Gene and drug delivery across the Blood Brain Barrier (BBB) by conjugation to new peptide constructs
|Karolinska institutet - Institutionen för biovetenskaper och näringslära
|Funding from Vinnova
|SEK 1 750 000
|December 2008 - February 2012
Purpose and goal
Delivering therapeutic agents to the brain presents a major challenge. This is particularly difficult for nucleic acids but also a general problem in drug delivery. For the applying research environment at Novum (R Strömberg, E. Smith, at KI and Avaris AB) nucleic acid delivery is of the highest priority. Design of novel peptide constructs with specific properties will be done by the project leader, Malgorzata Wenska, together with Jan Johanssons group at Medical Biochemistry, BMC/SLU in Uppsala that are experts in this field. Together the two environments will aim at new vectors and new methods for their attachment to cargos in order to promote brain uptake of nucleic acid material as well as peptides and low molecular weight drugs (primarily by receptor-mediated uptake or triggering of transcytosis).
Expected results and effects
It is expected that the efforts will lead to vectors for improved uptake of both drug candidates for Alzheimers disease (with involvement of AlphaBeta AB) and for oligonucleotide and gene therapy as well as to methodology development for attachment of different cargos to vectors. The methods and design skill by the project leader is expected to be utilized in the applying research environment for further development of gene delivery not only to the brain but also to other parts of the body. The latter is an important aspect not least for the Swedish biotechnology company Avaris AB, which develops products based on cell and gene therapy.
Planned approach and implementation
The project leader will design peptides with specific properties and make constructs that have motifs for triggering endocytosis and yet keep an alfa-helical structure even with a short peptide. In parallel she will also attach potential drug molecules (such as ligands for the Abeta-peptide) to shorter peptides and study how these are affected structurally. The work will include analysis of structure and conformation by several techniques, such as CD-spectroscopy, fluorescence spectroscopy, electron microscopy. A specific goal after the first year is to have at least 1-2 peptide construct that are promising enough to move into the next stage (see below). The project leader will also be developing attachment methods, make constructs based on initial studies and assess the extent of uptake over the blood brain barrier by animal experiments in collaboration with the applying research environment (Smith and Avaris). In this respect transfer across the BBB of cargos originating from both sites will be assessed. A specific goal to be reached after year two is at least two cargo-vector constructs have been assessed with respect to BBB transfer. The project leader is expected to become responsible for the development of utilizing peptides and other signals for gene and oligonucleotide delivery. The approach for BBB uptake will then be applied in full for oligonucleotide and gene delivery (it is expected that collaborative efforts on some of this work will have started before returning). A particular issue is design of peptides for pH-dependent endosomal escape.