About

Katherine A. High, M.D., is an Emeritus Professor of Pediatrics (Hematology) at the University of Pennsylvania's Perelman School of Medicine. She is also an Attending Physician at The Children's Hospital of Philadelphia, the Hospital of the University of Pennsylvania, and Presbyterian Hospital Medical Center. Dr. High serves as the Director of the Center for Cellular and Molecular Therapeutics at The Children's Hospital of Philadelphia and is President and Chief Scientific Officer at Spark Therapeutics. Her research focuses on the molecular basis of blood coagulation and the development of novel genetic therapies to treat hemophilia. She has pioneered the safe and effective clinical translation of genetic therapies for inherited disorders, leading to short-term correction of disease in hemophilia B and long-term improvements in Leber’s congenital amaurosis, a hereditary cause of blindness. Her major areas of investigation include structure-function analysis of clotting factors, regulation of gene expression in the liver, and establishing experimental and clinical bases for gene therapy of hemophilia using viral vectors, particularly AAV vectors expressing Factor IX. Dr. High's work also involves studying immune responses to gene therapy and assessing the safety and risk of germline transmission of vector sequences. Her contributions have significantly advanced the field of gene therapy for genetic blood disorders.

Research topics

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

Selected publications

• Gene therapy for hemophilia – From basic science to first approvals of “one-and-done” therapies

  Molecular Therapy · 2025-03-27 · 28 citations

  reviewOpen accessSenior author
  PublisherOA PDFDOI

• Validation of a quantitative cell-based relative potency assay for LUXTURNA

  Molecular Therapy — Methods & Clinical Development · 2025-01-25

  articleOpen accessSenior author

  cell-based relative potency assay for an AAV vector, which was used to evaluate lot-to-lot consistency, stability, and comparability following manufacturing changes and to successfully launch Luxturna, the first gene therapy approved in the US for a genetic disease.

  PublisherDOI

• Roadmap for direct and indirect translation of optogenetics into discoveries and therapies for humans

  Nature Neuroscience · 2025-11-18 · 4 citations

  articleOpen access
  PublisherOA PDFDOI

• Hemophilia B and gene therapy: a new chapter with etranacogene dezaparvovec

  Blood Advances · 2024-04-05 · 41 citations

  reviewOpen accessSenior author

  ABSTRACT: The US Food and Drug Administration (FDA)'s authorization of etranacogene dezaparvovec (Hemgenix) is a significant milestone, constituting not only the first FDA approval of a gene therapy for hemophilia but also the first approval of a liver-targeted adeno-associated virus vector gene therapy. This review summarizes the nonclinical studies and clinical development that supported regulatory clearance. Similar to other gene therapies for single gene disorders, both the short-term safety and the phenotypic improvement were unequivocal, justifying the modest-sized safety and efficacy database, which included 57 participants across the phase 2b (3 participants) and phase 3 (54 participants) studies. The most common adverse reactions included liver enzyme elevation, headache, flu-like symptoms, infusion-related reactions, creatine kinase elevation, malaise, and fatigue; these were mostly transient. One participant had hepatocellular carcinoma on a study-mandated liver ultrasound conducted 1 year after vector infusion; molecular analysis of the resected tumor showed no evidence of vector-related insertional mutagenesis as the etiology. A remarkable 96% of participants in the phase 3 trial were able to stop factor IX (FIX) prophylaxis, with the study demonstrating noninferiority to FIX prophylaxis in terms of the primary end point, annualized bleeding rate. Key secondary end points such as the annualized infusion rate, which declined by 97%, and the plasma FIX activity level at 18 months after infusion, with least squares mean increase of 34.3 percentage points compared with baseline, were both clinically and statistically significant. The FDA's landmark approval of Hemgenix as a pioneering treatment for hemophilia stands on the shoulders of >20 years of gene therapy clinical research and heralds a promising future for genomic medicines.

  PublisherOA PDFDOI

• THE JEREMIAH METZGER LECTURE: TURNING GENES INTO MEDICINES: HIGHLIGHTS AND HURDLES IN THE DEVELOPMENT OF GENE THERAPY FOR GENETIC DISEASE.

  PubMed · 2023-01-01

  articleOpen access1st authorCorresponding

  deficiency, a key to success was development and validation of a novel clinical endpoint for a disease that previously lacked a pharmacologic treatment.

