Retrograde axonal transport of an exogenous enzyme covalently linked to B-IIb fragment of tetanus toxin.
Attempt to replace enzymes in a number of fatal lysosomal storage disease involving the central nervous system have as yet been unsuccessful owing to the impermeability of the blood/brain barrier to macromolecules. In order to treat storage disease due to enzyme deficiencies, we investigated the feasibility of transporting an enzyme into the central nervous system without crossing the blood/brain barrier. Using the B-IIb fragment of tetanus toxin (because it is involved in recognition by the nerve-cell endings), retrograde axonal transport toward the spinal cord and trans-synaptic movement, and glucose oxidase as a marker, we demonstrated that a non-toxic enzyme-vector conjugate was taken up by axon terminals. After injection into the gastrocnemius muscle, the B-IIb-glucose oxidase conjugate was detected, both histologically and electrochemically, distally to a ligature on the sciatic nerve. Thus the B-IIb fragment could serve as a vector for glucose oxidase transport into the central nervous system. It was also verified that the transported enzyme retained its activity. Transport of this 150 kDa molecule by fragment B-IIb of tetanus toxin suggests that other enzymes of a lesser molecular mass may also be transported.
Laboratoire de Technologie Enzymatique, U.R.A. n. 523 du C.N.R.S., Université de Compiègne, France.
P
P
Beaude
A
A
Delacour
B
B
Bizzini
D
D
Domuado
M H
MH
Remy
D000818:Animals; D001370:Axonal Transport; D001369:Axons / Q000378:metabolism; D004337:Drug Carriers; D005949:Glucose Oxidase / Q000378:metabolism*; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism*; D012584:Sciatic Nerve / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D013744:Tetanus Toxin / Q000378:metabolism*
D004337:Drug Carriers; D010446:Peptide Fragments; D013744:Tetanus Toxin; C051903:tetanus toxin fragment BIIb; D005949:Glucose Oxidase