Viral Vectors in Primate Research: Examples from Parkinson’s Disease Research - Viral Vector Approaches in Neurobiology and Brain Diseases - page 326

mimics the volumes of distribution and pressure profi les observed
during in vivo studies. To that end, agarose gel (0.6 %) model was
developed in exploratory studies of CED as a surrogate for in vivo
brain tissues with respect to several critical physical characteristics
[ 77 , 78 ]. With this model, it has been shown that stepped cannula
dramatically reduces refl ux along the infusion device by restricting
initial backfl ow of fl uid fl ow beyond the step [ 79 - 81 ]. Furthermore,
during CED, distribution volume for a given vector depends not
only on the structural properties of the tissue being convected [ 75 ]
but also on the technical parameters of the infusion procedure such
as cannula design and placement, infusion volume, and rate [ 72 ,
81 ]. All these key parameters have been extensively investigated in
NHP in an effort to adapt CED for clinical use. For example, to
achieve CED it is necessary to use a catheter with an approximate
outer diameter of 0.25 mm and an infusion fl ow rate of 0.5 l/min

in order to prevent infusate refl ux [ 79 , 82 ]. Real-time magnetic
resonance image (MRI) was also developed to visualize the CED
process and used to improve the advance delivery of vector in the
CNS of monkey [ 74 , 76 , 83 ]. All these variables need to be taken
account for a better understanding of the parameters that deter-
mine vector distribution. It is expected that optimizing CED will
make this new delivery option for targeted gene therapy in the
treatment of neurodegenerative disorders such as PD [ 84 ].

μ

5 Conclusion

Considering all the above issues, it appears that gene therapy con-
tinues to be very attractive, particularly for neurodegenerative dis-
orders. With each therapy—neuroprotective versus symptomatic
strategies, LV versus AAV—the important objective is to develop
the necessary technology to effi ciently and specifi cally deliver the
therapeutic agent to the target cells. First, the delivery of therapeu-
tic agents with CED offers great potential although many key fac-
tors should be taken into account to get enhanced therapeutic
effi cacy. Further refi nements are necessary for successful clinical
translation from the animal model to human. Second, regarding
the large contribution of nonhuman primate in neuroscience fi eld
and particularly in PD area, they continue to have important roles
in basic and translational research, owing to their behavioral and
biological similarity to human beings. Finally, with the new
recombinant technologies, the vectors are safer and, in the absence
of any viral protein expression, they avoid harmful host immune
reactions. These recent improvements in engineering new vectors
give great optimism that within the next decade we will fi nally
reach the possibility to deliver globally a transgene to the entire
CNS offering unique opportunities for modeling human disease
onset, progression, and for validating therapeutic solutions.