Encapsulated cell technology delivers for the back of the eye

THE French biotechnology company, Neurotech, has recently made significant advances in the delivery of therapeutics to the back of the eye.

The advancement, reported in the journal, Investigative Ophthalmology and Visual Science, involved the use of so-called ‘encapsulated cell technology’ to deliver therapy for retinitis pigmentosa in dogs. [Investigative Ophthalmology & Visual Science 2002;43:3292-3298]
The findings have set the stage for the testing the drug delivery technique in Phase I human clinical trials.

Encapsulated Cell Technology, or ECT for short, is a novel medical device that can be implanted directly into the eye and from which therapeutic molecules can be released over time. Such technology has a significant advantage over the more cumbersome administration of drugs via intravitreal injection.

Neurotech, which is led by Bernard Chauvin MD, is focused on exploiting its technology to deliver treatments designed to counter the photoreceptor cell loss that characterises such ocular disorders as AMD, diabetic retinopathy, glaucoma and retinitis pigmentosa.
Neurotech’s first molecule for delivery using the ECT device is the ciliary neurotrophic growth factor (CNTF). Numerous studies, across a range of such different neurodegenerative diseases such as Parkinson’s disease, Alzheimers and Huntington’s disease — and in a number of distinct animal models — have clearly demonstrated the therapeutic efficacy of CNTF.

CNTF has been shown to have the effect of slowing cell loss. But two key historical challenges have been delivery and supply: how to get CNTF to where it is needed and how to ensure a continuous supply of the agent over time.
Neurotech’s ECT device shows promising advances in tackling these problems.The ECT device, according to their most recent publication, consists of a "scaffold, providing cell attachment within a sealed, hollow fibre membrane, and a retrieval loop at one end for surgical manipulation".

The device consists of genetically modified cells packaged in a hollow fibre, semi-permeable membrane. The hollow fibre membrane prevents immune molecules, such as antibodies, and host immune cells from entering the device; at the same time, it allows nutrients and therapeutic molecules to diffuse freely across the membrane.
The encapsulated cells, continuously secreting therapeutic agents, are maintained in a proprietary matrix material and derive nourishment form the host milieu. The device is anchored to the sclera at the pars plana by a small titanium wire loop.

Weng Tao MD, of Neurotech, and collaborators from three American institutions — the University of Pennsylvania Medical Centre, the Rhode Island Hospital, and the James A. Baker Institute for Animal Health at Cornell University — have reported that sustained release of CNTF from the ECT device maintains approximately 50% more cells in the outer nuclear layer of treated dogs compared to untreated dogs.

For their studies, the research team used the ‘rcd1’ canine model of retinitis pigmentosa in which photoreceptor degeneration begins approximately four weeks after birth and results in almost 80% photoreceptor cell loss within 10 weeks.
The additional advantage of the canine model is that the size of the eye is very similar to that of humans which may facilitate such design issues as testing progresses to Phase I human clinical trials.

A population of cells derived from the human retina was genetically engineered to churn out CNTF and approximately 400,000 cells were loaded into each capsular device. The surgical procedure for implanting the device within the orbit of the eye takes no more than 15 minutes and involves only a small incision in the pars plana.

Dogs born with retinitis pigmentosa had the device implanted in one eye only when they were seven weeks and the device was removed when the animals were 14 weeks old.
Following histological examination, untreated eyes had two to three layers of photoreceptor cells remaining in the outer nuclear layer, whereas treated eyes had five to six layers of photoreceptor cells remaining.
CNTF concentration

Furthermore, the researchers investigated the dose effect by controlling the concentration of CNTF delivered to the eye; the findings showed that even the lowest dosage levels conferred significant protection.

The implanted device also showed no signs of causing inflammation or damage to the retina. The cellular protection afforded to the retina by the presence of CNTF appeared to be entirely independent of its location within the eye.
Additionally, the researchers argue that “the ECT devices can be easily retrieved and replaced making the treatment reversible and renewable, providing a safer alternative to in vivo gene therapy”.

“The small intraocular device design, large number of therapeutic candidates, relatively simple surgical procedure for implantation and removal and minimal side-effects all contribute to the promise of this technology,” they said.

It is clear that the company’s investors are equally convinced of such potential, having recently backed Neurotech with an investment of E35 million in a third funding round.
The availability of delivery systems such as the ECT device may potentially accelerate not only the development of CNTF for retinitis pigmentosa but also the development of a range of therapies for such disorders as AMD and diabetic retinopathy.

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