Charles Gersbach

Positions:

John W. Strohbehn Distinguished Professor of Biomedical Engineering

Biomedical Engineering
Pratt School of Engineering

Professor of Biomedical Engineering

Biomedical Engineering
Pratt School of Engineering

Associate Professor of Surgery

Surgery, Surgical Sciences
School of Medicine

Associate Professor in Orthopaedic Surgery

Orthopaedics
School of Medicine

Associate Professor in Cell Biology

Cell Biology
School of Medicine

Associate of the Duke Initiative for Science & Society

Duke Science & Society
Institutes and Provost's Academic Units

Core Faculty in Innovation & Entrepreneurship

Duke Innovation & Entrepreneurship
Institutes and Provost's Academic Units

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Affiliate of the Duke Regeneration Center

Regeneration Next Initiative
School of Medicine

Education:

B.S. 2001

Georgia Institute of Technology

Ph.D. 2006

Georgia Institute of Technology

Grants:

Regulatory Mechanisms of CD4+ T Cell Differentiation

Administered By
Biostatistics & Bioinformatics
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Regulatory Mechanisms of CD4+ T Cell Differentiation

Administered By
Integrative Genomics
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Investigating Autophagy in GSD-Ia

Administered By
Pediatrics, Medical Genetics
Awarded By
National Institutes of Health
Role
Co Investigator
Start Date
End Date

Mechanotransduction in Meniscus Health and Repair

Administered By
Orthopaedics
Awarded By
National Institutes of Health
Role
Collaborator
Start Date
End Date

To support research on the development of CRISPR-based epigenome editing tools to refine genome wide association studies

Administered By
Biomedical Engineering
Role
Principal Investigator
Start Date
End Date

Publications:

Full-length dystrophin restoration via targeted exon integration by AAV-CRISPR in a humanized mouse model of Duchenne muscular dystrophy.

Targeted gene-editing strategies have emerged as promising therapeutic approaches for the permanent treatment of inherited genetic diseases. However, precise gene correction and insertion approaches using homology-directed repair are still limited by low efficiencies. Consequently, many gene-editing strategies have focused on removal or disruption, rather than repair, of genomic DNA. In contrast, homology-independent targeted integration (HITI) has been reported to effectively insert DNA sequences at targeted genomic loci. This approach could be particularly useful for restoring full-length sequences of genes affected by a spectrum of mutations that are also too large to deliver by conventional adeno-associated virus (AAV) vectors. Here, we utilize an AAV-based, HITI-mediated approach for correction of full-length dystrophin expression in a humanized mouse model of Duchenne muscular dystrophy (DMD). We co-deliver CRISPR-Cas9 and a donor DNA sequence to insert the missing human exon 52 into its corresponding position within the DMD gene and achieve full-length dystrophin correction in skeletal and cardiac muscle. Additionally, as a proof-of-concept strategy to correct genetic mutations characterized by diverse patient mutations, we deliver a superexon donor encoding the last 28 exons of the DMD gene as a therapeutic strategy to restore full-length dystrophin in >20% of the DMD patient population. This work highlights the potential of HITI-mediated gene correction for diverse DMD mutations and advances genome editing toward realizing the promise of full-length gene restoration to treat genetic disease.
Authors
Pickar-Oliver, A; Gough, V; Bohning, JD; Liu, S; Robinson-Hamm, JN; Daniels, H; Majoros, WH; Devlin, G; Asokan, A; Gersbach, CA
MLA Citation
Pickar-Oliver, Adrian, et al. “Full-length dystrophin restoration via targeted exon integration by AAV-CRISPR in a humanized mouse model of Duchenne muscular dystrophy.Mol Ther, vol. 29, no. 11, Nov. 2021, pp. 3243–57. Pubmed, doi:10.1016/j.ymthe.2021.09.003.
URI
https://scholars.duke.edu/individual/pub1497106
PMID
34509668
Source
pubmed
Published In
Molecular Therapy : the Journal of the American Society of Gene Therapy
Volume
29
Published Date
Start Page
3243
End Page
3257
DOI
10.1016/j.ymthe.2021.09.003

Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.

Colorectal cancer (CRC) metastasizes mainly to the liver, which accounts for the majority of CRC-related deaths. Here it is shown that metastatic cells undergo specific chromatin remodeling in the liver. Hepatic growth factor (HGF) induces phosphorylation of PU.1, a pioneer factor, which in turn binds and opens chromatin regions of downstream effector genes. PU.1 increases histone acetylation at the DPP4 locus. Precise epigenetic silencing by CRISPR/dCas9KRAB or CRISPR/dCas9HDAC revealed that individual PU.1-remodeled regulatory elements collectively modulate DPP4 expression and liver metastasis growth. Genetic silencing or pharmacological inhibition of each factor along this chromatin remodeling axis strongly suppressed liver metastasis. Therefore, microenvironment-induced epimutation is an important mechanism for metastatic tumor cells to grow in their new niche. This study presents a potential strategy to target chromatin remodeling in metastatic cancer and the promise of repurposing drugs to treat metastasis.
Authors
Wang, L; Wang, E; Prado Balcazar, J; Wu, Z; Xiang, K; Wang, Y; Huang, Q; Negrete, M; Chen, K-Y; Li, W; Fu, Y; Dohlman, A; Mines, R; Zhang, L; Kobayashi, Y; Chen, T; Shi, G; Shen, JP; Kopetz, S; Tata, PR; Moreno, V; Gersbach, C; Crawford, G; Hsu, D; Huang, E; Bu, P; Shen, X
MLA Citation
Wang, Lihua, et al. “Chromatin Remodeling of Colorectal Cancer Liver Metastasis is Mediated by an HGF-PU.1-DPP4 Axis.Adv Sci (Weinh), vol. 8, no. 19, Oct. 2021, p. e2004673. Pubmed, doi:10.1002/advs.202004673.
URI
https://scholars.duke.edu/individual/pub1493278
PMID
34378358
Source
pubmed
Published In
Advanced Science (Weinheim, Baden Wurttemberg, Germany)
Volume
8
Published Date
Start Page
e2004673
DOI
10.1002/advs.202004673

