Oh, patents! Cellectra® Inovio’s DNA plasmid delivery technology (2)

Copyright © Françoise Herrmann 

Cellectra®, Inovio’s smart device for delivering DNA plasmids, is designed to solve one of the most pervasive technical challenges of gene therapy: the unaltered delivery of engineered nucleic acid molecules (DNA or mRNA) to human cells. Safe delivery that enables the engineered molecules to carry out their instructions in vivo, such as the production of target antigens. Indeed, “naked” engineered nucleic acid molecules are fragile with very low cell uptake, when they are administered via intramuscular injection alone. Thus, different approaches to resolving the issue of delivering DNA or mRNA gene therapy, inside cells, have been proposed. Approaches each aimed at increasing cell uptake, and thus obtaining more optimal expression of the gene therapy within cells.

 One approach to engineered nucleic acid delivery is viral vector-based (Naso et al.,2017). An approach where nucleic acid instructions are transported to cells via the DNA of another virus, engineered as a harmless vector. For example, adenoviruses (common cold viruses) might be engineered as harmless vectors for nucleic acid instructions, systematically delivering the new payload upon entry through cell membranes.  Specifically, adenovirus viral vector technology was the approach used for the development of the Johnson & Johnson COVID-19 vaccine. A SARS CoV-2 vaccine candidate, still under investigation in the Ensemble Phase III clinical trials (Staff J&J, Dec. 17, 2020).

Another approach, to gene therapy delivery is lipid nanoparticle (LNP) technology (Reichmuth et al., 2016). LNP technology encapsulates nucleic acid molecules to protect them during administration into the human body, through to cell membranes, thus allowing engineered genes to deliver their instructions directly inside cells. Specifically, LNP technology was invoked as part of the galenic formulation of the engineered mRNA strands of both the Pfizer-BioNTech, and Moderna,  COVID 19 vaccines. A nucleic acid delivery technology that is not without potential side-effects, since polyethylene glycol (PEG), one of the components of the LNP technology was, quite recently, hypothesized as potentially responsible for the very rare severe allergic reactions to the Pfizer-BionTech vaccine (de Vrieze, Dec. 21, 2020).

Inovio’s solution to the problematic situation of gene therapy delivery is a mechanical one that bypasses previous approaches. The company has invented an electroporation (EP) smart device, designated Cellectra®.  Cellectra® reversibly opens cell pores via application of brief (and tolerable) electrical pulses. The pulses open aqueous pathways in the otherwise less permeable cell membrane, through which large molecules such as DNA can pass to carry out their instructions from within cells. Thus, the Cellectra® device increases cell uptake of the engineered genes, which in turn results in better immune responses, and more efficient gene therapy doses. The Cellectra® device is further designed nearly painless (per score of visual analog scale) for pediatric use. Cellectra® is also designed user-friendly and cost-efficient for mass manufacture. Specifically, for example, Cellectra® was effectively used for delivery of the Inovio (INO-4800) SARS CoV-2 vaccine candidate, in Phase I clinical trials  (Tebas,et al., 2020). Similarly, prior to the COVID-19 pandemic, the Cellectra® EP device was also found effective in Phase I clinical trials for delivery of the MERS-CoV DNA vaccine candidate, co-developed by GeneOne Life Science and  Inovio (Carlson, 2020). 

The Cellectra® invention is recited in the US utility patent US10668279, titled Minimally invasive dermal electroporation device. The invention recites a hand-held, electroporation (EP) smart device, for delivering gene therapy, intradermally or intramuscularly, directly to cells. The abstract of this invention is included below, together with the patent Figure 1A of an embodiment of the device, and an image of a corresponding embodiment of the marketed Cellectra® product.

The disclosure is directed to a device for electroporating and delivering one or more antigens and a method of electroporating and delivering one or more antigens to cells of epidermal tissues using the device. The device comprises a housing, a plurality of electrode arrays projecting from the housing, each electrode array including at least one electrode, a pulse generator electrically coupled to the electrodes, a programmable microcontroller electrically coupled to the pulse generator, and an electrical power source coupled to the pulse generator and the microcontroller. The electrode arrays define spatially separate sites.     [Abstract US 10668279 ]

 

The patent Figure 1A depicts the Minimally Invasive Device (MID) 100, comprising a housing 102 and a tip portion 104. A plurality of electrode arrays 106, 108 for electroporating, are coupled to the tip 104. The tip 104 of the MID 100, and the electrode arrays 106, 108, together or separately, are detachable, sterilizable and thus re-usable.  Alternatively, the tip 104, and/or arrays 106, 108, might be designed for single use. The electrodes are arranged in 4x4 arrays. Each electrode array 106, 108, is configured to vary the electroporating pulse, thus enabling heterogeneous delivery of gene therapy (e.g.; when an adjuvant plasmid is used, in combination with an antigen plasmid). The number, dimension and pattern of each electrode array 106, 108, may vary, depending on the embodiment of the MID. Pulse generators (undepicted), electrically coupled to a programmable microcontroller (undepicted), are connected to each of the electrode arrays 106, 108. In response to input, the microcontroller adjusts the electroporation parameters (e.g.; pulse voltage, current, duration and quantity of applied pulses) of each electrode array 106, 108, depending on usage, or requirements of the gene therapy.

The Inovio Youtube video below illustrates the delivery of DNA plasmids, using the Cellectra® EP device.

References

Carlson, R. MD (July 2020)  INO-4700 MERS-CoV Vaccine.
https://www.precisionvaccinations.com/vaccines/ino-4700-mers-cov-vaccine

GeneOne Life Science, Inc. (Company website) http://www.genels.com/en/

Inovio Pharmaceuticasl Inc. (Company website) www.inovio.com

Naso, M.F., Tomkowicz, B.,  Perry, III, W. L.,  and W.R. Strohl 2 (July 1,2017) Adeno-Associated Virus (AAV) as a vector for gene therapy.  BioDrugs. 2017; 31(4): 317–334. Published online 2017 Jul 1. DOI: 10.1007/s40259-017-0234-5   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5548848/  https://link.springer.com/article/10.1007/s40259-017-0234-5

Reichmuth, A.M.,  Oberli, M.A.,   Jaklenec, A., Langer, R. and D.l Blankschtein (2016) mRNA vaccine delivery using lipid nanoparticles. Ther Deliv. 2016 May; 7(5): 319–334. DOI: 10.4155/tde-2016-0006    https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&log%24=relatedarticles&logdbfrom=pmc&from_uid=27075952

Staff (Dec. 17, 2020) Johnson & Johnson announces its first phase 3 COVID-19 vaccine trial ENSEMBLE is fully enrolled. JNJ Company website.  https://www.jnj.com/our-company/johnson-johnson-announces-its-first-phase-3-covid-19-vaccine-trial-ensemble-is-fully-enrolled

Tebas, P., et al. (2020) Safety and immunogenicity of INO-4800 DNA vaccine against SARS-CoV-2: A preliminary report of an open-label, Phase 1 clinical trial. EClinical Medicine – The Lancet, December 23, 2020. DOI: https://doi.org/10.1016/j.eclinm.2020.100689   https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(20)30433-8/fulltext

de Vrieze, J. (Dec. 21, 2020) Suspicions grow that nanoparticles in Pfizer’s COVID-19 vaccine trigger rare allergic reactions. Sciencemag.org https://www.cnet.com/how-to/recycling-electronics-what-to-do-with-your-old-laptops-phones-cameras-and-batteries/?ftag=CAD-03-10aaj8j