Cerebellomedullary Cistern Injection of Viral Vectors in Nonhuman Primates

α-Fetoprotein Gene Delivery to the Nasal Epithelium of Nonhuman Primates by Human Parainfluenza Viral Vectors

Human Gene Therapy ◽

10.1089/hum.2010.065 ◽

2010 ◽

Vol 21 (12) ◽

pp. 1657-1664 ◽

Cited By ~ 6

Author(s):

Liqun Zhang ◽

Maria P. Limberis ◽

Catherine Thompson ◽

Marcelo B. Antunes ◽

Cindy Luongo ◽

...

Keyword(s):

Gene Delivery ◽

Viral Vectors ◽

Nonhuman Primates ◽

Nasal Epithelium

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Phagocytosis-shielded lentiviral vectors improve liver gene therapy in nonhuman primates

Science Translational Medicine ◽

10.1126/scitranslmed.aav7325 ◽

2019 ◽

Vol 11 (493) ◽

pp. eaav7325 ◽

Cited By ~ 21

Author(s):

Michela Milani ◽

Andrea Annoni ◽

Federica Moalli ◽

Tongyao Liu ◽

Daniela Cesana ◽

...

Keyword(s):

Gene Therapy ◽

Viral Vectors ◽

Nonhuman Primates ◽

Surface Engineering ◽

Coagulation Factor ◽

Lentiviral Vectors ◽

Factor Ix ◽

Coagulation Disorder ◽

Viral Immunity ◽

Immune Sensing

Liver-directed gene therapy for the coagulation disorder hemophilia showed safe and effective results in clinical trials using adeno-associated viral vectors to replace a functional coagulation factor, although some unmet needs remain. Lentiviral vectors (LVs) may address some of these hurdles because of their potential for stable expression and the low prevalence of preexisting viral immunity in humans. However, systemic LV administration to hemophilic dogs was associated to mild acute toxicity and low efficacy at the administered doses. Here, exploiting intravital microscopy and LV surface engineering, we report a major role of the human phagocytosis inhibitor CD47, incorporated into LV cell membrane, in protecting LVs from uptake by professional phagocytes and innate immune sensing, thus favoring biodistribution to hepatocytes after systemic administration. By enforcing high CD47 surface content, we generated phagocytosis-shielded LVs which, upon intravenous administration to nonhuman primates, showed selective liver and spleen targeting and enhanced hepatocyte gene transfer compared to parental LV, reaching supraphysiological activity of human coagulation factor IX, the protein encoded by the transgene, without signs of toxicity or clonal expansion of transduced cells.

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Detection of infusate leakage in the brain using real-time imaging of convection-enhanced delivery

Journal of Neurosurgery ◽

10.3171/jns/2008/109/11/0874 ◽

2008 ◽

Vol 109 (5) ◽

pp. 874-880 ◽

Cited By ~ 71

Author(s):

Vanja Varenika ◽

Peter Dickinson ◽

John Bringas ◽

Richard LeCouteur ◽

Robert Higgins ◽

...

Keyword(s):

Mr Imaging ◽

Real Time ◽

Viral Vectors ◽

Nonhuman Primates ◽

Therapeutic Agents ◽

Convection Enhanced Delivery ◽

Before And After ◽

Normal Monkey ◽

Significant Attenuation ◽

The Brain

Object The authors have shown that convection-enhanced delivery (CED) of gadoteridol-loaded liposomes (GDLs) into different regions of normal monkey brain results in predictable, widespread distribution of this tracking agent as detected by real-time MR imaging. They also have found that this tracking technique allows monitoring of the distribution of similar nanosized agents such as therapeutic liposomes and viral vectors. A limitation of this procedure is the unexpected leakage of liposomes out of targeted parenchyma or malignancies into sulci and ventricles. The aim of the present study was to evaluate the efficacy of CED after the onset of these types of leakage. Methods The authors documented this phenomenon in a study of 5 nonhuman primates and 7 canines, comprising 54 CED infusion sessions. Approximately 20% of these infusions resulted in leakage into cerebral ventricles or sulci. All of the infusions and leakage events were monitored with real-time MR imaging. The authors created volume-distributed versus volume-infused graphs for each infusion session. These graphs revealed the rate of distribution of GDL over the course of each infusion and allowed the authors to evaluate the progress of CED before and after leakage. Results The distribution of therapeutics within the target structure ceased to increase or resulted in significant attenuation after the onset of leakage. Conclusions An analysis of the cases in this study revealed that leakage undermines the efficacy of CED. These findings reiterate the importance of real-time MR imaging visualization during CED to ensure an accurate, robust distribution of therapeutic agents.

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