Dr. Saravanabhavan Thangavel

Career Interests

Genome editing for Therapeutic applications

Haematopoietic stem cell expansion

Enhanced genome editing

Education

• 05/2011-02/2015 : Post Doctoral Scientist, Saint Louis University, Missouri, USA.
• 07/2010-05/2011 : Post Doctoral Scientist, ICGEB, Italy.
• 01/2007-06/2010 : PhD Molecular Biology, ICGEB, Italy.
• 2004-2006 : MSC Biotechnology, Bharathidasan University, TN, India.

Awards

• GET in award by IUSSTF.
• DST-SERB Early career award.
• ICGEB Post-doctoral award.

Gene-edited autologous hematopoietic stem and progenitor cells (HSPCs) represent a groundbreaking approach with immense potential for treating a range of inherited and acquired hematological disorders. We develop gene-edited HSPCs for various gene therapy applications. Our primary focus is on developing a cure for Beta hemoglobinopathies, the most prevalent monogenic-inherited disorder, and the infectious disease HIV. We are also committed to advancing technologies that facilitate the production and application of gene-edited stem cells, including creating optimized culture platforms for HSPCs and innovative delivery systems for gene-editing reagents.

β-hemoglobinopathies gene therapy: We are actively developing multiple gene editing approaches to reverse β-hemoglobinopathies permanently. Our team reported a CRISPR-Cas9-based gene editing method targeting a regulatory region in the human beta-globin locus. Our approach reduced the production of defective adult hemoglobin and increased the beneficial fetal hemoglobin reversing sickle cell disease and B-thalassemia phenotypes. The gene-edited stem cells transplanted in mouse models further demonstrated the long-term in vivo effect (Venkatesan V et al., Mol Ther Nucleic Acids.2023).

As a second approach, we developed Cas9 RNP-ssODN-mediated homology-directed gene editing to mimic two naturally occurring HBG promoter point mutations in HSPCs. These editing resulted in high HbF levels in erythroblasts in vivo, sufficient to reverse the disease phenotype (Chandraprabha P et al.,Stem Cell Research & Therapy 2024)

HIV gene therapy: CCR5 gene-edited autologous HSPCs can be a potential alternative to hematopoietic stem cell transplantation (HSCT) from HLA-matched CCR5 null donors. We demonstrated the CCR5 gene editing of a subpopulation of HSCs provides an ideal gene manipulation strategy for autologous HSCT-based gene therapy for HIV infection (Karrupusamy K et al., Front Immunol 2022).

Hematopoietic stem cell culture

The ex vivo culture and gene manipulation steps of HSPC graft preparation significantly reduce the frequency of HSCs, We have developed a small molecule cocktail that preserves the stemness of HSCs during gene manipulation ex vivo (Christopher AC et al., Human gene therapy 2022)

We have developed an ex vivo culture-free/reduced procedure for developing CRISPR-Cas9-based gene-edited hematopoietic stem cells (Venkatesan V et al., Mol Ther Nucleic Acids.2023).

We are also actively looking at other potential opportunities to develop therapy for diseases where we believe genome editing will be beneficial.

Write to us if you would like to participate/learn more about our work.

Selected Publications :

