scholarly journals Convection Enhanced Delivery to the Brain: Preparing for Gene Therapy and Protein Delivery to the Brain for Functional and Restorative Neurosurgery by Understanding Low-Flow Neurocatheter Infusions Using the Alaris® System Infusion Pump

2013 ◽  
Vol 20 (2) ◽  
Author(s):  
Karl Sillay ◽  
Angelica Hinchman ◽  
Erinc Akture ◽  
Shahriar Salamat ◽  
Gurwattan Miranpuri ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Protein Delivery ◽  
Infusion Pump ◽  
Low Flow ◽  
Convection Enhanced Delivery ◽  
The Brain

scholarly journals Design and Validation of a Multi-Point Injection Technology for MR-Guided Convection Enhanced Delivery in the Brain

2021 ◽  
Vol 3 ◽  
Author(s):  
Kayla Prezelski ◽  
Megan Keiser ◽  
Joel M. Stein ◽  
Timothy H. Lucas ◽  
Beverly Davidson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Low Flow ◽  
Limiting Factor ◽  
Volume Distribution ◽  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Point Injection ◽  
Subcortical Regions ◽  
Injection Technology

Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 μL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.

scholarly journals Design and validation of a multi-point injection technology for MR-guided convection enhanced delivery in the brain

2021 ◽  
Author(s):  
Kayla Prezelski ◽  
Megan Keiser ◽  
Joel M. Stein ◽  
Timothy H. Lucas ◽  
Beverly Davidson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Low Flow ◽  
Limiting Factor ◽  
Volume Distribution ◽  
Convection Enhanced Delivery ◽  
Flow Rates ◽  
Point Injection ◽  
Subcortical Regions ◽  
Injection Technology

Convection enhanced delivery (CED) allows direct intracranial administration of neuro-therapeutics. Success of CED relies on specific targeting and broad volume distributions (VD). However, to prevent off-target delivery and tissue damage, CED is typically conducted with small cannulas and at low flow rates, which critically limit the maximum achievable VD. Furthermore, in applications such as gene therapy requiring injections of large fluid volumes into broad subcortical regions, low flow rates translate into long infusion times and multiple surgical trajectories. The cannula design is a major limiting factor in achieving broad VD, while minimizing infusion time and backflow. Here we present and validate a novel multi-point cannula specifically designed to optimize distribution and delivery time in MR-guided intracranial CED of gene-based therapeutics. First, we evaluated the compatibility of our cannula with MRI and common viral vectors for gene therapy. Then, we conducted CED tests in agarose brain phantoms and benchmarked the results against single-needle delivery. 3T MRI in brain phantoms revealed minimal susceptibility-induced artifacts, comparable to the device dimensions. Benchtop CED of adeno-associated virus demonstrated no viral loss or inactivation. CED in agarose brain phantoms at 3, 6, and 9 microL/min showed >3x increase in volume distribution and 60% time reduction compared to single-needle delivery. This study confirms the validity of a multi-point delivery approach for improving infusate distribution at clinically-compatible timescales and supports the feasibility of our novel cannula design for advancing safety and efficacy of MR-guided CED to the central nervous system.

scholarly journals Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice

2020 ◽  
Vol 11 (1) ◽  
pp. 241-250
Author(s):  
Zhenyu Li ◽  
Guangqian Ding ◽  
Yudi Wang ◽  
Zelong Zheng ◽  
Jianping Lv
Keyword(s):  
Gene Therapy ◽  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Brain Tissue ◽  
Inflammatory Responses ◽  
Tissue Samples ◽  
Protein Levels ◽  
Virus Serotype ◽  
Transcription Factor Eb ◽  
The Brain

AbstractTranscription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.

