Minimally invasive convection-enhanced delivery of biologics into dorsal root ganglia: Validation in the pig model and prospective modeling in humans

Josef Pleticha, Timothy Maus, Jodie A. Christner, Michael P. Marsh, Kendall H Lee, W. Michael Hooten, Andreas S Beutler

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Dorsal root ganglia (DRG) are critical anatomical structures involved in nociception. Intraganglionic (IG) drug delivery is therefore an important route of administration for novel analgesic therapies. Although IG injection in large animal models is highly desirable for preclinical biodistribution and toxicology studies of new drugs, no method to deliver pharmaceutical agents into the DRG has been reported in any large species. The present study describes a minimally invasive technique of IG agent delivery in domestic swine, one of the most common large animal models. The technique utilizes CT guidance for DRG targeting and a custom-made injection assembly for convectionenhanced delivery (CED) of therapeutic agents directly into DRG parenchyma. The DRG were initially visualized by CT myelography to determine the optimal access route to the DRG. The subsequent IG injection consisted of 3 steps. First, a commercially available guide needle was advanced to a position dorsolateral to the DRG, and the dural root sleeve was punctured, leaving the guide needle contiguous with, but not penetrating, the DRG. Second, the custom-made stepped stylet was inserted through the guide needle into the DRG parenchyma. Third, the stepped stylet was replaced by the custom-made stepped needle, which was used for the IG CED. Initial dye injections performed in pig cadavers confirmed the accuracy of DRG targeting under CT guidance. Intraganglionic administration of adeno-associated virus in vivo resulted in a unilateral transduction of the injected DRG, with 33.5% DRG neurons transduced. Transgene expression was also found in the dorsal root entry zones at the corresponding spinal levels. The results thereby confirm the efficacy of CED by the stepped needle and a selectivity of DRG targeting. Imaging-based modeling of the procedure in humans suggests that IG CED may be translatable to the clinical setting.

Original languageEnglish (US)
Pages (from-to)851-858
Number of pages8
JournalJournal of Neurosurgery
Volume121
Issue number4
DOIs
StatePublished - Oct 1 2014

Fingerprint

Convection
Spinal Ganglia
Biological Products
Swine
Needles
Injections
Animal Models
Pharmaceutical Preparations
Dependovirus
Myelography
Nociception
Spinal Nerve Roots
Transgenes
Cadaver
Toxicology
Analgesics

Keywords

  • Computed tomography
  • Convection-enhanced delivery
  • Dorsal root ganglia
  • Gene therapy
  • Intraganglionic injection
  • Pain
  • Peripheral nerve

ASJC Scopus subject areas

  • Clinical Neurology
  • Surgery
  • Medicine(all)

Cite this

Minimally invasive convection-enhanced delivery of biologics into dorsal root ganglia : Validation in the pig model and prospective modeling in humans. / Pleticha, Josef; Maus, Timothy; Christner, Jodie A.; Marsh, Michael P.; Lee, Kendall H; Hooten, W. Michael; Beutler, Andreas S.

In: Journal of Neurosurgery, Vol. 121, No. 4, 01.10.2014, p. 851-858.

Research output: Contribution to journalArticle

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