• Koodamvetty A and Thangavel S. Advancing Precision Medicine: Recent Innovations in Gene Editing Technologies. Advanced Science. Manuscript in press.
• Chandraprabha PB, Azhagiri MKK, Venkatesan V, Magis W, Prasad K, Suresh S, Pai AA, Marepally S, Srivastava A, Mohankumar KM, Martin DIK, Thangavel S. Enhanced fetal hemoglobin production via dual-beneficial mutation editing of the HBG promoter in hematopoietic stem and progenitor cells for β-hemoglobinopathies. Stem Cell Res Ther. 2024 Dec 31;15(1):504. doi: 10.1186/s13
• Babu Chandraprabha P, Thangavel S. Endocytosis as a critical regulator of hematopoietic stem cell fate -implications for hematopoietic stem cell and gene therapy.
  Stem Cell Res Ther. 2024 Sep 27;15(1):319. doi: 10.1186/s13287-024-03927-6.
• Arjunan P, Mahalingam G, Sankar P, Kathirvelu D, Suresh S, Rani S, Mohankumar KM, Thangavel S, Marepally S. Base-modified factor VIII mRNA delivery with galactosylated lipid nanoparticles as a protein replacement therapy for haemophilia A. Biomater Sci. 2024 Sep 25;12(19):5052-5062. doi: 10.1039/d4bm00909f.PMID: 39210734
• Prasad K, Devaraju N, George A, Ravi NS, Paul J, Mahalingam G, Rajendiran V, Panigrahi L, Venkatesan V, Lakhotiya K, Periyasami Y, Pai AA, Nakamura Y, Kurita R, Balasubramanian P, Thangavel S, Velayudhan SR, Newby GA, Marepally S, Srivastava A, Mohankumar KM. Precise correction of a spectrum of β-thalassemia mutations in coding and non-coding regions by base editors.
  Mol Ther Nucleic Acids. 2024 May 3;35(2):102205. doi: 10.1016/j.omtn.2024.102205. eCollection 2024 Jun 11.PMID: 38817682
• Rajendiran V, Devaraju N, Haddad M, Ravi NS, Panigrahi L, Paul J, Gopalakrishnan C, Wyman S, Ariudainambi K, Mahalingam G, Periyasami Y, Prasad K, George A, Sukumaran D, Gopinathan S, Pai AA, Nakamura Y, Balasubramanian P, Ramalingam R, Thangavel S, Velayudhan SR, Corn JE, Mackay JP, Marepally S, Srivastava A, Crossley M, Mohankumar KM. Base editing of key residues in the BCL11A-XL-specific zinc finger domains derepresses fetal globin expression. Mol Ther. 2024 Mar 6;32(3):663-677. doi: 10.1016/j.ymthe.2024.01.023. Epub 2024 Jan 24. PMID: 38273654 PMCID: PMC10928131
• Mahalingam G, Rachamalla HK, Arjunan P, Karuppusamy KV, Periyasami Y, Mohan A, Subramaniyam K, Salma M, Rajendran V, Moorthy M, Varghese GM, Mohankumar KM, Thangavel S, Srivastava A, Marepally S. SMART-lipid nanoparticles enabled mRNA vaccine elicits cross-reactive humoral responses against the omicron sub-variants. Mol Ther. 2024 Feb 27:S1525-0016(24)00097-2. doi: 10.1016/j.ymthe.2024.02.028. Online ahead of print. PMID: 38414245.
• Venkatesan V, Christopher AC, Rhiel M, Azhagiri MKK, Babu P, Walavalkar K, Saravanan B, Andrieux G, Rangaraj S, Srinivasan S, Karuppusamy KV, Jacob A, Bagchi A, Pai AA, Nakamura Y, Kurita R, Balasubramanian P, Pai R, Marepally SK, Mohankumar KM, Velayudhan SR, Boerries M, Notani D, Cathomen T, Srivastava A, Thangavel S. Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies. Mol Ther Nucleic Acids. 2023 Jun 13;32:671-688. doi: 10.1016/j.omtn.2023.04.024. eCollection 2023 Jun. PMID: 37215154; PMCID: PMC10197010.
• Mahalingam G, Arjunan P, Periyasami Y, Dhyani AK, Devaraju N, Rajendiran V, Christopher AC, Kt RD, Dhanasingh I, Thangavel S, Murugesan M, Moorthy M, Srivastava A, Marepally S. Correlating the differences in the receptor binding domain of SARS-CoV-2 spike variants on their interactions with human ACE2 receptor. Sci Rep. 2023 May 30;13(1):8743. doi: 10.1038/s41598-023-35070-2. PMID: 37253762; PMCID: PMC10227802.