  PublisherOA PDF

• Gene and cell therapy in 2023: Rich pipeline, slimming resources?

  Molecular Therapy · 2023-12-19 · 1 citations

  editorialOpen access1st authorCorresponding
  PublisherOA PDFDOI

• Trial by “Firsts”: Clinical Trial Design and Regulatory Considerations in the Development and Approval of the First AAV Gene Therapy Product in the United States

  Cold Spring Harbor Perspectives in Medicine · 2022-09-12 · 13 citations

  reviewOpen accessSenior author

  Given the therapeutic potential of supplying a normal copy of a mutant gene to the correct target tissue, gene therapy holds extraordinary promise for the treatment of genetic disease. Like other novel classes of therapeutics however, gene therapies must overcome a range of clinical, regulatory, and manufacturing hurdles to reach regulatory approval. This paper reviews key aspects of clinical trial design, development, and evaluation of a novel primary end point, and regulatory interactions that resulted in the first approval by the U.S. Food and Drug Administration (FDA) of an adeno-associated virus (AAV) gene therapy product.

  PublisherOA PDFDOI

• Preclinical assessment of an optimized AAV-FVIII vector in mice and non-human primates for the treatment of hemophilia A

  Molecular Therapy — Methods & Clinical Development · 2021-11-24 · 17 citations

  articleOpen access

  Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent SPK-8011, currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 1012 vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic. Extensive clinical data from liver-mediated gene therapy trials have shown that dose-dependent immune responses against the vector capsid may impair or even preclude transgene expression if not managed successfully with prompt immune suppression. The goal of this preclinical study was to generate an adeno-associated viral (AAV) vector capable of expressing therapeutic levels of B-domain deleted factor VIII (FVIII) at the lowest possible vector dose to minimize the potential Risk of a capsid-mediated immune response in the clinical setting. Here, we describe the studies that identified the investigational agent SPK-8011, currently being evaluated in a phase 1/2 study (NCT03003533) in individuals with hemophilia A. In particular, the potency of our second-generation expression cassettes was evaluated in mice and in non-human primates using two different bioengineered capsids (AAV-Spark100 and AAV-Spark200). At 2 weeks after gene transfer, primates transduced with 2 × 1012 vg/kg AAV-Spark100-FVIII or AAV-Spark200-FVIII expressed FVIII antigen levels of 13% ± 2% and 22% ± 6% of normal, respectively. Collectively, these preclinical results validate the feasibility of lowering the AAV capsid dose for a gene-based therapeutic approach for hemophilia A to a dose level orders of magnitude lower than the first-generation vectors in the clinic.

  PublisherOA PDFDOI

• 89 Five-year update for the Phase III voretigene neparvovec study in biallelic RPE65 mutation–associated inherited retinal disease

  Abstracts · 2021-10-01 · 3 citations

  articleOpen access

  <h3>Goal</h3> To determine whether ambulatory navigation, light sensitivity, and visual field (VF) improvements 1 year after voretigene neparvovec (VN) administration in patients with biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD) are maintained at 5 years and review safety outcomes over the entire period. <h3>Methods</h3> This is an open label, randomized, controlled Phase III trial performed at 2 sites in the United States. Patients were randomized to either original intervention (OI: bilateral subretinal VN at baseline; n=20) or delayed intervention (DI: VN after 1 year; n=9). The primary endpoint was bilateral performance on the Multi-Luminance Mobility Test (MLMT) at 7 standard light levels as measured by a change in score. Additional endpoints were full-field light sensitivity threshold (FST) testing, visual acuity (VA), and Goldmann kinetic VF (GVF), each averaged over both eyes. Safety outcomes included adverse event reporting, laboratory testing, and changes in physical and ophthalmic examinations. <h3>Results</h3> For OI patients at Year 5 (n=18) and DI patients at Year 4 (n=8), the mean (standard deviation) MLMT bilateral light level score change was 1.6 (1.1) and 2.4 (1.5) levels, respectively, compared with baseline. Subsequent to the 1-year outcomes, a change of 1 light level occurred in 6 patients (none were below pre-treatment performance) and no change in the remaining 20 (N=26). Mean change in white light FST in log10 (cd.s/m2) averaged over both eyes was −2.02 (1.45) log10 at Year 5 for OI patients (n=17) and −2.58 (1.04) log10 at Year 4 for DI patients (n=8). Mean change in VA (Holladay Scale) averaged over both eyes (logMAR was −0.00 (0.64) at Year 5 for OI patients (n=18) and −0.06 (0.26) at Year 4 for DI patients (n=8). Mean change in GVF III4e sum total degrees averaged over both eyes was 166.6 (208.7) at Year 5 for OI patients (n=15) and 178.8 (241.9) at Year 4 for DI patients (n=8). Five years after treatment, the safety profile (N=29) was consistent with vitrectomy and subretinal injection procedure with 2 reports of cataract, 1 of ptosis, and 1 new report of retinal detachment since the last update. No deleterious immune responses were reported. <h3>Conclusion</h3> Improvements in ambulatory navigation, light sensitivity, and VF are maintained for at least 5 years after VN administration in most OI patients. Improvements in DI patients were consistent with those observed in OI patients. The safety profile of VN is consistent with the administration procedure.

