Research Profile

Patrick Harrison

Biography

Gene Editing for Research and Therapy

The research focus of the Harrison Lab is the development of CRISPR gene, base and prime editing to study and potentially treat genetic disorders such as cystic fibrosis (CF). 

What is CRISPR gene editing?  

CRISPR gene editing is a Nobel Prize winning technique (https://www.nobelprize.org/prizes/chemistry/2020/summary/) that enables the sequence of DNA of a living cell to be precisely changed, and has at least three major biomedical applications:
  • First, this ability to precisely change a DNA sequence within a cell allows researchers to learn how particular DNA sequences control the normal structure and functions of individual cells.
  • Second, it enables us to learn of how certain mutations in the DNA sequence, either acquired or inherited, can cause more than 100 different types of cancer or over 7,000 genetic disorders.
  • Third, gene editing could be developed as the basis for a potential treatments for many of these diseases, such as cystic fibrosis (CF), sickle-cell anaemia and cystinosis.   
How are we using CRISPR to understand Cystic Fibrosis?  

In 2012, we reported the use of ZFN to correct the most common CF mutation known as F508del.
https://pubmed.ncbi.nlm.nih.gov/23514673/

In 2016, we were able to do this more effectively with CRISPR
https://pubmed.ncbi.nlm.nih.gov/27557525/

In 2017, we demonstrated the use of a novel CRISPR approach to correct other CF causing variants
https://pubmed.ncbi.nlm.nih.gov/28863137/
 
We are currently working on three new approaches Base Editing, HITI and Prime editing as outlined in recent publications
https://pubmed.ncbi.nlm.nih.gov/29233638/ Gene Editing and Stem Cells (2018)
https://pubmed.ncbi.nlm.nih.gov/31117296/ Base Editing and Disease (2019)
https://pubmed.ncbi.nlm.nih.gov/34031549/ Prime Editing (2021)
https://www.karger.com/Article/Pdf/511678/ ATMP policy discussion (2021)

In the last year, we have published data from the first of our CF projects, along with peers from two collaborations with groups in Liverpool and Auckland on different disease mechanisms.

https://pubmed.ncbi.nlm.nih.gov/32198276/ Cystinosis iPSc model (2020)
https://pubmed.ncbi.nlm.nih.gov/33671852/ CRISPR to study gene regulation (2021)
https://pubmed.ncbi.nlm.nih.gov/34103250/ - CF gene editing (2021)

 
Our current work is supported by grants from CF Trust (UK) and CF Foundation (USA).

Research Interests

2020 onwards - Prime Editing, ABE and HITI for Cystic Fibrosis
The current focus of the Harrison Lab is the development of gene, base and prime editing to repair disease-causing mutations in the human genome funded by CFF foundation (USA) and CF Trust (UK)

2017 to 2019 - CRISPR NHEJ and HITI for Cystic Fibrosis and Atopic Dermatitis
The focus was on NHEJ based methods. A published study showed effective excision of CF-causing deep intronic mutations (Sanz et al., 2017), but focus moved to use of HITI to correct multiple mutations with a single donor and Cas9/gRNA combination. This work was supported by grants from CF Foundation Therapeutics (USA) and CF Trust (UK). The lab was also a member of the CF Trust's first Strategic Research Centre for Gene Editing during this period, and colaboration with Carlos Farinha in Lisbon to create novel cell lines to study rare CF mutations (part funded by CF Foundation) using gene and base editing

2013 to 2016 - CRISPR HDR for Cystic Fibrosis
In 2013, the lab starting using the CRISPR Cas9/gRNA system for gene editing to correct the F508del mutation by HDR (Hollywood et al., 2016) with grants from CF Foundation Therapeutics (USA) and CF Trust (UK). The lab has funded collaborative projects with Alan Davidson and Jennifer Hollywood in Auckland (funded by Cystinosis Ireland and Health Research Board), and Isabelle Sermet in Paris (funded by HRB).

