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

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: A Chip with Blood Vessels

Biochips have been developed at TU Wien (Vienna), on which tissue can be produced and examined. This allows supplying the tissue with different substances in a very controlled way.

Cultivating human cells in the Petri dish is not a big challenge today. Producing artificial tissue, however, permeated by fine blood vessels, is a much more...

Im Focus: A Leap Into Quantum Technology

Faster and secure data communication: This is the goal of a new joint project involving physicists from the University of Würzburg. The German Federal Ministry of Education and Research funds the project with 14.8 million euro.

In our digital world data security and secure communication are becoming more and more important. Quantum communication is a promising approach to achieve...

Im Focus: Research icebreaker Polarstern begins the Antarctic season

What does it look like below the ice shelf of the calved massive iceberg A68?

On Saturday, 10 November 2018, the research icebreaker Polarstern will leave its homeport of Bremerhaven, bound for Cape Town, South Africa.

Im Focus: Penn engineers develop ultrathin, ultralight 'nanocardboard'

When choosing materials to make something, trade-offs need to be made between a host of properties, such as thickness, stiffness and weight. Depending on the application in question, finding just the right balance is the difference between success and failure

Now, a team of Penn Engineers has demonstrated a new material they call "nanocardboard," an ultrathin equivalent of corrugated paper cardboard. A square...

Im Focus: Coping with errors in the quantum age

Physicists at ETH Zurich demonstrate how errors that occur during the manipulation of quantum system can be monitored and corrected on the fly

The field of quantum computation has seen tremendous progress in recent years. Bit by bit, quantum devices start to challenge conventional computers, at least...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

“3rd Conference on Laser Polishing – LaP 2018” Attracts International Experts and Users

09.11.2018 | Event News

On the brain’s ability to find the right direction

06.11.2018 | Event News

European Space Talks: Weltraumschrott – eine Gefahr für die Gesellschaft?

23.10.2018 | Event News

 
Latest News

Epoxy compound gets a graphene bump

14.11.2018 | Materials Sciences

Microgel powder fights infection and helps wounds heal

14.11.2018 | Health and Medicine

How algae and carbon fibers could sustainably reduce the athmospheric carbon dioxide concentration

14.11.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>