About My Research
Additional Harvard Medical School Titles
Associate Director, Ocular Genomics Institute
Member, Biological and Biomedical Sciences, Virology, Therapeutics Graduate Programs
Additional Mass. Eye and Ear Titles
Associate Scientist
Center/Research Area Affiliations
- AMD Center of Excellence
- Cornea Center of Excellence
- Mobility Enhancement and Vision Rehabilitation Center of Excellence
- Ocular Genomics Institute
- Ocular Regenerative Medicine Institute
- Berman-Gund Laboratory for the Study of Retinal Degenerations
Biography
Through the study and development of technologies that overcome current translational hurdles, Dr. Vandenberghe is helping to position gene therapy as a broadly applicable clinical modality in ophthalmology. Previously, he developed a novel adeno-associated viral vector (AAV) platform, and in translational studies, he characterized those for safety and efficacy parameters in large animal models. His current research focuses on gene therapy for neurosensory disorders, especially retinal blindness. He is on the editorial board of Molecular Therapy and is an active member of the American Society of Cell and Gene Therapy, for which he chairs the educational committee. In addition, he co-founded GenSight Biologics, a biotech entity that pursues innovative ocular gene therapy strategies.
Education
2008: MSc, PhD, Biological Engineering in Cellular and Genetic Biotechnology, Katholieke Universiteit Leuven, Belgium
Postgraduate Training
2007-2010: Postdoctoral fellowship (James M. Wilson, MD, PhD), Perelman School of Medicine, University of Pennsylvania
2010-2012: Postdoctoral fellowship (Jean Bennett, MD, PhD), Perelman School of Medicine, University of Pennsylvania
Honors
2016: RPB Nelson Trust Awardee for Retinitis Pigmentosa
2017: Ed Gollob Board of Directors' Award, Foundation Fighting Blindness
2018: Outstanding New Investigator Award, American Society of Gene and Cell Therapy
- Correlating physicochemical and biological properties to define critical quality attributes of a rAAV vaccine candidate. Mol Ther Methods Clin Dev. 2023 Sep 14; 30:103-121.
- Efficient in vivo genome editing prevents hypertrophic cardiomyopathy in mice. Nat Med. 2023 02; 29(2):412-421.
- High-efficiency purification of divergent AAV serotypes using AAVX affinity chromatography. Mol Ther Methods Clin Dev. 2023 Mar 09; 28:146-159.
- Subretinal gene therapy delays vision loss in a Bardet-Biedl Syndrome type 10 mouse model. Mol Ther Nucleic Acids. 2023 Mar 14; 31:164-181.
- Ancestral library identifies conserved reprogrammable liver motif on AAV capsid. Cell Rep Med. 2022 11 15; 3(11):100803.
- Gene therapy with a synthetic adeno-associated viral vector improves audiovestibular phenotypes in Pjvk-mutant mice. JCI Insight. 2022 10 24; 7(20).
- Selective retinal ganglion cell loss and optic neuropathy in a humanized mouse model of familial dysautonomia. Hum Mol Genet. 2022 06 04; 31(11):1776-1787.
- Efficient Delivery of Adeno-Associated Virus into Inner Ear In Vivo Through Trans-Stapes Route in Adult Guinea Pig. Hum Gene Ther. 2022 07; 33(13-14):719-728.
- Durable immunogenicity, adaptation to emerging variants, and low-dose efficacy of an AAV-based COVID-19 vaccine platform in macaques. Mol Ther. 2022 09 07; 30(9):2952-2967.
- Immunogenicity of an AAV-Based COVID-19 Vaccine in Murine Models of Obesity and Aging. Viruses. 2022 04 15; 14(4).
- Computed tomography and [18F]-FDG PET imaging provide additional readouts for COVID-19 pathogenesis and therapies evaluation in non-human primates. iScience. 2022 Apr 15; 25(4):104101.
- Choice of vector and surgical approach enables efficient cochlear gene transfer in nonhuman primate. Nat Commun. 2022 03 15; 13(1):1359.
- Early disruption of photoreceptor cell architecture and loss of vision in a humanized pig model of usher syndromes. EMBO Mol Med. 2022 04 07; 14(4):e14817.
- AAV capsid design: A Goldilocks challenge. Trends Mol Med. 2022 03; 28(3):183-193.
- An AAV-based, room-temperature-stable, single-dose COVID-19 vaccine provides durable immunogenicity and protection in non-human primates. Cell Host Microbe. 2021 09 08; 29(9):1437-1453.e8.