2005 to 2012 - Application of ZFN HDR to cystic fibrosis
Since 2005, my lab has been working on the production of ZFNs to target the most common gene defect in patients with cystic fibrosis. This work was started by a PhD student, Rowan Flynn, and is currently under further investigation by Ciaran Lee and Jennifer Hollywoord. Using an in vitro system, we developed ZFNs which can target and correct the F508del mutation in the cftr gene http://online.liebertpub.com/doi/abs/10.1089/biores.2012.0218

2008 to 2012 - Application of ZFN HDR to cystinosis 
Cystinosis is a rare genetic disorder affecting less than 10 individuals in Ireland. The disease which is a multisystem disorder invariably leads to kidney failure. The gene defect was characterised in 1999, and Dr. Harrison and Dr. Scallan were recently been awarded funding from Cystinosis Ireland (www.cystinosis.ie) and the HRB (www.hrb.ie), as well as the Cystinosis Research Foundation (www.natalieswish.org) to study the applicability of ZFN HDR technology,  virus vector delivery and Tale nuclease gene repair. This work has been conducted by Katrin Kaschig and Ciaran Lee.

2001 to 2007 - Molecular Physiology
Between 2001 and 2007, the Department hosted five 10-day residential workshop to provide training for physiologists in molecular biological techniques (Harrison, 2004). The workshop was sponsored by the Physiological Society and the Wellcome Trust, and offered training in experimental procedures in molecular physiology, including the handling of DNA and RNA, sub-cloning, restriction enzyme digests, the use of siRNA technology, western blots, RT-PCR, site-directed mutagenesis and transfection techniques. During this time over 80 physiologists at PhD or post-doctoral level attended these workshops. Further details of other courses organised by the physiological society can be found at www.physoc.org. In 2010, the Department hosted two shorter workshops for physiologists, again sponsored by the Physiological Society.

Research Grants

 ProjectFunding
Body
Start DateEnd DateAward
Gene Editing of CFTR.Foreign Research Institute01-OCT-2130-SEP-24€160,542.00
Project Title: 25,000 non-drug alleles fixed with 15 (or less) CRISPR PRIME pegRNAsFoundation Funded Research01-JUL-2030-JUN-22€236,084.00
Temporal-spatial CRISPR Base Editing to Identify Target Cells for CFTR RepairForeign Research Institute01-JUL-2130-JUN-22€93,696.00
Cystic Fibrosis TrustFoundation Funded Research01-MAY-1631-MAR-20€152,003.00
Splicing mutationsForeign Research Institute17-NOV-1431-JAN-20€59,963.00
Permanent correction of 80% of Disease causing Mutations in Human CF cells.Foreign Research Institute01-OCT-1331-JAN-20€62,458.00
Down's Symdrome StudyForeign Research Institute22-FEB-1831-DEC-19€1,000.00
Isogenic Cell Models to Chareterise Disease Siganutures of Seven CF-Causing Mutations and HITI-Gene Editing to Correct Them.Foundation Funded Research01-DEC-1730-NOV-19€46,900.00
Isogenic models to study CF disease signatures: HITI gene edit to fix themFoundation Funded Research01-OCT-1730-SEP-19€117,945.00
Cystic Fibrosis- Gene Editing of Non-Druggable CFTR Mutations.Irish Research Council01-FEB-1730-JUN-18€2,425.00
Cystic Fibrosis Foundation Therapeutics CRISPR Knock-Out of Class 1 CF Splicing Mutations.Foreign Research Institute01-OCT-1431-MAY-18€162,902.00
Modelling cystinosis with human stem cells and the therapeutic potential of aspartic acidHealth Research Board01-NOV-1430-OCT-17€295,000.00
Science Foundation of Ireland01-FEB-1631-JUL-16€3,000.00