Thymidine kinase-mediated killing of rat brain tumors

1993 ◽  
Vol 79 (5) ◽  
pp. 729-735 ◽  
Author(s):  
David Barba ◽  
Joseph Hardin ◽  
Jasodhara Ray ◽  
Fred H. Gage
Keyword(s):  
Gene Therapy ◽  
Brain Tumors ◽  
Tumor Cells ◽  
Wild Type ◽  
Cns Disorders ◽  
Content Type ◽  
Potential Applications ◽  
Ganciclovir Treatment ◽  
The Brain ◽  
Fine Print

✓ Gene therapy has many potential applications in central nervous system (CNS) disorders, including the selective killing of tumor cells in the brain. A rat brain tumor model was used to test the herpes simplex virus (HSV)-thymidine kinase (TK) gene for its ability to selectively kill C6 and 9L tumor cells in the brain following systemic administration of the nucleoside analog ganciclovir. The HSV-TK gene was introduced in vitro into tumor cells (C6-TK and 9L-TK), then these modified tumor cells were evaluated for their sensitivity to cell killing by ganciclovir. In a dose-response assay, both C6-TK and 9L-TK cells were 100 times more sensitive to killing by ganciclovir (median lethal dose: C6-TK, 0.1 µg ganciclovir/ml; C6, 5.0 µg ganciclovir/ml) than unmodified wild-type tumor cells or cultured fibroblasts. In vivo studies confirmed the ability of intraperitoneal ganciclovir administration to kill established brain tumors in rats as quantified by both stereological assessment of brain tumor volumes and studies of animal survival over 90 days. Rats with brain tumors established by intracerebral injection of wild-type or HSV-TK modified tumor cells or by a combination of wild-type and HSV-TK-modified cells were studied with and without ganciclovir treatments. Stereological methods determined that ganciclovir treatment eliminated tumors composed of HSV-TK-modified cells while control tumors grew as expected (p < 0.001). In survival studies, all 10 rats with 9L-TK tumors treated with ganciclovir survived 90 days while all untreated rats died within 25 days. Curiously, tumors composed of combinations of 9L and 9L-TK cells could be eliminated by ganciclovir treatments even when only one-half of the tumor cells carried the HSV-TK gene. While not completely understood, this additional tumor cell killing appears to be both tumor selective and local in nature. It is concluded that HSV-TK gene therapy with ganciclovir treatment does selectively kill tumor cells in the brain and has many potential applications in CNS disorders, including the treatment of cancer.

Adenovirus in the brain: recent advances of gene therapy for neurodegenerative diseases

1998 ◽  
Vol 55 (4) ◽  
pp. 333-341 ◽  
Author(s):  
M. Barkats ◽  
A. Bilang-Bleuel ◽  
M.H. Buc-Caron ◽  
M.N. Castel-Barthe ◽  
O. Corti ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Neurodegenerative Diseases ◽  
Recent Advances ◽  
The Brain

EXTH-31. BRAIN DISTRIBUTION, CLEARANCE AND TOXICITY EVALUATION OF SMALL-MOLECULE INHIBITORS FOLLOWING CONVECTION-ENHANCED DELIVERY TO THE BRAINSTEM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi170-vi170
Author(s):  
Erica Power ◽  
Juhee Oh ◽  
Jonghoon Choi ◽  
William Elmquist ◽  
David Daniels
Keyword(s):  
Small Molecule ◽  
Drug Concentration ◽  
Small Molecule Inhibitors ◽  
Efflux Pump ◽  
Sprague Dawley ◽  
Convection Enhanced Delivery ◽  
Efflux Pump Inhibitor ◽  
Delivery Technique ◽  
The Brain