- ImmTOR nanoparticles enhance AAV transgene expression after initial and repeat dosing in a mouse model of methylmalonic acidemia. Mol Ther Methods Clin Dev. 2021 Sep 10; 22:279-292.
- Efficient cardiac gene transfer and early-onset expression of a synthetic adeno-associated viral vector, Anc80L65, after intramyocardial administration. J Thorac Cardiovasc Surg. 2022 Dec; 164(6):e429-e443.
- MCOLN1 gene therapy corrects neurologic dysfunction in the mouse model of mucolipidosis IV. Hum Mol Genet. 2021 05 29; 30(10):908-922.
- Voices of biotech research. Nat Biotechnol. 2021 03; 39(3):281-286.
- Immunogenicity of an AAV-based, room-temperature stable, single dose COVID-19 vaccine in mice and non-human primates. bioRxiv. 2021 Jan 19.
- Homologous Recombination Offers Advantages over Transposition-Based Systems to Generate Recombinant Baculovirus for Adeno-Associated Viral Vector Production. Biotechnol J. 2021 Jan; 16(1):e2000014.
- Gene Therapy Preserves Retinal Structure and Function in a Mouse Model of NMNAT1-Associated Retinal Degeneration. Mol Ther Methods Clin Dev. 2020 Sep 11; 18:582-594.
- Efficient in Utero Gene Transfer to the Mammalian Inner Ears by the Synthetic Adeno-Associated Viral Vector Anc80L65. Mol Ther Methods Clin Dev. 2020 Sep 11; 18:493-500.
- COVID-19: Gene Transfer to the Rescue? Hum Gene Ther. 2020 06; 31(11-12):605-607.
- Hair Cell Transduction Efficiency of Single- and Dual-AAV Serotypes in Adult Murine Cochleae. Mol Ther Methods Clin Dev. 2020 Jun 12; 17:1167-1177.
- Cross-Packaging and Capsid Mosaic Formation in Multiplexed AAV Libraries. Mol Ther Methods Clin Dev. 2020 Jun 12; 17:107-121.
- Filling Adeno-Associated Virus Capsids: Estimating Success by Cryo-Electron Microscopy. Hum Gene Ther. 2019 12; 30(12):1449-1460.
- GPR108 Is a Highly Conserved AAV Entry Factor. Mol Ther. 2020 02 05; 28(2):367-381.
- In Situ Modification of Tissue Stem and Progenitor Cell Genomes. Cell Rep. 2019 04 23; 27(4):1254-1264.e7.
- AAV Engineering Identifies a Species Barrier That Highlights a Portal to the Brain. Mol Ther. 2019 05 08; 27(5):901-903.
- Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality. Neuron. 2019 Apr 03; 102(1):263.
- Residues on Adeno-associated Virus Capsid Lumen Dictate Interactions and Compatibility with the Assembly-Activating Protein. J Virol. 2019 04 01; 93(7).
- Therapeutic AAV Gene Transfer to the Nervous System: A Clinical Reality. Neuron. 2019 03 06; 101(5):839-862.
- Quantitative and Digital Droplet-Based AAV Genome Titration. Methods Mol Biol. 2019; 1950:51-83.
- FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia. JCI Insight. 2018 12 06; 3(23).
- Novel engineered, membrane-localized variants of vascular endothelial growth factor (VEGF) protect retinal ganglion cells: a proof-of-concept study. Cell Death Dis. 2018 10 03; 9(10):1018.
- Breaking and Sealing Barriers in Retinal Gene Therapy. Mol Ther. 2018 09 05; 26(9):2081-2082.
- Efficient Gene Transfer to the Central Nervous System by Single-Stranded Anc80L65. Mol Ther Methods Clin Dev. 2018 Sep 21; 10:197-209.
- Efficient Gene Transfer to Kidney Mesenchymal Cells Using a Synthetic Adeno-Associated Viral Vector. J Am Soc Nephrol. 2018 09; 29(9):2287-2297.
- The Assembly-Activating Protein Promotes Stability and Interactions between AAV's Viral Proteins to Nucleate Capsid Assembly. Cell Rep. 2018 05 08; 23(6):1817-1830.
- Synthetic Adeno-Associated Viral Vector Efficiently Targets Mouse and Nonhuman Primate Retina In Vivo. Hum Gene Ther. 2018 07; 29(7):771-784.