Publications

Peer Reviewed Journals

 YearPublication
(2021)'CRISPR Deletion of a SVA Retrotransposon Demonstrates Function as a cis-Regulatory Element at the TRPV1/TRPV3 Intergenic Region'
Price E;Gianfrancesco O;Harrison PT;Frank B;Bubb VJ;Quinn JP; (2021) 'CRISPR Deletion of a SVA Retrotransposon Demonstrates Function as a cis-Regulatory Element at the TRPV1/TRPV3 Intergenic Region'. International Journal of Molecular Sciences, 22 (4) [DOI] [Details]
(2021)'Prime editing - an update on the field'
Scholefield J;Harrison PT; (2021) 'Prime editing - an update on the field'. Gene Therapy, 28 (7-8) [DOI] [Details]
(2021)'Comparison of Cas9 and Cas12a CRISPR editing methods to correct the W1282X-CFTR mutation'
Santos L;Mention K;Cavusoglu-Doran K;Sanz DJ;Bacalhau M;Lopes-Pacheco M;Harrison PT;Farinha CM; (2021) 'Comparison of Cas9 and Cas12a CRISPR editing methods to correct the W1282X-CFTR mutation'. Journal of Cystic Fibrosis, [DOI] [Details]
(2020)'Polycystic kidney disease ryanodine receptor domain (Pkdrr) proteins in oomycetes'
Zheng L.;Prestwich B.D.;Harrison P.T.;Mackrill J.J. (2020) 'Polycystic kidney disease ryanodine receptor domain (Pkdrr) proteins in oomycetes'. Journal of Pathogens, 9 (7):1-19 [DOI] [Details]
(2019)'Minigene Assay to Evaluate CRISPR/Cas9-based Excision of Intronic Mutations that Cause Aberrant Splicing in Human Cells'
Sanz, DJ;Harrison, PT (2019) 'Minigene Assay to Evaluate CRISPR/Cas9-based Excision of Intronic Mutations that Cause Aberrant Splicing in Human Cells'. Bio-Protocol, 9 [DOI] [Details]
(2019)'Gene and Base Editing as a Therapeutic Option for Cystic Fibrosis-Learning from Other Diseases'
Mention K;Santos L;Harrison PT; (2019) 'Gene and Base Editing as a Therapeutic Option for Cystic Fibrosis-Learning from Other Diseases'. Genes, 10 (5) [DOI] [Details]
(2018)'The Regulation of Monoamine Oxidase A Gene Expression by Distinct Variable Number Tandem Repeats'
Manca, M;Pessoa, V;Lopez, AI;Harrison, PT;Miyajima, F;Sharp, H;Pickles, A;Hill, J;Murgatroyd, C;Bubb, VJ;Quinn, JP (2018) 'The Regulation of Monoamine Oxidase A Gene Expression by Distinct Variable Number Tandem Repeats'. Journal of Molecular Neuroscience, 64 :459-470 [DOI] [Details]
(2017)'Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA'
Sanz, DJ;Hollywood, JA;Scallan, MF;Harrison, PT (2017) 'Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA'. Plos One, 12 [DOI] [Details]
(2018)'Gene Editing of Stem Cells to Model and Treat Disease'
Hollywood, JA;Sanz, DJ;Davidson, AJ;Harrison, PT (2018) 'Gene Editing of Stem Cells to Model and Treat Disease'. Current Stem Cell Reports, 4 :253-263 [DOI] [Details]
(2018)'A beginner's guide to gene editing'
Harrison, Patrick T.; Hart, Stephen (2018) 'A beginner's guide to gene editing'. Experimental Physiology,   [DOI] [Full Text] [Details]
(2017)'Double TALEN-edited T-cells kick B-ALL into touch'
Harrison PT (2017) 'Double TALEN-edited T-cells kick B-ALL into touch'. Gene Therapy, 24 (3)   [Details]
(2017)'Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA'
Sanz DJ, Hollywood JA, Scallan MF, Harrison PT (2017) 'Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA'. Plos One, 12 (9)   [Details]
(2017)'Genetic therapies for cystic fibrosis lung disease'
Hart, SL;Harrison, PT (2017) 'Genetic therapies for cystic fibrosis lung disease'. Current Opinion In Pharmacology, 34 :119-124 [DOI] [Details]
(2016)'Analysis of gene repair tracts from Cas9/gRNA double-stranded breaks in the human CFTR gene'
Hollywood, JA,Lee, CM,Scallan, MF,Harrison, PT (2016) 'Analysis of gene repair tracts from Cas9/gRNA double-stranded breaks in the human CFTR gene'. Scientific Reports, 6 [DOI] [Details]
(2016)'Impact of gene editing on the study of cystic fibrosis'
Harrison PT;Sanz DJ;Hollywood JA; (2016) 'Impact of gene editing on the study of cystic fibrosis'. Human Genetics, 135 (9) [DOI] [Details]
(2016)'Genetic medicines for CF: Hype versus reality'
Alton EW;Boyd AC;Davies JC;Gill DR;Griesenbach U;Harrison PT;Henig N;Higgins T;Hyde SC;Innes JA;Korman MS; (2016) 'Genetic medicines for CF: Hype versus reality'. Pediatric Pulmonology, 51 (S44) [DOI] [Details]
(2012)'Correction of the ΔF508 mutation in the CFTR gene by zinc finger nuclease homology-directed repair'
Lee, CM, Flynn, R, Hollywood, JA, Scallan, MF and Harrison, PT (2012) 'Correction of the ΔF508 mutation in the CFTR gene by zinc finger nuclease homology-directed repair'. BioResearch Open Access, 1 (2):99-108   [DOI] [Details]

