Brain-derived neurotrophic factor gene delivery in an animal model of multiple sclerosis using bone marrow stem cells as a vehicle.
Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, is neuroprotective in animal models of neurodegenerative diseases. However, BDNF has a short half-life and its efficacy in the central nervous system (CNS), when delivered peripherally, is limited due to the blood-brain barrier (BBB). We have developed a means of delivering BDNF into the CNS using genetically engineered bone marrow stem cells (BMSCs) as a vehicle, and have explored the clinical effects of BDNF on outcomes in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). BDNF-engineered-BMSCs were transplanted (i.v.) into irradiated 2-week-old SJL/J female mice. Eight weeks after transplantation, mice were immunized with a peptide of proteolipid protein (PLP(139-151)). Mice, which had received BDNFengineered BMSCs, showed a significant delay in EAE onset and a reduction in overall clinical severity compared to mice receiving BMSC transfected with an empty vector lacking the BDNF gene. In addition, pathological examination showed that BDNF delivery reduced demyelination and increased remyelination. Inhibition of pro-inflammatory cytokines TNF-alpha and IFN-gamma and enhanced expression of the antiinflammatory cytokines IL-4, IL-10, and IL-11 were found in the CNS tissues of the BDNF transplanted group. These results support the use of BMSCs as vehicles to deliver BDNF into the CNS of EAE animals. This is a potentially novel therapeutic approach that might be used to deliver BDNF gene or genes for other therapeutic proteins into the CNS in MS or in other diseases of the CNS in which accessibility of therapeutic proteins is limited due to the BBB.
Makar
Tapas K
TK
VA Maryland Healthcare System, Baltimore, MD 21201, United States. tmakar@som.umaryland.edu
Bever
Christopher T
CT
Singh
Ishwar S
IS
Royal
Walter
W
Sahu
Surasri Nandan
SN
Sura
Tushar P
TP
Sultana
Shireen
S
Sura
Karna T
KT
Patel
Niraj
N
Dhib-Jalbut
Suhayl
S
Trisler
David
D
D000818:Animals; D016026:Bone Marrow Transplantation / Q000379:methods*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000627:therapeutic use*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D018991:Myelin Proteolipid Protein / Q000276:immunology; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010446:Peptide Fragments / Q000276:immunology; D016896:Treatment Outcome
D019208:Brain-Derived Neurotrophic Factor; D016207:Cytokines; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151)