- An Alternate Route for Adeno-associated Virus (AAV) Entry Independent of AAV Receptor. J Virol. 2018 04 01; 92(7).
- Delivery of Adeno-Associated Virus Vectors in Adult Mammalian Inner-Ear Cell Subtypes Without Auditory Dysfunction. Hum Gene Ther. 2018 04; 29(4):492-506.
- Evaluating Efficiencies of Dual AAV Approaches for Retinal Targeting. Front Neurosci. 2017; 11:503.
- Single stranded adeno-associated virus achieves efficient gene transfer to anterior segment in the mouse eye. PLoS One. 2017; 12(8):e0182473.
- Genome editing abrogates angiogenesis in vivo. Nat Commun. 2017 07 24; 8(1):112.
- Corrigendum: Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction. Sci Rep. 2017 05 22; 7:46827.
- AAV-ID: A Rapid and Robust Assay for Batch-to-Batch Consistency Evaluation of AAV Preparations. Mol Ther. 2017 06 07; 25(6):1375-1386.
- Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunction. Sci Rep. 2017 04 03; 7:45524.
- Exosome-associated AAV2 vector mediates robust gene delivery into the murine retina upon intravitreal injection. Sci Rep. 2017 03 31; 7:45329.
- A synthetic AAV vector enables safe and efficient gene transfer to the mammalian inner ear. Nat Biotechnol. 2017 03; 35(3):280-284.
- Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol. 2017 03; 35(3):264-272.
- In vitro and in vivo rescue of aberrant splicing in CEP290-associated LCA by antisense oligonucleotide delivery. Hum Mol Genet. 2016 06 15; 25(12):2552-2563.
- Understanding Cone Photoreceptor Cell Death in Achromatopsia. Adv Exp Med Biol. 2016; 854:231-6.
- Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids. Methods Mol Biol. 2016; 1382:133-49.
- In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science. 2016 Jan 22; 351(6271):407-411.
- In Silico Reconstruction of the Viral Evolutionary Lineage Yields a Potent Gene Therapy Vector. Cell Rep. 2015 Aug 11; 12(6):1056-68.
- What Is Next for Retinal Gene Therapy? Cold Spring Harb Perspect Med. 2015 Apr 15; 5(10).
- Perspectives on best practices for gene therapy programs. Hum Gene Ther. 2015 Mar; 26(3):127-33.
- Efficient transduction and optogenetic stimulation of retinal bipolar cells by a synthetic adeno-associated virus capsid and promoter. EMBO Mol Med. 2014 Sep; 6(9):1175-90.
- Adeno-associated virus: fit to serve. Curr Opin Virol. 2014 Oct; 8:90-7.
- Promising and delivering gene therapies for vision loss. Vision Res. 2015 Jun; 111(Pt B):124-33.
- Formation of newly synthesized adeno-associated virus capsids in the cell nucleus. Hum Gene Ther Methods. 2014 Jun; 25(3):179-80.
- Gene therapy: charting a future course--summary of a National Institutes of Health Workshop, April 12, 2013. Hum Gene Ther. 2014 Jun; 25(6):488-97.
- The structure of AAVrh32.33, a novel gene delivery vector. J Struct Biol. 2014 May; 186(2):308-17.
- Progress in gene therapy for neurological disorders. Nat Rev Neurol. 2013 May 14.
- Progress in gene therapy for neurological disorders. Nat Rev Neurol. 2013 May; 9(5):277-91.
- Retinal gene therapy coming of age. Hum Gene Ther. 2013 Mar; 24(3):242-4.
- AAV9 targets cone photoreceptors in the nonhuman primate retina. PLoS One. 2013; 8(1):e53463.
- Adeno-associated viruses as liver-directed gene delivery vehicles: focus on lipoprotein metabolism. Methods Mol Biol. 2013; 1027:273-307.
- Gene therapy for deaf mice goes viral. Mol Ther. 2012 Oct; 20(10):1836-7.
- Influence of serotype, cell type, tissue composition, and time after inoculation on gene expression in recombinant adeno-associated viral vector-transduced equine joint tissues. Am J Vet Res. 2012 Aug; 73(8):1178-85.
- Novel adeno-associated viral vectors for retinal gene therapy. Gene Ther. 2012 Feb; 19(2):162-8.
- Human CRB1-associated retinal degeneration: comparison with the rd8 Crb1-mutant mouse model. Invest Ophthalmol Vis Sci. 2011 Aug 29; 52(9):6898-910.
