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 Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel

nachricht Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Powerful IT security for the car of the future – research alliance develops new approaches

The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.

Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...

Im Focus: Molecular switch will facilitate the development of pioneering electro-optical devices

A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.

The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...

Im Focus: LZH showcases laser material processing of tomorrow at the LASYS 2018

At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.

At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...

Im Focus: Self-illuminating pixels for a new display generation

There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?

At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...

Im Focus: Explanation for puzzling quantum oscillations has been found

So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics

Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

In focus: Climate adapted plants

25.05.2018 | Event News

Save the date: Forum European Neuroscience – 07-11 July 2018 in Berlin, Germany

02.05.2018 | Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

 
Latest News

In focus: Climate adapted plants

25.05.2018 | Event News

Flow probes from the 3D printer

25.05.2018 | Machine Engineering

Less is more? Gene switch for healthy aging found

25.05.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>