Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

High yield at high selectivity – lentiviral vectors with Nipah envelope proteins developed

10.06.2016

To transfer genes exclusively into the patient’s therapy relevant cells is in the focus of current research approaches in gene therapy. Researchers of the Paul-Ehrlich-Institut have succeeded in modifying envelope proteins of Nipah virus (NiV) and to combine them with lentiviruses in such a way that they can now be used for a highly selective and efficient gene transfer to selected cells. Another advantage of these new vectors is that they can be produced at higher yields, which is required for clinical applications. PLOS Pathogens reports on these research results in its online edition of 09.06.2016.

Modified virus particles targeted to specific surface receptors are developed as tools for selective gene transfer. To make them clinically usable and safe and effective in their application, these so-called “vectors” must on the one hand be produced in sufficient quantities and, on the other hand, not be deactivated by the patient’s immune response.


Left: EM image of the vector with envelope proteins (arrows). Right: Structure of a surface receptor (Her2/neu). Binding of the vector in the green zone allows membrane fusion and gene transfer.

Source: Bender RR et al.: PLOS Pathog. 09. June 2016 and PEI

Besides, it must be assured for at least some therapeutic approaches that the genes to be transferred enter only those cells which are relevant for the therapeutic approach.

Extensive research is performed on lentiviruses for their therapeutic use. These viruses belong to the family of retroviruses and can mediate long-term expression and integration of therapeutic genes into the cellular genome.

Lentiviral vectors can also transfer genes into resting cells. Thus, they have a potentially broad spectrum of application in gene therapy. Lentiviral vectors which have been used previously in clinical applications are usually pseudotyped (combined) with the envelope protein of the vesicular stomatitis virus (VSV). Although the latter guarantees high stability and production yields of the vector particles, it mediates an entirely non-selective gene transfer to almost all cells of the body.

In the past, the envelope proteins of the measles virus could be biotechnologically modified in such a way that they mediated gene transfer only in those cells which carry those particular surface proteins to which they were targeted. These vectors are functional in principle, however, they are also marked by relevant disadvantages. These include insufficient production yields or only very short-term efficacy due to the patient’s immune response based on measles vaccination.

To bypass or eliminate these disadvantages while making use of the high selectivity that can be created for measles virus envelope proteins, Professor Christian J. Buchholz, head of the research group "Molecular Biotechnology and Gene Therapy" of the president of the Paul-Ehrlich-Institut and his research group for the first time modified envelope proteins that originated from the Nipah virus.

The virus was characterised in 1999 after it has caused an outbreak of infectious encephalitis. Since there are no vaccination programmes against the virus, no neutralising antibodies are expected in the patients. At the same time, no hazards can be expected from the virus itself, since only its envelope proteins are used in a modified form.

For “receptor targeting”, Buchholz and co-workers developed 27 different variants of envelope proteins of the Nipah virus and addressed eight different cell surface proteins. Gene transfer assays were performed to test whether the respective lentiviral vectors would be able to enter into target receptor-positive cell types, and, if so, how efficiently they were able to do so.

The researchers established that cell entry worked best if the distance of the particles from the cell membrane was less than 100 Å. If this distance was longer, cell entry and thus gene delivery became inefficient or not functional at all. As the researchers interpret these results, the contact between the envelope proteins and the receptor will lead to a defined distance between the viral membrane and the cell membrane, which results in successful cell entry.

The newly developed lentiviral vectors with Nipah envelope proteins lead to higher productivity than previous vectors. This is of key significance with regard to clinical applications.

Non-replicating lentiviral vector particles equipped with these artificially generated Nipah virus glycoproteins showed a 10- to 600-fold more efficient gene transfer activity than corresponding vectors with measles virus glycoproteins. At the same time they showed high selectivity for those cells which had the targeted receptor on their surface. “With the modified Nipah virus envelope proteins, we can direct gene transfer with lentiviral vectors to the desired target cells at high efficiency”, explained Professor Buchholz.