- Dosage thresholds for AAV2 and AAV8 photoreceptor gene therapy in monkey. Sci Transl Med. 2011 Jun 22; 3(88):88ra54.
- Identification and functional characterization in vivo of a novel splice variant of LDLR in rhesus macaques. Physiol Genomics. 2011 Aug 16; 43(15):911-6.
- The AAV9 receptor and its modification to improve in vivo lung gene transfer in mice. J Clin Invest. 2011 Jun; 121(6):2427-35.
- Evaluation of adeno-associated viral vectors for liver-directed gene transfer in dogs. Hum Gene Ther. 2011 Aug; 22(8):985-97.
- Efficient and stable transduction of dopaminergic neurons in rat substantia nigra by rAAV 2/1, 2/2, 2/5, 2/6.2, 2/7, 2/8 and 2/9. Gene Ther. 2011 May; 18(5):517-27.
- Gene therapy in a humanized mouse model of familial hypercholesterolemia leads to marked regression of atherosclerosis. PLoS One. 2010 Oct 19; 5(10):e13424.
- Rapid, simple, and versatile manufacturing of recombinant adeno-associated viral vectors at scale. Hum Gene Ther. 2010 Oct; 21(10):1259-71.
- Efficient serotype-dependent release of functional vector into the culture medium during adeno-associated virus manufacturing. Hum Gene Ther. 2010 Oct; 21(10):1251-7.
- Efficient gene transfer into the mouse lung by fetal intratracheal injection of rAAV2/6.2. Mol Ther. 2010 Dec; 18(12):2130-8.
- Naturally occurring singleton residues in AAV capsid impact vector performance and illustrate structural constraints. Gene Ther. 2009 Dec; 16(12):1416-28.
- The pleiotropic effects of natural AAV infections on liver-directed gene transfer in macaques. Mol Ther. 2010 Jan; 18(1):126-34.
- Systematic evaluation of AAV vectors for liver directed gene transfer in murine models. Mol Ther. 2010 Jan; 18(1):118-25.
- A new genetic vaccine platform based on an adeno-associated virus isolated from a rhesus macaque. J Virol. 2009 Dec; 83(24):12738-50.
- Adeno-associated virus-mediated gene transfer to nonhuman primate liver can elicit destructive transgene-specific T cell responses. Hum Gene Ther. 2009 Sep; 20(9):930-42.
- Hepatic regulatory T cells and Kupffer cells are crucial mediators of systemic T cell tolerance to antigens targeting murine liver. Hepatology. 2009 Aug; 50(2):612-21.
- Isolation and characterization of adenoviruses persistently shed from the gastrointestinal tract of non-human primates. PLoS Pathog. 2009 Jul; 5(7):e1000503.
- Adeno-associated virus capsid structure drives CD4-dependent CD8+ T cell response to vector encoded proteins. J Immunol. 2009 May 15; 182(10):6051-60.
- Functional cystic fibrosis transmembrane conductance regulator expression in cystic fibrosis airway epithelial cells by AAV6.2-mediated segmental trans-splicing. Hum Gene Ther. 2009 Mar; 20(3):267-81.
- Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009 Feb 01; 199(3):381-90.
- Host immune responses to chronic adenovirus infections in human and nonhuman primates. J Virol. 2009 Mar; 83(6):2623-31.
- Transduction efficiencies of novel AAV vectors in mouse airway epithelium in vivo and human ciliated airway epithelium in vitro. Mol Ther. 2009 Feb; 17(2):294-301.
- Tailoring the AAV vector capsid for gene therapy. Gene Ther. 2009 Mar; 16(3):311-9.
- Expanded repertoire of AAV vector serotypes mediate unique patterns of transduction in mouse brain. Mol Ther. 2008 Oct; 16(10):1710-8.
- Impact of preexisting vector immunity on the efficacy of adeno-associated virus-based HIV-1 Gag vaccines. Hum Gene Ther. 2008 Jul; 19(7):663-9.
- Specific AAV serotypes stably transduce primary hippocampal and cortical cultures with high efficiency and low toxicity. Brain Res. 2008 Jan 23; 1190:15-22.
- AAV as an immunogen. Curr Gene Ther. 2007 Oct; 7(5):325-33.
- Novel adeno-associated virus serotypes efficiently transduce murine photoreceptors. J Virol. 2007 Oct; 81(20):11372-80.
- A comparative analysis of novel fluorescent proteins as reporters for gene transfer studies. J Histochem Cytochem. 2007 Sep; 55(9):931-9.
