Sustained intrathecal therapeutic protein delivery using genetically transduced tissue implants in a freely moving rat model

J. P. Aronson, H. A. Katnani, I. Pomerantseva, N. Shapir, H. Tse, R. Miari, H. Goltsman, O. Mwizerwa, C. M. Neville, G. A. Neil, Emad N. Eskandar, C. A. Sundback

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Systemic delivery of therapeutic proteins to the central nervous system (CNS) is challenging because of the blood-brain barrier restrictions. Direct intrathecal delivery is possible but does not produce stable concentrations. We are proposing an alternative approach for localized delivery into the CNS based on the Transduced Autologous Restorative Gene Therapy (TARGT) system. This system was previously developed using a gene therapy approach with dermal tissue implants. Lewis rat dermal tissue was transduced to secrete human EPO (hEPO). TARGT viability and function were retained following cryopreservation. Upon implantation into the rat cisterna magna, a mild inflammatory response was observed at the TARGT-brain interface throughout 21-day implantation. hEPO expression was verified immunohistochemically and by secreted levels in cerebrospinal fluid (CSF), serum, and in vitro post explant. Detectable CSF hEPO levels were maintained during the study. Serum hEPO levels were similar to rat and human basal serum levels. In vitro, the highest hEPO concentration was observed on day 1 post-explant culture and then remained constant for over 21 days. Prolonged incubation within the cisterna magna had no negative impact on TARGT hEPO secretion. These promising results suggest that TARGTs could be utilized for targeted delivery of therapeutic proteins to the CNS.

Original languageEnglish (US)
Pages (from-to)42-49
Number of pages8
JournalInternational Journal of Pharmaceutics
Volume534
Issue number1-2
DOIs
StatePublished - Dec 20 2017
Externally publishedYes

Fingerprint

Genetic Therapy
Proteins
Cisterna Magna
Central Nervous System
Therapeutics
Cerebrospinal Fluid
Serum
Skin
Cryopreservation
Blood-Brain Barrier
Brain
In Vitro Techniques

Keywords

  • Blood brain barrier
  • Brain
  • Central nervous system
  • Dermal implant
  • Gene therapy
  • Targeted delivery

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Sustained intrathecal therapeutic protein delivery using genetically transduced tissue implants in a freely moving rat model. / Aronson, J. P.; Katnani, H. A.; Pomerantseva, I.; Shapir, N.; Tse, H.; Miari, R.; Goltsman, H.; Mwizerwa, O.; Neville, C. M.; Neil, G. A.; Eskandar, Emad N.; Sundback, C. A.

In: International Journal of Pharmaceutics, Vol. 534, No. 1-2, 20.12.2017, p. 42-49.

Research output: Contribution to journalArticle

Aronson, JP, Katnani, HA, Pomerantseva, I, Shapir, N, Tse, H, Miari, R, Goltsman, H, Mwizerwa, O, Neville, CM, Neil, GA, Eskandar, EN & Sundback, CA 2017, 'Sustained intrathecal therapeutic protein delivery using genetically transduced tissue implants in a freely moving rat model', International Journal of Pharmaceutics, vol. 534, no. 1-2, pp. 42-49. https://doi.org/10.1016/j.ijpharm.2017.10.002
Aronson, J. P. ; Katnani, H. A. ; Pomerantseva, I. ; Shapir, N. ; Tse, H. ; Miari, R. ; Goltsman, H. ; Mwizerwa, O. ; Neville, C. M. ; Neil, G. A. ; Eskandar, Emad N. ; Sundback, C. A. / Sustained intrathecal therapeutic protein delivery using genetically transduced tissue implants in a freely moving rat model. In: International Journal of Pharmaceutics. 2017 ; Vol. 534, No. 1-2. pp. 42-49.
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