factor VIIIa Inactivation in Hemophilia A

  NIH · $160k · 2019–2024

• Therapeutic Applications of Factor VIIIa Inactivation in Hemophilia A

  NIH · $538k · 2019–2024

Frequent coauthors

• Benjamin J. Samelson‐Jones

  Children's Hospital of Philadelphia

  34 shared

• Rodney M. Camire

  University of Pennsylvania

  29 shared

• Ben J. Samelson-Jones

  Children's Hospital of Philadelphia

  27 shared

• Katherine A. High

  Rockefeller University

  27 shared

• John E.J. Rasko

  Royal Prince Alfred Hospital

  22 shared

• Spencer K. Sullivan

  University of Pennsylvania

  19 shared

• Jerome Teitel

  St. Michael's Hospital

  18 shared

• Xavier M. Anguela

  17 shared

Labs

• Lindsey A. George LaboratoryPI

Awards & honors

• Member of the National Academy of Medicine Emerging Leaders…
• Past member of the Board of Directors of the American Societ…