• Lohchania B, Christopher AC, Arjunan P, Mahalingam G, Kathirvelu D, Prasannan A, Venkatesan V, Taneja P, Kumar Km M, Thangavel S, Marepally S. Diosgenin enhances liposome-enabled nucleic acid delivery and CRISPR/Cas9-mediated gene editing by modulating endocytic pathways. Front Bioeng Biotechnol. 2023 Jan 9;10:1031049. doi: 10.3389/fbioe.2022.1031049. eCollection 2022. PMID: 36698628; PMCID: PMC9868636.
• George A, Ravi NS, Babu V, Marepally S, Thangavel S, Velayudhan SR, Srivastava A, Mohankumar KM. Editing of highly homologous gamma-globin genes by nickase deficient Base Editor mitigates large intergenic deletions. bioRxiv. 2023:2023.12.04.569931.
• Murugesan R, Karuppusamy KV, Marepally S, Thangavel S. Current approaches and potential challenges in the delivery of gene editing cargos into hematopoietic stem and progenitor cells. Front Genome Ed. 2023;5:1148693. doi: 10.3389/fgeed.2023.1148693. Published online 2023 Sep 15. PMCID: PMC10540692. PMID: 37780116.
• Venkatesan V, Christopher A, Karuppusamy K, Babu P, Azhagiri M and Thangavel S. CRISPR/Cas9 Gene Editing of Hematopoietic Stem and Progenitor Cells for Gene Therapy Applications. JoVE. August 9, 2022 doi: 10.3791/64064
• Venkatesan V, Christopher A, Babu P,   Azhagiri M, Walavalkar K,  Saravanan B, Srinivasan, Karuppusamy K, Jacob A, Rangaraj S, Bagchi A,  Pa Ai,  Nakamura Y,  Balasubramanian P, Pai R, Marepally S, Mohankumar K.M, Velayudhan S Notani D, Srivastava and  Thangavel S Editing the core region in HPFH deletions alters fetal and adult globin expression for treatment of β-hemoglobinopathies. Biorxiv doi: https://doi.org/10.1101/2022.07.11.499646
• Bagchi A, Devaraju N, Chambayil K, Rajendiran V, Venkatesan V, Sayed N, Pai AA, Nath A, David E, Nakamura Y, Balasubramanian P, Srivastava A, Thangavel S, Mohankumar KM, Velayudhan SR (2022) Erythroid lineage-specific lentiviral RNAi vectors suitable for molecular functional studies and therapeutic applications. Sci Rep. 2022 Aug 18;12(1):14033. doi: 10.1038/s41598-022-13783-0.
• Daisy Precilla S, Kuduvalli SS, Angeline Praveena E, Thangavel S, Anitha TS (2022) Integration of synthetic and natural derivatives revives the therapeutic potential of temozolomide against glioma- an in vitro and in vivo perspective. Life Sci. https://doi.org/10.1016/J.LFS.2022.120609
• Rapaka H, Manturthi S, Arjunan P, Venkatesan V, Thangavel S, Marepally S, Patri S V. (2022) Influence of Hydrophobicity in the Hydrophilic Region of Cationic Lipids on Enhancing Nucleic Acid Delivery and Gene Editing. ACS Appl bio Mater 5:1489–1500
• Mahalingam G, Rachamalla HK, Arjunan P, Thangavel S, et al (2022) Optimization of SARS-CoV-2 Pseudovirion Production in Lentivirus Backbone With a Novel Liposomal System. Front Pharmacol. https://doi.org/10.3389/FPHAR.2022.840727
• Karuppusamy K, Demosthenes J, Venkatesan V, Christopher A, Babu P, Azhagiri M, Jacob A, Ramalingam V, Rangaraj S, Mohankumar K.M, Marepally S, Varghese G, Srivastava A, Kannangai R and Thangavel S. The CCR5 gene-edited CD34+CD90+ Hematopoietic stem cell population serves as an optimal graft source for HIV gene therapy.  Front. Immunol., 14 March 2022.
• Ravi NS, Wienert B, Wyman SK, Bell HW, George A, Mahalingam G, Vu JT, Prasad K, Bandlamudi BP, Devaraju N, Rajendiran V, Syedbasha N, Pai AA, Nakamura Y, Kurita R, Narayanasamy M, Balasubramanian P, Thangavel S, Marepally S, Velayudhan SR, Srivastava A, DeWitt MA, Crossley M, Corn JE, Mohankumar KM (2022) Identification of novel HPFH-like mutations by CRISPR base editing that elevates the expression of fetal hemoglobin. eLife 2022 Feb 11;11:e65421. doi: 10.7554/eLife.65421.
• Manoj Kumar K. Azhagiri, Prathibha Babu, Vigneshwaran Venkatesan, Thangavel S. Homology-directed gene-editing approaches for hematopoietic stem and progenitor cell gene therapy. Stem Cell Research & Therapy. 12; 500 (2021). https://doi.org/10.1186/s13287-021-02565-6.