Abstract BACKGROUND Diffuse midline gliomas (DMGs) harboring the H3K27M mutation are highly aggressive, fatal brainstem tumors that primarily occur in children. The blood-brain barrier (BBB) prevents numerous drugs from reaching CNS tumors, like DMG, at cytotoxic concentrations. Convection-enhanced delivery (CED) has emerged as a drug delivery technique that bypasses the BBB through a direct interstitial infusion under a pressure gradient. However, drug distribution and clearance from the brain following CED is poorly understood and has been cited as a potential reason for the lack of efficacy observed in prior clinical trials. OBJECTIVE The objective of this study was to understand how two small molecule inhibitors (alisertib, ponatinib) that inhibit cell growth and proliferation in DMG cells in vitro distribute and clear from the brain following CED to the brainstem. METHODS Sprague-dawley rats underwent a single 60mL CED infusion of drug to the brainstem (200mM alisertib, 10mM ponatinib) and were sacrificed 0.083, 1, 2, 4, 8 and 24 hours following the completion of the infusion. Brains were dissected and drug concentration was determined via HPLC analysis. RESULTS No rats showed any clinical or neurological signs of toxicity post-infusion. Both drugs showed significant differences in drug concentration based on anatomical brain region where higher concentrations were observed in the pons and cerebellum compared to the cortex. Drug half-life in the brain was ~0.5 hours for alisertib and ~1 hour for ponatinib, but this was not significantly increased following co-administration of elacridar, a BBB efflux pump inhibitor. CONCLUSIONS These results suggest that elimination of drugs from the brain in a complex, multifactorial mechanism that warrants further preclinical investigation prior to the initiation of a clinical trial.

Computational Model of Interstitial Transport in the Rat Brain Using Diffusion Tensor Imaging

2007 ◽  
Author(s):  
Jung Hwan Kim ◽  
Thomas H. Mareci ◽  
Malisa Sarntinoranont
Keyword(s):  
Diffusion Tensor ◽  
Therapeutic Potential ◽  
Treatment Optimization ◽  
Convection Enhanced Delivery ◽  
Tissue Properties ◽  
Large Molecules ◽  
Macromolecular Drugs ◽  
Interstitial Transport ◽  
Blood Spinal Cord Barrier ◽  
The Brain

In spite of the high therapeutic potential of macromolecular drugs, it has proven difficult to apply them to recovery after injury and treatment of cancer, Parkinson’s disease, and other neurodegenerative diseases. One barrier to systemic administration is low capillary permeability, i.e., the blood-brain and blood-spinal cord barrier. To overcome this barrier, convection-enhanced delivery (CED) infuses agents directly into tissue to supplement diffusion and increase the distribution of large molecules in the brain [1,2]. Predictive models of distribution during CED would be useful in treatment optimization and planning. To account for large infusion volumes, such models should incorporate tissue boundaries and anisotropic tissue properties.

scholarly journals Convection-Enhanced Arborizing Catheter System Improves Local/Regional Delivery of Infusates Versus a Single-Port Catheter in Ex Vivo Porcine Brain Tissue

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Egleide Y. Elenes ◽  
Jason N. Mehta ◽  
Fang-Chi Hsu ◽  
Christopher T. Whitlow ◽  
Waldermar Debinski ◽  
...  
Keyword(s):  
Standard Treatment ◽  
Single Port ◽  
Ex Vivo ◽  
Volume Of Distribution ◽  
Port Catheter ◽  
Convection Enhanced Delivery ◽  
Alternative Approach ◽  
The Brain ◽  
Regional Delivery ◽  
Porcine Brain Tissue

Abstract Standard treatment for glioblastoma is noncurative and only partially effective. Convection-enhanced delivery (CED) was developed as an alternative approach for effective loco-regional delivery of drugs via a small catheter inserted into the diseased brain. However, previous CED clinical trials revealed the need for improved catheters for controlled and satisfactory distribution of therapeutics. In this study, the arborizing catheter, consisting of six infusion ports, was compared to a reflux-preventing single-port catheter. Infusions of iohexol at a flow rate of 1 μL/min/microneedle were performed, using the arborizing catheter on one hemisphere and a single-port catheter on the contralateral hemisphere of excised pig brains. The volume dispersed (Vd) of the contrast agent was quantified for each catheter. Vd for the arborizing catheter was significantly higher than for the single-port catheter, 2235.8 ± 569.7 mm3 and 382.2 ± 243.0 mm3, respectively (n = 7). Minimal reflux was observed; however, high Vd values were achieved with the arborizing catheter. With simultaneous infusion using multiple ports of the arborizing catheter, high Vd was achieved at a low infusion rate. Thus, the arborizing catheter promises a highly desirable large volume of distribution of drugs delivered to the brain for the purpose of treating brain tumors.

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