Original publication:
Bender RR, Muth A, Schneider IC, Friedel T, Hartmann J, Plückthun A, Maisner A, Buchholz CJ (2016): Receptor-targeted Nipah virus glycoproteins improve cell-type selective gene delivery and reveal a preference for membrane proximal cell attachment. PLOS Pathog 09. June 2016
DOI: http://dx.doi.org/10.1371/journal.ppat.1005641


The Paul-Ehrlich-Institut, the Federal Institute for Vaccines and Biomedicines, in Langen near Frankfurt/Main is a senior federal authority reporting to the Federal Ministry of Health (Bundesministerium für Gesundheit, BMG). It is responsible for the research, assessment, and marketing authorisation of biomedicines for human use and immunological veterinary medicinal products. Its remit also includes the authorisation of clinical trials and pharmacovigilance, i.e. recording and evaluation of potential adverse effects.

Other duties of the institute include official batch control, scientific advice and inspections. In-house experimental research in the field of biomedicines and life science form an indispensable basis for the manifold tasks performed at the institute.

The Paul-Ehrlich-Institut, with its roughly 800 members of staff, also has advisory functions nationally (federal government, federal states (Länder)), and internationally (World Health Organisation, European Medicines Agency, European Commission, Council of Europe etc.).

Weitere Informationen:

http://dx.plos.org/10.1371/journal.ppat.1005641 - Link to the article
http://www.pei.de/EN/information/journalists-press/press-releases/2016/12-high-y... - This press release on the PEI-Website

Dr. Susanne Stöcker | idw - Informationsdienst Wissenschaft

More articles from Life Sciences:

nachricht Topologische Quantenchemie
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

nachricht Topological Quantum Chemistry
21.07.2017 | Max-Planck-Institut für Chemische Physik fester Stoffe

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Manipulating Electron Spins Without Loss of Information

Physicists have developed a new technique that uses electrical voltages to control the electron spin on a chip. The newly-developed method provides protection from spin decay, meaning that the contained information can be maintained and transmitted over comparatively large distances, as has been demonstrated by a team from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute. The results have been published in Physical Review X.

For several years, researchers have been trying to use the spin of an electron to store and transmit information. The spin of each electron is always coupled...

Im Focus: The proton precisely weighted

What is the mass of a proton? Scientists from Germany and Japan successfully did an important step towards the most exact knowledge of this fundamental constant. By means of precision measurements on a single proton, they could improve the precision by a factor of three and also correct the existing value.

To determine the mass of a single proton still more accurate – a group of physicists led by Klaus Blaum and Sven Sturm of the Max Planck Institute for Nuclear...

Im Focus: On the way to a biological alternative

A bacterial enzyme enables reactions that open up alternatives to key industrial chemical processes

The research team of Prof. Dr. Oliver Einsle at the University of Freiburg's Institute of Biochemistry has long been exploring the functioning of nitrogenase....

Im Focus: The 1 trillion tonne iceberg

Larsen C Ice Shelf rift finally breaks through

A one trillion tonne iceberg - one of the biggest ever recorded -- has calved away from the Larsen C Ice Shelf in Antarctica, after a rift in the ice,...

Im Focus: Laser-cooled ions contribute to better understanding of friction

Physics supports biology: Researchers from PTB have developed a model system to investigate friction phenomena with atomic precision

Friction: what you want from car brakes, otherwise rather a nuisance. In any case, it is useful to know as precisely as possible how friction phenomena arise –...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Closing the Sustainability Circle: Protection of Food with Biobased Materials

21.07.2017 | Event News

»We are bringing Additive Manufacturing to SMEs«

19.07.2017 | Event News

The technology with a feel for feelings

12.07.2017 | Event News

 
Latest News

NASA looks to solar eclipse to help understand Earth's energy system

21.07.2017 | Earth Sciences

Stanford researchers develop a new type of soft, growing robot

21.07.2017 | Power and Electrical Engineering

Vortex photons from electrons in circular motion

21.07.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>