• Abisha Crystal Christopher, Vigneshwaran Venkatesan, Karthik V Karuppusamy, Saranya Srinivasan, Prathibha Babu, Manoj Kumar K Azhagiri, Karthik C, Abhirup Bagchi, Vignesh Rajendiran, Nithin Sam Ravi, Sanjay Kumar, Srujan Kumar Marepally, Kumarasamypet Murugesan Mohankumar, Alok Srivastava, Shaji R Velayudhan, Thangavel S. Preferential expansion of human CD34+CD133+CD90+ hematopoietic stem cells enhances gene-modified cell frequency for gene therapy. Hum Gene Ther. 2021 Sep 5. doi: 10.1089/hum.2021.089. Online ahead of print.
• Karuppasamy K, Babu P and Thangavel S. The strategies and challenges of CCR5 gene editing in Hematopoietic stem and progenitor cells for the treatment of HIV. Stem Cell Reviews and Reports. In press
• Bagchi A , Nath A, Thamodaran V ,  Ijee S , Palani D , Rajendiran V , Venkatesan V, Datari P,  Pai A , Janet N ,  Balasubramanian P , Nakamura Y , Srivastava A,, Murugesan Mohankumar 1 , Thangavel S and Velayudhan S. Direct Generation of Immortalized Erythroid Progenitor Cell Lines from Peripheral Blood Mononuclear Cells. Cells. 2021 March.
• Venkatesan V, Srinivasan S, Babu P, Thangavel S. Manipulation of Developmental Gamma-Globin Gene Expression: an Approach for Healing Hemoglobinopathies. Mol Cell Biol. 2020 Dec 21;41(1):e00253-20.
• Ramalingam S and Thangavel S CRISPR-Cas9 Probing of Infectious Diseases and Genetic Disorders. Indian J Pediatr. 2019 Dec;86(12):1131-1135.
• Chen BR, Quinet A, Byrum AK, Jackson J, Berti M, Thangavel S, Bredemeyer AL, Hindi I, Mosammaparast N, Tyler JK, Vindigni A, Sleckman BP XLF and H2AX function in series to promote replication fork stability. J Cell Biol. 2019 Jul 1;218(7):2113-2123.
• Rangasami VK, Lohchania B, Voshavar C, Rachamalla HR, Banerjee R, Dhayani A, Thangavel S, Vemula PK, Marepally S Exploring membrane permeability of Tomatidine to enhance lipid mediated nucleic acid transfections. Biochim Biophys Acta Biomembr. 2019 Jan;1861(1):327-334.
• Dharmalingam P, Rachamalla HKR, Lohchania B, Bandlamudi B, Thangavel S, Murugesan MK, Banerjee R, Chaudhuri A, Voshavar C, Marepally S Green Transfection: Cationic Lipid Nanocarrier System Derivatized from Vegetable Fat, Palmstearin Enhances Nucleic Acid Transfections. ACS Omega. 2017 Nov 30;2(11):7892-7903.
• Thangavel S, Berti M, Levikova M, Pinto C, Gomathinayagam S, Vujanovic M, Zellweger R, Moore H, Lee EH, Hendrickson EA, Cejka P, Stewart S, Lopes M, Vindigni A.DNA2 drives processing and restart of reversed replication forks in human cells. J Cell Biol. 2015 Mar 2;208(5):545-62.
• Berti M, Ray Chaudhuri A, Thangavel S, Gomathinayagam S, Kenig S, Vujanovic M, Odreman F, Glatter T, Graziano S, Mendoza-Maldonado R, Marino F, Lucic B, Biasin V, Gstaiger M, Aebersold R, Sidorova JM, Monnat RJ Jr, Lopes M, Vindigni A.Human RECQ1 promotes restart of replication forks reversed by DNA topoisomerase I inhibition. Nat Struct Mol Biol. 2013 Mar;20(3):347-54.
• Li XL, Lu X, Parvathaneni S, Bilke S, Zhang H, Thangavel S, Vindigni A, Hara T, Zhu Y, Meltzer PS, Lal A, Sharma S. Identification of RECQ1-regulated transcriptome uncovers a role of RECQ1 in regulation of cancer cell migration and invasion. Cell Cycle. 2014;13(15):2431-45. doi: 10.4161/cc.29419.
• Xu D, Muniandy P, Leo E, Yin J, Thangavel S, Shen X, Ii M, Agama K, Guo R, Fox D 3rd, Meetei AR, Wilson L, Nguyen H, Weng NP, Brill SJ, Li L, Vindigni A, Pommier Y, Seidman M, Wang W. Rif1 provides a new DNA-binding interface for the Bloom syndrome complex to maintain normal replication. EMBO J. 2010 Sep 15;29(18):3140-55.
• Thangavel S, Mendoza-Maldonado R, Tissino E, Sidorova JM, Yin J, Wang W, Monnat RJ Jr, Falaschi A, Vindigni A. Human RECQ1 and RECQ4 helicases play distinct roles in DNA replication initiation. Mol Cell Biol. 2010 Mar;30(6):1382-96.

