The foundation of the Encapsulated Cell Therapy (ECT) Platform is the customizable NTC-200 cell line. NTC-200 cells thrive under low oxygen and low nutrient conditions while being amenable to genetic manipulations under stringent selection methods. The NTC-200 cell line can be genetically engineered to produce clinically relevant levels of therapeutic protein.
The cell line can be engineered for various indications.
ECT is a unique and versatile platform with the ability to continuously produce and deliver targeted therapeutics both singly or in combination, to the back of the eye long-term. ECT protects the cells from host immunological components. Recombinant cell lines derived from transfected NTC-200 cells are able to secrete major classes of therapeutics, including antibodies, fusion proteins, and growth factors, potentially enabling the ECT platform to treat a broad array of chronic ocular diseases. (Image 1 & 2)
NTC-201-6A cells are engineered to produce CNTF, a neurotrophic factor naturally produced by neurons and Müller cells, has been extensively studied since its identification over three decades ago. In several model systems of retinal disease.
CNTF has been shown to have a neuroprotective effect on photoreceptors and retinal ganglion cells, the neurons that capture light and transmit vision to the brain, respectively. As shown in a model of the photoreceptor degeneration (Image 3), the eyes treated with CNTF have a higher number of photoreceptors remaining in the outer nuclear layer (ONL), while the non-treated diseased eyes progressively lost photoreceptors.
CNTF is hypothesized to function by binding to a tripartite receptor consisting of CNTFR, LIFR and GP130 which activates the JAK/STAT pathway and engages cell survival pathways in degenerating neurons to Müller glia cells. In macular telangiectasia, the degeneration of Müller glia cells is thought to be associated with the onset of photoreceptor loss. (Image 4)
Tao et al., IOVS 2002 43:3292-3298
To circumvent the relatively short half-lives of therapeutic protein drugs and provide a steady-state therapeutic and safe concentration following single intraocular application, a novel cell-therapy technology has been developed and advanced into human clinical studies by Neurotech Pharmaceuticals. Encapsulated Cell Therapy (ECT) potentially mitigates the risk associated with repeated intraocular injections or drugs, sub-retinal injections required of gene therapy and bypasses the restrictions of conventional allogeneic cellular transplantation by supplying an immunoisolated microenvironment optimized for cell survival and consistent drug delivery based on the target indication and cell type.
Compared to other forms of intraocular drug delivery, ECT affords the ability to control the dose of drug delivered to the eye at a constant rate over an extended period of years for chronic, degenerative ocular diseases. Combined with our proprietary cell line, ECT has evolved to the point of providing long-term implant survival, safety and therapeutic efficacy demonstrated in humans.
In combination with robust device design and attention to manufacturing quality, the hardiness of the encapsulated, proprietary cell line has proven to be a foundation of the NT-501 product shown to slow the loss of visual photoreceptors in macular telangiectasia as well as prevention of ganglion cell death in glaucoma, each with direct benefits in the design of future products targeting a wide range of untreated or undertreated ocular diseases.
The ECT Platform has been optimized to deliver a therapeutic protein from engineered human mammalian cells for greater than 2 years, with near zero-order kinetics as demonstrated in Neurotech’s ophthalmic human clinical programs targeting Dry AMD and RP (Kauper et al., 2012). The environment of the vitreous is one of low nutrients and high oxygen tension, factors that would normally preclude this site from cell-based delivery. Cellular encapsulation technology is designed to permit therapeutic cells to survive in diseased conditions and to replace or assist the function of the failing target cells or tissue.
There are several distinct advantages to ECT. Foremost, it offers the potential for any gene encoding a therapeutic protein to be engineered into a cell and therefore has a broad range of applications. In addition, the therapeutic protein is freshly synthesized and released in situ; thus, a relatively small amount of the protein is needed to achieve a therapeutic effect in comparison to pulsatile dosing. Stable, endogenous secretion of the protein assures that the availability of the protein at the target site is not only continuous but also long-term. Furthermore, the output of an ECT implant can be controlled to achieve the optimal dose for treatment. Finally, treatment by ECT can be terminated if necessary, by simply retrieving the implant. Thus, ECT is a potentially effective means of long-term delivery of proteins and polypeptides to the retina.