  PublisherOA PDFDOI

• Molecular defect (Gla+ 14----Lys) and its functional consequences in a hereditary factor X deficiency (factor X" Vorarlberg").

  UNC Libraries · 2021-07-03

  articleOpen access

  Factor X (FX) "Vorarlberg" is a congenital FX deficiency characterized clinically by a mild bleeding tendency. Homozygous individuals have a FX activity of less than 10% in the extrinsic system and 25% in the intrinsic system. FX antigen is 20%. Using molecular techniques, two point mutations were detected in the coding sequence of the FX Vorarlberg gene: a G----A at base pair 160 in exon II resulting in a change of Gla14 (GAA) to Lys (AAA); a G----A at base pair 424 in exon V resulting in a change from Glu102 (GAG) to Lys (AAG). The mutations abolished a TaqI restriction site in exon II and an MnlI site in exon V. To determine whether these mutations are present on one or on both alleles, restriction analyses of amplified exon II and exon V fragments were performed. Analysis of the pedigree showed that the genotype for the mutation on exon II (homozygous versus heterozygous) correlates with the severity of the phenotypic coagulation defect. We therefore conclude that the mutation in exon II is responsible for the functional defect in FX Vorarlberg. We have also purified the mutant FX protein from patient plasma. Purified FX Vorarlberg is indistinguishable from normal FX on sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Its activity is 15% of normal FX upon activation with factor VIIa/tissue factor, 75% upon activation with factor IXa/factor VIIIa, and 100% upon activation with RVV. Activation at varying Ca2+ concentrations shows that the affinity of FX Vorarlberg for Ca2+ is decreased. Factor Xa Vorarlberg is able to convert prothrombin at a normal rate but also shows decreased affinity for Ca2+ in this interaction. Upon addition of Ca2+, FX Vorarlberg does not undergo the same conformational change as normal FX. Our data show that FX Vorarlberg has a decreased affinity for Ca2+ which impedes a normal conformational change. This leads to a decreased rate of activation by factor VIIa/tissue factor and by factor IXa. The decrease is much more marked for the extrinsic than for the intrinsic pathway.

  PublisherDOI

Recent grants

• NIH Grant R01HL048322

  NIH · $2.5M · 2000

• NIH Grant K08HL001922

  NIH · $324k · 1992

• NIH Grant G20RR030997

  NIH · $2.0M · 2014

• NIH Grant P01HL064190

  NIH · $25.4M · 2017

• NIH Grant R01HL053668

  NIH · $2.0M · 1999

Frequent coauthors

• Valder R. Arruda

  292 shared

• Roland W. Herzog

  Indiana University – Purdue University Indianapolis

  282 shared

• Linda B. Couto

  Spark Therapeutics (United States)

  187 shared

• Federico Mingozzi

  Ark Therapeutic (United States)

  160 shared

• J. Fraser Wright

  135 shared

• Peter J. Larson

  Jackson Laboratory

  115 shared

• Shing Jen Tai

  Children's Hospital of Philadelphia

  107 shared

• Mark A. Kay

  Stanford University

  107 shared

Labs

• Katherine A. High LaboratoryPI