Gene delivery to the CNS using non-viral vectors

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Biochemical Society Transactions ( 1999) Volume 27, part 5

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THE BASIC SCIENCE OF BRAIN TUMOUR GENE THERAPY: ADVANTAGES AND CHALLENGES AHEAD. LOWENSTEIN. P.R. Molecular Medicine Unit, School o f Medicine, University of Manchester, Stopford Building, Room: 1.302, Manchester M I 3 9PT.

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c10 CLINICAL TRIALS OF BRAIN GLIOBLASTOMA USING RETROVIRAL VECTORS Dr D Klatzman, Paris University 6, Grp Hopital La Pitie Salpetrie, CNRS 107, L a b o r a t o i r e Biol & Therapeut Pathologie Immuitaires, F7565 I , Park 13, France

Survival of patients suffering from brain tumours has improved only marginally during the last 50 years, in spite of important advances in the surgery, pharmacology, and radiotherapy of brain tunours. Thus, brain tumours constitute an appropriate therapeutic target of gene therapy. Gene therapy of brain tiimours has been attempted using retroviral and adenoviral vectors. However, important aspects of the efficiency and cytotoxicity of this treatment remain unexplored. Adenoviral vectors have advantages over retroviral vectors, in that they can infect and express transgenes in nondividing, in addition to dividing tumour cells. Since tumours recur due to the activation of tumour cells which are quiescent at the time of therapy, the characteristics of adenovirus vectors could represent an important clinical advantage. However, the inflammatory potential of adenoviruses needs to be taken into account when devising new gene therapies based on adenovirus. Our laboratory has recently shown a rapid release of cytokines following the injection of adenoviruses into the brain; this effect was independent of the transgene encoded by the vectors. Furthermore, acute inflammatory responses occur, which are dependent on viral dose, and last for about 30 days. Also, transgene expression from adenoviruses was thought to be relatively short lived, with most transgene expression down to almost background levels by 6090 days post-viral administration. Using a syngeneic brain tumour model and adenoviruses encoding the conditional cytotoxic gene thymidine kinase of herpes simplex virus type 1 , we have demonstrated that, following administration rrf ganciclovir we completely inhibit tumour growth. Importantly, we have detected long term persistence, at a high level, of the transgene encoded by the adenoviral vector; also, we detected a chronic inflammatory response at the site of tumour and virus implantation, but not at distant sites. Understanding the mechanisms underlying these phenomena may allow us to devise more efficient gene therapies for the treatment of brain glioblastoma. Caftmell, et al., The Journal of Neuroscience 19 (4) 1517-1523, 1999 Supported by the CRC, BBSRC, and The Lister Institute of Preventive Medicine

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P Aebischer Division of Surgical Research and Gene Therapy Center, Centre Hospitalier Universitaue Vaudois. Lausanne University Medical School, Switzerland Neurodegenwative diseases such as Parkinson’s disease (PD). Alzheimer’s disease (AD), Huntington’s diseases (HD)or amyotrophic lateral sclerosis ( A L S ) are charactenzed by the progressive loss of specific sets of neurons The degenerative process may be slowed down, stopped or even reversed by the localized delivery of neurotrophic factors Our laboratory is investigating the potential of transplanting encapsulated cell lines genetically engineered to release neurotrophic factors in various animal models of neurodegeneratve diseases Encapsulated cells engineered to rel,ase glial cell line-denved neurotrophic factor (GDNF) are being evaluated in rodent and pnmate models of PD. whereas cells engineered to release ciliary neurotrophic factor (CNTF) are being evaluated in rodent and pnmate models of HD Significant morphological and behavioral improvements were observed in several of these models The technique ot transplanting polymer encapsulared cells genetically engineered to release a neurotrophic factor has been recently implemented in patients sufferiiig from amyotrophic lateral sclerosis and Huntington disease These clinical trials based CP the intrathecal delivery of CNTF in ALS and HD have demonstrated the safety of the technique, the viability of the transplanted xenogeneic cells as well as the long-term expression of the transgene Trangeiiic ariimdl model, of vdrious neu.cdegenerative diseases have been developed recently Vual vectors aimed dt the molecular correction of specific mutations or deletions are being currently tested in these models, opening new avenues for the treatment of ttiece diseases

Gene delivery to the CNS using non-viral vectors L.B. Barrett’ ,L.W. S e v w1 ,K.D. Fisher’, W.Ying4, P.R. Dash’ ,M. Berry’, A. L o g a d , A.M. Gonzalez‘, A. Baird4. Departments of ‘Cancer Studies and ’Medicine, Universiry of Birmingham, BII 2TA; Department of Anatomy a n d Cell Biology, LIMDS, London S E l 9R7;. ‘Selective Genetics Inc., San Diego, C A 92121, USA.