- Comparative analysis of adeno-associated viral vector serotypes 1, 2, 5, 7, and 8 in mouse brain. Hum Gene Ther. 2007 Mar; 18(3):195-206.
- Heparin binding directs activation of T cells against adeno-associated virus serotype 2 capsid. Nat Med. 2006 Aug; 12(8):967-71.
- New recombinant serotypes of AAV vectors. Curr Gene Ther. 2005 Jun; 5(3):285-97.
- Complete nucleotide sequences and genome organization of four chimpanzee adenoviruses. Virology. 2004 Jul 01; 324(2):361-72.
- Clades of Adeno-associated viruses are widely disseminated in human tissues. J Virol. 2004 Jun; 78(12):6381-8.
- Folate receptor alpha and caveolae are not required for Ebola virus glycoprotein-mediated viral infection. J Virol. 2003 Dec; 77(24):13433-8.
- CD28 and inducible costimulatory protein Src homology 2 binding domains show distinct regulation of phosphatidylinositol 3-kinase, Bcl-xL, and IL-2 expression in primary human CD4 T lymphocytes. J Immunol. 2003 Jul 01; 171(1):166-74.
- Adeno-associated viruses undergo substantial evolution in primates during natural infections. Proc Natl Acad Sci U S A. 2003 May 13; 100(10):6081-6.
- DC-SIGN and DC-SIGNR bind ebola glycoproteins and enhance infection of macrophages and endothelial cells. Virology. 2003 Jan 05; 305(1):115-23.
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Biology of Adeno-Associated Virus (AAV)
Dr. Vandenberghe is interested in studying the biology of AAV transduction, including binding, entry, post-entry, replication, viral assembly, and release, as well as AAV epidemiology and immunology.
Viral Evolution
Dr. Vandenberghe studies the evolution of viruses currently in use for gene transfer applications. He hypothesizes that the study of the natural history of the viruses on which vectors are based highlight underlying biology relevant to their application as vectors and fundamental findings in how viruses assemble, package DNA, and transduce a particular cell target.
Delivering Large Therapeutic Expression Cassettes to the Retina
Current vector systems are limited in terms of how much genetic cargo they can effectively shuttle. Dr. Vandenberghe is interested in developing technologies to overcome this limitation.
Immunology of Retinal Gene Transfer
The eye is generally seen as an immune-privileged organ due to passive and active means of tolerance. Many gene therapy approaches rely on the delivery of a protein or vector system that is foreign to the host and may elicit an immune-response. Dr. Vandenberghe's laboratory studies and develops assays to monitor these processes in an effort to maximize the safety of the therapeutic strategy.
Genome Editing Therapy
While many ideas use genetic information to treat disease are built on adding, augmenting or silencing genes to the host cell, tissue or organ, Dr. Vandenberghe is also exploring ways that novel methods to somatically alter cellular genomic information could be used therapeutically in blindness.
Vector Development
Delivery of a gene to a cell is cornerstone of genetic therapy. Its efficiency, safety, specificity, longevity and many of the other parameters essential for a treatment are determined by the vector the gene is shuttled into the cell. Dr. Vandenberghe's laboratory continuously pursues the optimization of current vectors and the discovery and generation of new vector technologies.
Translational Gene Therapy Programs
Dr. Vandenberghe's laboratory is dedicated to using existing technologies in preclinical and clinical programs for indications with an unmet clinical needs.
Laboratory Members
Senior Research Technologists
- Julio Sanmiguel
- Allegra Fieldsend
Senior Scientists
- Christopher Tipper, PhD
- Carmen Unzu, PhD
Postdoctoral Research Fellows
- Amanda Dudek, PhD
- Weiwei Wang, PhD
- Xia Wang, PhD
PhD Candidates
- Michael Florea
- Anna C. Maurer
- Pauline Schmidt
- Eric Zinn
Research Specialist
- Fotini Nicolaou, MA
Animal Care Technician
- Jennifer Santos-Franceschini
Research Assistants
- Reynette Estelien
- Ana Karla Cepeda Diaz
- Cheikh Diop
- Erin Merkel
- Urja Bhatt
- Rakesh Gurrala
- Bioinformaticist
- Yanhe Wen
Members of the Gene Transfer Vector Core
Associate Director, Gene Transfer Vector Core
- Ru Xiao, M.D., MS
Research Assistants
- Trisha Barungi
- Haiyan Qiu, MSc
- Allison Cucalon