Cookies

Like most websites The Ophthalmologist uses cookies. In order to deliver a personalized, responsive service and to improve the site, we remember and store information about how you use it. Learn more.
Subscribe to Newsletter
Subspecialties Retina, Business and Innovation

A Tiny Factory

Macular telangiectasia type 2 (MacTel) is an uncommon, progressive, degenerative eye disease that can leave older patients with devastating reductions in their quality of sight and quality of life. Given that there was no medical, surgical, or lifestyle intervention to alter disease progression, Neurotech Pharmaceuticals stepped up to the plate with an encapsulated cell therapy (ECT) device. For MacTel patients, it could represent the first real chance to slow the disease’s destructive effects and pace of ongoing vision loss. 

Understanding how ECT can improve MacTel patient outcomes relies on understanding the general mechanism of action and the specific design choices made during development. These factors also highlight the potential for new encapsulated cell therapies to treat a variety of under- and untreated eye diseases. In short, ECT is a promising realm for clinical research and technical innovation.

ECT and NT-501
 

The concept of encapsulating cells to treat disease has been around since the 1930s, but only recently has the technology matured to the point where reliable therapeutic effects can be offered to patients. In essence, ECT introduces a miniature medicine factory into the body to continuously deliver a therapeutic agent directly where needed. To treat MacTel, and possibly other eye diseases, the drug-producing device – the NT-501 – is placed into the vitreous cavity, where it manufactures and delivers drug to the retina or other targetable intraocular structures. The NT-501 comprises four key elements: i) specially engineered human retinal pigment epithelium (RPE) cells (the drug-making machinery), ii) the scaffold to which the cells attach (the factory’s bricks and mortar), iii) a porous membrane that houses the cells and scaffold, iv) the caps where a titanium loop is affixed to facilitate manipulation during implantation (see box for more details).

Which drug to make? Ciliary neurotrophic factor (CNTF) is a well-studied neurotrophic factor produced endogenously by neurons and Müller glial cells. It has been demonstrated to be effective in retarding photoreceptor neuron loss in animal models of retinal degeneration. However, CTNF has an extremely short half-life, requiring it to be produced and delivered continuously. Unlike other retinal therapies that may only require one injection per month, CTNF would require multiple injections each day. That’s what makes ECT such an elegant solution for MacTel; the effective drug is made constantly, right where it’s needed. Put simply, we obtained, verified, and transfected the CNTF gene into our master stock cells to form a new cell line: NTC-201-6A.

After implantation of NT-501, the NTC-201-6A cells continually produce and release CNTF into the vitreous cavity. Importantly, the cells within the implant are protected from the host’s immune system.

NT-501 deep dive
 

The NT-501 device is sterile, non-pyrogenic, and retrievable. The current implant is approximately 6.5 mm long and is placed, via a pars plana incision, well outside the visual axis. The device’s housing consists of a sealed, semipermeable, hollow fiber membrane (HFM) capsule surrounding a scaffold of six strands of polyethylene terephthalate (PET) yarn. Produced by wet-spinning technology using similar methods to those used to manufacture kidney dialysis or plasma filtration membranes, the HFM is fabricated from polyethersulfone (PES) and provides the functional body of the NT-501. The membrane portion of the implant houses the encapsulated NTC-201-6A cells, allowing the outward diffusion of therapeutic agents while supporting cells with the inward diffusion of environmental nutrients, and preventing the host immune system from “seeing” the NTC-201-6A cells.

The hydrophilic polymer polyvinyl pyrrolidone (PVP), which improves the overall hydrophilic characteristic of the membrane, is incorporated into the chemical synthesis of the membrane. This hydrophilic membrane modification results in very low levels of protein binding to the inner and outer structure of the membrane during in vitro and in vivo exposure to encapsulated cell-produced proteins, to culture media proteins, and to host implant proteins and cells. The co-formulation of PES and PVP structure enhances the stabilization of the device membrane pore structure compared to membrane formulations of PES alone. This ensures that the functionality of the medicinal product is not impacted by the medical device for the duration of treatment.

The NTC-201-6A cells come from our NTC-200 cell master stock, which traces its ancestry back to ARPE-19 cells, a spontaneously arising RPE cell line derived from a human donor in 1986. This particular cell culture had marked potential for growth, extensive pigmentation, and large areas of polygonal cells when compared with other RPE cultures. The ARPE-19 cell line was purified to remove weakly adherent and fibroblastic cells – a process that was repeated until a uniform, highly epithelial culture of RPE cells was obtained. Cells from the original explant culture were ultimately expanded to create a bank of cells, which were heavily tested for contaminants and thoroughly studied.

PET yarn was chosen as the scaffolding material to provide surface area for cell attachment and growth within the capsule. The scaffolding is distributed within the membrane interior, with voids residing between individual monofilaments, maximizing the permeability between cells, and cell access to diffused nutrients from outside the device. Additionally, the PET monofilaments impart strength to the assembled PAC. Each implantable NT-501 is loaded with human CNTF-secreting NTC-201-6A cells before the capsule is sealed with methacrylate adhesive. A titanium loop is attached to one end to aid placement and retrieval of the implant. The cell number expands and growth stops due to cell contact inhibition.

Beyond MacTel
 

Neurotech Pharmaceuticals has almost 20 years of experience with the versatile and hardy cells that power NT-501, so we are well poised to create devices that “manufacture” other therapies within the vitreous cavity, producing different drugs, proteins, peptides, or other therapeutic agents. Our cell biologists and engineers are working diligently to exploit this opportunity, and I have confidence that we’ll be able to modify our encapsulated cell technology to treat a variety of intraocular diseases. 

I am excited about the future of ECT in ophthalmology – and even more excited to help introduce the resulting real-world therapeutics!

Receive content, products, events as well as relevant industry updates from The Ophthalmologist and its sponsors.

When you click “Subscribe” we will email you a link, which you must click to verify the email address above and activate your subscription. If you do not receive this email, please contact us at [email protected].
If you wish to unsubscribe, you can update your preferences at any point.

About the Author
Thomas Aaberg, Jr.

Retinal surgeon at the Retina Specialists of Michigan, and the Chief Medical Officer of Neurotech Pharmaceuticals. He is based in Michigan, USA.

Related Product Profiles
Uncover the Unique DNA of SPECTRALIS®

| Contributed by Heidelberg Engineering

Subspecialties Retina
ForeseeHome® – remote monitoring to help detect wet AMD earlier and improve outcomes

| Contributed by Notal Vision

Product Profiles

Access our product directory to see the latest products and services from our industry partners

Here
Most Popular
Register to The Ophthalmologist

Register to access our FREE online portfolio, request the magazine in print and manage your preferences.

You will benefit from:
  • Unlimited access to ALL articles
  • News, interviews & opinions from leading industry experts
  • Receive print (and PDF) copies of The Ophthalmologist magazine

Register