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Projects / Programmes source: ARIS

Hierarchical DNA assembly for advanced applications in biopharmaceuticals production and cell therapy

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Research activity

Code Science Field Subfield
4.06.00  Biotechnical sciences  Biotechnology   

Code Science Field
2.09  Engineering and Technology  Industrial biotechnology 
Keywords
DNA assembly, cell therapy, biologic drugs
Evaluation (rules)
source: COBISS
Evaluation of bibliographic research performance indicators according to ARIS methodology
Points
2,424.2
A''
330.59
A'
1,107.53
A1/2
1,406.27
CI10
4,763
CImax
211
h10
35
A1
8.34
A3
0.86
Data for the last 5 years (citations for the last 10 years) on April 19, 2024; A3 for period 2018-2022
Data for ARIS tenders ( 04.04.2019 – Programme tender, archive )
Citations Citations for bibliographic records in COBIB.SI that are linked to records in citation databases
source: WoS source: Scopus source: COBISS
Database Linked records Citations Pure citations Average pure citations
WoS  277  7,963  6,566  23.7 
Scopus  281  8,600  7,150  25.44 
Researchers (15)
no. Code Name and surname Research area Role Period No. of publications
1.  57013  Katja Doberšek  Biotechnology  Researcher  2022 - 2024  8 
2.  06416  PhD Marko Dolinar  Biochemistry and molecular biology  Head  2021 - 2024  341 
3.  29152  PhD Barbara Hubad  Biochemistry and molecular biology  Researcher  2021 - 2024  47 
4.  07673  PhD Dušan Kordiš  Biochemistry and molecular biology  Researcher  2021 - 2024  215 
5.  35319  PhD Mojca Ogrizović  Biochemistry and molecular biology  Researcher  2021  35 
6.  20213  PhD Toni Petan  Biochemistry and molecular biology  Researcher  2021 - 2024  177 
7.  20653  PhD Uroš Petrovič  Biochemistry and molecular biology  Researcher  2021 - 2024  292 
8.  32113  PhD Jelka Pohar  Biotechnology  Researcher  2022 - 2024  97 
9.  04570  PhD Jože Pungerčar  Biochemistry and molecular biology  Researcher  2021 - 2024  320 
10.  33201  PhD Anže Smole  Biotechnology  Researcher  2021 - 2024  74 
11.  29886  PhD Franc Smrekar  Biochemistry and molecular biology  Researcher  2021 - 2024  54 
12.  21553  PhD Jernej Šribar  Biochemistry and molecular biology  Researcher  2021 - 2024  108 
13.  51958  PhD Petra Tavčar Verdev  Biochemistry and molecular biology  Researcher  2022 - 2024  30 
14.  56000  Mia Žganjar  Biochemistry and molecular biology  Researcher  2022 - 2024  11 
15.  54712  Gašper Žun  Biochemistry and molecular biology  Junior researcher  2021 - 2024  24 
Organisations (4)
no. Code Research organisation City Registration number No. of publications
1.  0103  University of Ljubljana, Faculty of Chemistry and Chemical Technology  Ljubljana  1626990  23,083 
2.  0105  National Institute of Biology  Ljubljana  5055784  13,256 
3.  0106  Jožef Stefan Institute  Ljubljana  5051606000  90,682 
4.  3141  JAFRAL, biotechnology research and development, LTD  Ljubljana  3891518  133 
Abstract
This project proposal is a joint initiative of one industrial (Lek) and three academic partners (IJS, NIB and FCCT). The project group is proposing a project in development and improvement of hierarchical DNA assembly for advanced applications in biopharmaceuticals production and cell therapy. Lek is a lead pharmaceutical company in Slovenia that develops cell lines to produce biopharmaceuticals, and NIB focuses on the development of advanced cell therapies for cancer and autoimmune diseases. Both institutions are facing similar challenges in their research projects, which is assembly of complex DNA molecules encoding genes for multiple proteins. Although DNA synthesis costs dropped significantly in the past decade, it is currently not possible to order an advanced molecular cloning service on the market. Laboratories must therefore rely on their own capabilities for the assembly of synthetic genes into DNA constructs that can be delivered into biological systems, which can be time-consuming and expensive. Therefore, Lek and NIB identified two key collaboration academic institutions (FCCT & JSI) both having substantial knowledge and capabilities in solving this challenge. Production of biopharmaceuticals requires testing the effect of multiple genes, promoters, shRNAs, and other features that affect the production and/or stability of the production cell lines before products reach the quality required for production. Also for cell therapy, many different immune receptors and accessory molecules are tested in order to improve effectiveness and safety of engineered cells. In this proposal, our overarching goal is to develop a hierarchical DNA assembly platform for advanced applications in biopharmaceutical production and cell therapy. We will achieve this aim with three objectives: (1) Develop a DNA assembly platform, (2) Validate and improve generated construct in mammalian cells, and (3) Demonstrate the utility of the platform by two distinct biomedical implementations. The design of immune receptors emerged as one of the critical factors in developing efficacious cellular products for the immunotherapy of cancer and autoimmune diseases. We will first utilize the hierarchical DNA assembly platform to assemble a complex genetic construct that comprises an immune receptor, an accessory molecule, and a selection marker. Next, we will utilize a shRNA-enabled hierarchical DNA assembly platform to downregulate T-cell receptor (TCR) expression. Together, this will demonstrate how our proposed molecular cloning platform can be utilized to (1) generate an advanced genetic construct for cell therapy and (2) provide a unique solution to one of the outstanding challenges in engineered T cell therapies, which is the downregulation of endogenous TCR surface expression. In vitro methods for DNA assembly are the cornerstone of genetic engineering and have been well developed. However, assembly of large DNA fragments and especially fast and efficient combinations of such elements is far from trivial. We will combine in vitro techniques with an in vivo DNA assembly relying on homologous recombination in yeast Saccharomyces cerevisiae cells. This approach, named hierarchical DNA assembly is not entirely new, but its potential implications have not been fully investigated. Based on our previous results and expertise we are confident that hierarchical DNA assembly is the way to solve the challenges by which Lek and NIB have been confronted. The project is expected to generate a patentable technology platform for hierarchical DNA assembly. Commercialization of the technology platform is foreseen within a newly established spin-out company, which will provide capacities for customary DNA assemblies to Lek and other customers.
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