Editorship

 YearPublication
(2017)Double TALEN-edited T-cells kick B-ALL into touch.
Harrison, PT (2017) Double TALEN-edited T-cells kick B-ALL into touch. LONDON: Editorship [DOI] [Details]

Reviews

 YearPublication
(2019)Gene and Base Editing as a Therapeutic Option for Cystic FibrosisLearning from Other Diseases.
Mention, K;Santos, L;Harrison, PT (2019) Gene and Base Editing as a Therapeutic Option for Cystic FibrosisLearning from Other Diseases. BASEL: Reviews [DOI] [Details]
(2018)Gene editing & stem cells.
Harrison, PT;Hoppe, N;Martin, U (2018) Gene editing & stem cells. AMSTERDAM: Reviews [DOI] [Details]
(2016)Impact of gene editing on the study of cystic fibrosis.
Harrison, PT;Sanz, DJ;Hollywood, JA (2016) Impact of gene editing on the study of cystic fibrosis. NEW YORK: Reviews [DOI] [Details]
(2008)Viral vectors in cancer immunotherapy: Which vector for which strategy?.
Collins, SA;Guinn, BA;Harrison, PT;Scallan, MF;O'Sullivan, GC;Tangney, M (2008) Viral vectors in cancer immunotherapy: Which vector for which strategy?. SHARJAH: Reviews [Details]

Teaching Activities

Teaching Interests

Teaching interest include CRISPR gene editing and gene therapy, molecular physiology, and introductory physiology.

Recent Postgraduates

 Graduation YearStudent NameInstitutionDegree TypeThesis Title
2022Lúcia Santos Technical University of LisbonPHD
2020Karen Mention NUI (UCC)PHDCRISPR Editing of CFTR
2013Jennifer Hollywood PHDCystic fibrosis gene repair : correction of ΔF508 using ZFN and CRISPR/Cas9 guide RNA gene editing tools
2013Katrin Kaschig PHDZinc finger nuclease gene repair as a treatment for cystinosis
2013Ana Marie Landin PHDMolecular regulation of B cell deficiency with age : a study of E47 and Pax-5
2011Sarah Collins PHDAdeno-Associated virus vectors for cancer gene therapy
2010Ciaran Lee UCCPHDCystic fibrosis gene repair : development of zinc finger nucleases for homology directed repair of the CFTR
2007Rowan Flynn UCCPHD1 THESIS Cystic fibrosis gene repair : design and evaluation of zinc finger nucleases for homology-directed r
2006David B O'Sullivan UCCPHDEstablishment of growth/differentiation factor 5-expressing cells for transplantation in a model of Parkinson's disease
2001Melanie McCarthy-Troke University of GlasgowPHD
2001Pavel Mistrik University of GlasgowPHD

Modules Taught

 Term (ID))TitleLinkSubject
2022Gene Targeting Tools for Physiology PL4007Gene Targeting Tools for Physiology
2022Cell and Epithelial Physiology PL3005Cell and Epithelial Physiology
2022Introductory Physiology I PL2021Introductory Physiology I

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Physiology Department

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Western Gateway Building Western Road University College Cork

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