Novel Platform for MRI-Guided Convection-Enhanced Delivery of Therapeutics: Preclinical Validation in Nonhuman Primate Brain

Richardson, R. Mark; Kells, Adrian P.; Martin, Alastair J.; Larson, Paul; Starr, Philip A.; Piferi, Peter G.; Bates, Geoffrey; Tansey, Lisa; Rosenbluth, Kathryn H.; Bringas, John; Berger, Mitchel S.; Bankiewicz, Krystof S.

doi:10.1159/000323544

Cited by 89 publications

(75 citation statements)

References 76 publications

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“…We and others have continued to optimize CED as a minimally invasive approach (33)(34)(35)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93)(94)(95)(96)(97). This way of drugs delivery is discussed in Part II of the chapter (page 347).…”

Section: Promising Treatment Bypassing the Bbbmentioning

confidence: 99%

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

2017

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Glioblastoma (GBM), a primary brain tumor, remains an unmet medical need. One of the major obstacles to GBM treatment is the adequate properties of drugs. Complex pathobiology of GBM, including local invasion and intratumoral heterogeneity, represent major challenges to generating effective therapies. We discuss here the design of targeted cytotoxic drugs with an increased access to tumors and pathophysiologically important tumor compartments. Our research and others' have shown that interleukin 13 receptor alpha 2 (IL-13RA2), EphA2, and EphA3 receptors are overexpressed in most patients with GBM, but not in normal brain, and also in spontaneous canine high-grade gliomas like GBM, an excellent translational model of GBM. These receptors and also the EphB2 receptor are overexpressed and are functional in several GBM compartments involved Delivering Cytotoxic Therapies to Glioblastoma 342 in tumor progression and/or resistance to therapies. We pursue the novel idea of targeting all four receptors with one targeted cytotoxic compound (QUAD-CTX). We are constructing a molecularly targeted anti-GBM drug that (i) may not require patient prescreening, (ii) will attack most tumor compartments known to be pathobiologically important, and (iii) performs these functions in one pharmaceutical entity, so it will be suitable for monotherapy. We thus wish to take advantage of a unique opportunity to produce an off-the-shelf, highly specific, molecularly targeted drug candidate suitable to treat perhaps even all patients with GBM. We envision that this "molecular resection" will translate into clear-cut durable responses in patients suffering from this dreadful disease.

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Section: Promising Treatment Bypassing the Bbbmentioning

confidence: 99%

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

2017

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“…While a limited number of complications were noted with the stereotactic surgical procedures (hemorrhages, venous infarcts) [62], none were directly implicated to result from either the viral vectors or transgenes utilized. While hemorrhagic complications associated with functional neurosurgery are well known, and infrequent [63], additional reductions in frequency may be achieved through the use of imageguided stereotactic approaches in the future [64]. To date, all of these gene transfer treatments were carried out on patients significantly affected (moderate to severe, Hoehn and Yahr Stage III or IV off medication) by idiopathic PD.…”

Section: The Current Use Of Gene Transfer Technologies In Human Parkimentioning

confidence: 99%

Can population genomics guide future therapeutic gene transfer strategies for Parkinson’s disease?

Fiandaca¹,

Padilla²,

Conteh³

et al. 2013

OJGen

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“…The SmartFlow cannula and ClearPoint targeting system (with SmartFrame skull attachment modified for NHP use; Richardson et al, 2011a) were used ( Fig. 1) to infuse either AAV2-hAADC (n = 6) or PBS (n = 4) to the right caudate nucleus and putamen (total of 20 cannula insertions).…”

Section: Performance Of Delivery Platform and Cannulamentioning

confidence: 99%

“…Because the acute tracer distribution matches the distribution of transgene expression , Gd can be used as a real-time surrogate for visualizing vector infusion. We have evolved a method for visually monitored CED (real-time convective delivery, or RCD) that has been modeled extensively in NHP (Fiandaca et al, 2008Richardson et al, 2009Richardson et al, , 2011aGimenez et al, 2011). This innovation not only reduces the potential for adverse effects but also provides surgeons with intraoperative feedback on infusate distribution.…”

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confidence: 99%

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

et al. 2012

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Degeneration of nigrostriatal neurons in Parkinson's disease (PD) causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa (l-DOPA) into dopamine in the striatum. Because loss of this enzyme appears to be a major driver of progressive impairment of response to the mainstay drug, l-DOPA, one promising approach has been to use gene therapy to restore AADC activity in the human putamen and thereby restore normal l-DOPA response in patients with PD. An open-label phase I clinical trial of this approach in patients with PD provided encouraging signs of improvement in Unified Parkinson's Disease Rating Scale scores and reductions in antiparkinsonian medications. However, such improvement was modest compared with the results previously reported in parkinsonian rhesus macaques. The reason for this discrepancy may have been that the relatively small volume of vector infused in the clinical study restricted the distribution of AADC expression, such that only about 20% of the postcommissural putamen was covered, as revealed by l-[3-18 F]-a-methyltyrosine-positron emission tomography. To achieve more quantitative distribution of vector, we have developed a visual guidance system for parenchymal infusion of AAV2. The purpose of the present study was to evaluate the combined magnetic resonance imaging-guided delivery system with AAV2-hAADC under conditions that approximate the intended clinical protocol. Our data indicate that this approach directed accurate cannula placement and effective vector distribution without inducing any untoward effects in nonhuman primates infused with a high dose of AAV2-hAADC.

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Novel Platform for MRI-Guided Convection-Enhanced Delivery of Therapeutics: Preclinical Validation in Nonhuman Primate Brain

Cited by 89 publications

References 76 publications

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

Maximizing Local Access to Therapeutic Deliveries in Glioblastoma. Part I: Targeted Cytotoxic Therapy

Can population genomics guide future therapeutic gene transfer strategies for Parkinson’s disease?

Safety and Tolerability of Magnetic Resonance Imaging-Guided Convection-Enhanced Delivery of AAV2-hAADC with a Novel Delivery Platform in Nonhuman Primate Striatum

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