Oxford BioMedica PLC (OXBDF)

[georgejjl]

The latest news regarding the new improved ProSavin

Hum Gene Ther Clin Dev. 2016 Jul 28. [Epub ahead of print]
Optimising transgene configuration and protein fusions to maximise dopamine production for the gene therapy of Parkinson's Disease.
Stewart HJ1, Ralph GS2, Fong-Wong L3, Strickland IT4, McCloskey L5, Barnes L6, Blount I7, Wells O8, Truran CJ9, Kingsman AJ10, Palfi S11, Mitrophanous K12.
Author information
1Oxford BioMedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
2Oxford Biomedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
3University of Bristol, 1980, Henry Wellcome L.I.N.E, Bristol, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
4University of Bristol, Henry Wellcome L.I.N.E, Bristol, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
5Oxford BioMedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
6Oxford BioMedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
7Oxford BioMedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
8Oxford BioMedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
9Oxford BioMedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
10Oxford BioMedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
11AP-HP, AP-HP, Groupe Henri-Mondor Albert-Chenevier, Créteil, France ; [e-mail].
12Oxford BioMedica (UK) Ltd, Oxford, United Kingdom of Great Britain and Northern Ireland ; [e-mail].
Abstract
Pharmacological dopamine replacement therapies provide the most well-established treatments for Parkinson's disease (PD). However, these long-term treatments can lead to motor complications and off-target effects. ProSavin^®, a lentiviral vector (LV)-based gene therapy approach aimed at restoring local and continuous dopamine production, through delivery of three enzymes in the dopamine biosynthesis pathway, was demonstrated to be safe and well-tolerated in a phase I/II clinical study of patients with advanced Parkinson's disease. Although improvements in motor behaviour were observed, the data indicated that higher levels of dopamine replacement may be required to maximise benefit. We attempted to increase production of dopamine, and its precursor L-Dopa in LV transduced cells, by optimising the gene order in the ProSavin^® expression cassette, and by creating fusions of two or three of the transgenes, using linker sequences. In vitro analysis showed that several gene arrangements provided significantly increased dopamine and/or L-Dopa production compared with ProSavin^®, and that LV titres and transgene expression were not affected by introducing gene fusions. One vector, EIAV-TCiA, was selected for further characterisation and showed significant improvements in dopamine and L-Dopa production compared with ProSavin^®, in human neuronal cells. Further characterisation of EIAV-TCiA demonstrated expression of all three dopamine enzymes in vivo and faithful delivery and integration of the expected gene expression cassette within the genome of target cells, as assessed by northern and Southern blotting. In conclusion, we have developed a novel LV vector with an increased capacity for L-Dopa and dopamine production compared with the current ProSavin^® vector. Clinical evaluation of this vector will be performed to assess the benefits in patients with PD.

http://www.ncbi.nlm.nih.gov/pubmed/27470285

Good luck and GOD bless,

George