• Dr. Srujan Marepally, CSCR, CMC, Vellore
• Dr. Mohankumar Murugesan, CSCR, CMC, Vellore
• Dr Alok Srivastava, CSCR, CMC, Vellore
• Prof. Abi Abraham, Haematology, CMC Vellore
• Dr. Rajesh Kannangai, Department of Clinical Virology, CMC, Vellore
• Dr. George M Varghese, Department of Infectious Diseases, CMC, Vellore
• Dr. Poonkuzhali Balasubramanian, Haematology, CMC, Vellore
• Prof.David IK Martin, UCSF- Children's Hospital Oakland Research Institute, California (CHORI)
• Prof. Mauro Giacca, Kings college London
• Prof. H. Trent Spencer, Emory University School of Medicine

• Department of Biotechnology
• DBT/Wellcome Trust India Alliance
• DST-SERB
• Indo-U.S. Science and Technology Forum (IUSSTF)

Alumni

Dr. Abisha Crystal Christopher

PhD.,(2017-2022)

Current position : On Maternity break

Dr. Karthik V Karuppusamy

PhD.,( 2019-2023)

Current position : Post Doctoral Fellow at Andre Lieber Lab, University of Washington.

Dr. Vigneshwaran Venkatesan

PhD.,( 2018-2024)

Current position : Post Doctoral Fellow at Prof.Luigui Naldini Lab, SR-TIGET.

Project Trainees

• SWATHI  RADHAKRISHNAN (year of working: 2018)
• SHALINI (assistant manager at dr. Aggarwal’s eye institute, year of working: 2018)
• SAHANA  (year of working: 2018)
• PORKIZHI (phd at CSCR, year of working: 2018)
• MUTHUGANESH (phd at RGCB, year of working: 2018)
• SWETHA A P (senior research associate, syngene international limited, year of working: 2019)
• DHAKSHANYA (phd student at MAHE, year of working: 2020)
• UMESH (regulatory engineer, ICAL TECH, ,year of working: 2020)
• ELAMATHI (research assistant, washington university, year of working: 2020)
• SHEMMA (graduated student washington university, year of working: 2020)
• JHAGAN (IISER (master's thesis, year of working: 2020)
• SASRIKA VENKATACHALAPATHY (Mater’s Student at Johns Hopkins University, Year of working: 2023)
• NAMEETA JESUDOSS (PhD at the Institute of Immunology, University Hospital Hamburg- Eppendorf, Germany, Year of working: 2023)
• ANANT KUMAR (JRF at CSCR, Year of working: 2023)
• UDIT MILLENN R (Year of working: 2024)
• KEVIN (Year of working: 2024)
• SWATHI (JRF at CSCR, Year of working: 2024)
• JEEVAN (Year of working: 2024)