Transgenic mice for in vivo epigenome editing with CRISPR-based systems.

CRISPR-Cas9 technologies have dramatically increased the ease of targeting DNA sequences in the genomes of living systems. The fusion of chromatin-modifying domains to nuclease-deactivated Cas9 (dCas9) has enabled targeted epigenome editing in both cultured cells and animal models. However, delivering large dCas9 fusion proteins to target cells and tissues is an obstacle to the widespread adoption of these tools for in vivo studies. Here, we describe the generation and characterization of two conditional transgenic mouse lines for epigenome editing, Rosa26:LSL-dCas9-p300 for gene activation and Rosa26:LSL-dCas9-KRAB for gene repression. By targeting the guide RNAs to transcriptional start sites or distal enhancer elements, we demonstrate regulation of target genes and corresponding changes to epigenetic states and downstream phenotypes in the brain and liver in vivo, and in T cells and fibroblasts ex vivo. These mouse lines are convenient and valuable tools for facile, temporally controlled, and tissue-restricted epigenome editing and manipulation of gene expression in vivo.
Authors
Gemberling, MP; Siklenka, K; Rodriguez, E; Tonn-Eisinger, KR; Barrera, A; Liu, F; Kantor, A; Li, L; Cigliola, V; Hazlett, MF; Williams, CA; Bartelt, LC; Madigan, VJ; Bodle, JC; Daniels, H; Rouse, DC; Hilton, IB; Asokan, A; Ciofani, M; Poss, KD; Reddy, TE; West, AE; Gersbach, CA
MLA Citation
Gemberling, Matthew P., et al. “Transgenic mice for in vivo epigenome editing with CRISPR-based systems.Nat Methods, vol. 18, no. 8, Aug. 2021, pp. 965–74. Pubmed, doi:10.1038/s41592-021-01207-2.
URI
https://scholars.duke.edu/individual/pub1492755
PMID
34341582
Source
pubmed
Published In
Nat Methods
Volume
18
Published Date
Start Page
965
End Page
974
DOI
10.1038/s41592-021-01207-2

Integrating Biomaterials and Genome Editing Approaches to Advance Biomedical Science.

The recent discovery and subsequent development of the CRISPR-Cas9 (clustered regularly interspaced short palindromic repeat-CRISPR-associated protein 9) platform as a precise genome editing tool have transformed biomedicine. As these CRISPR-based tools have matured, multiple stages of the gene editing process and the bioengineering of human cells and tissues have advanced. Here, we highlight recent intersections in the development of biomaterials and genome editing technologies. These intersections include the delivery of macromolecules, where biomaterial platforms have been harnessed to enable nonviral delivery of genome engineering tools to cells and tissues in vivo. Further, engineering native-like biomaterial platforms for cell culture facilitates complex modeling of human development and disease when combined with genome engineering tools. Deeper integration of biomaterial platforms in these fields could play a significant role in enabling new breakthroughs in the application of gene editing for the treatment of human disease.
Authors
Abdeen, AA; Cosgrove, BD; Gersbach, CA; Saha, K
MLA Citation
Abdeen, Amr A., et al. Integrating Biomaterials and Genome Editing Approaches to Advance Biomedical Science. Vol. 23, 2021, pp. 493–516. Epmc, doi:10.1146/annurev-bioeng-122019-121602.
URI
https://scholars.duke.edu/individual/pub1493251
PMID
33909475
Source
epmc
Volume
23
Published Date
Start Page
493
End Page
516
DOI
10.1146/annurev-bioeng-122019-121602

CRISPR Clocks: The Times They Are a-Changin'.

Authors
Bodle, JC; Gersbach, CA
MLA Citation
Bodle, Josephine C., and Charles A. Gersbach. “CRISPR Clocks: The Times They Are a-Changin'.The Crispr Journal, vol. 4, no. 2, Apr. 2021, pp. 160–63. Epmc, doi:10.1089/crispr.2021.29123.ger.
URI
https://scholars.duke.edu/individual/pub1481834
PMID
33876949
Source
epmc
Published In
The Crispr Journal
Volume
4
Published Date
Start Page
160
End Page
163
DOI
10.1089/crispr.2021.29123.ger