Cell Encapsulation Technology As A Therapeutic Strategy Biology Essay

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The cell encapsulation technology involves the use of living cell for the delivery of biologically active compound to the target tissue, by manipulating genetically, to develop biological substitutes for the implantation into the body (Nerem and Sambanis, 1995). The idea of bio encapsulation was proposed by T.M.S Chang in the year 1964. The progress in the field of molecular biology over the span of 20 years, many proteins molecules were discovered with various therapeutic potentials .The cell encapsulation technology requires a cell based delivery system which has a range of promising therapeutic treatments for chronic disorder eye and the central nervous system. This strategy involves the use of genetically engineered producer cells that secrets a protein with therapeutic potential. The cells are encapsulated immunoisolatiting enzyme and implanted into the body. The capsule permits the release recombinant protein which asserts a therapeutic effect on the specific tissue. The most commonly use material used for encapsulation is polysaccharide alginate. A wide spectrum of cells and tissue has been encapsulated and implanted in both animals and humans which is applicable for both research and medical purpose including Retinal Degenerative diseases.

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For the delivery of protein to the retina or the CNS, typical approach are quite limited, which is a typical example of the failure of clinical trial with systemically use of ciliary cytokines neurotrophic (NT) factors (CNTF)which belongs to interleuleukin (IL)-6 family. In this trail, the systemic administration of the CNTF results in no therapeutic benefits even though high dose is used, however the high peripheral concentrations of CNTF resulted in side effects like fatigue, fever and chemical changes in blood that are consistent with functional response of acute phase. Hence, the systemic mode administration of large molecules like CNTF and other NT factors are non effective approach towards the CNS and ocular disorders. The alternative for the protein delivery into the retina are by injection of purified recombinant proteins bolus and gene therapy. The Bolus is then injected for clinical therapy which requires prolong administration and for a long term. The gene therapy on the other hand can attain sustained expression for protein delivery.

The Encapsulation cell technology (ECT) is a delivery system which involves the use of living cells secreting a therapeutic active agent which is usually achieved by specific cells through genetically engineering. These engineered cells encapsulated by polymer capsule which is semi permeable. The capsule is implanted at the targeted sites. Thus ECT is an effective means of long-term delivery of biological proteins and polypeptides in the retina or the CNS.

Neurotech has developed an intraocular implantable device prototype for the long term delivery of therapeutically active agent's treatment of the ophthalmic disorders. These devices consist of genetically engineered cells packed in the hollow semi permeable tube which prevents from the immune bodies such as antibodies of the host, from entering into the device. The capsule is only permeable to nutrients and therapeutic molecules. The Encapsulated cells secrete therapeutically active agents continuously and derive its nutrients from the host. The encapsulated cell is designed in such a way that it can be implanted through a small incision and the device is attached to sclera with help a small titanium wire loop. This device measures about 6 mm in length and approx 1mm in diameter which enables the device to be out of the visual axis in the human eye.

Fig. 1. Schematic illustration of the ECT device. The two ends of the polymer section are sealed and a titanium loop is placed on the anchoring end.

Discussion:

Ophthalmic disorders are considered as rapidly growing diseases areas which are associated with an increase in aging population. The potential blinding diseases have become major segments for the healthcare about more than 50 million patients in United States alone. The site of these patients is also threatened by age related factors retinitis pigmentosa (RP) etc.

In the present date only a few treatments of retinal degenerative disorder are known. The recently developed NT factor provides a great promising treatment of these diseases. On the other hand, without the practical delivery system the treatment of these diseases is very tricky. The ECT device is specifically design for the intraocular implantation. The NT-501 device is an ECT-CNTF product that consist of encapsulated cell that secrets CNTF. While manufacturing the device should be sterile, nonpyrogenic and retrievable. It is proposed to deliver CNTF intraocular for the treatment of photoreceptors degenerations.

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The influence of the growth factor as potential therapeutics on the photoreceptor degeneration was demonstrated in 1990. Many growth factors, NT factors and cytokines has been tested in various degenerative models, mainly by intravitreal injection of purified for short term experiments, since then. Among these factors, CNTF has been shown to be the most effective one of all models. However, the chronic nature of RP makes repetitive administration of purified recombinant CNTF impractical through intraocular injection. These obstacles of intraocular delivery have prevented the initiation of clinical trials and its further development. The factors that shown protective effect in animal models of retinal degeneration includes brain- derived NT factor, NT- 4, axokine, basic fibroblast growth factor, basic fibroblast growth factor, insulin- like growth factor II transforming growth factor-β2, IL-1β.

RP affects approx 100,000 Americans. RP come in the categories of retinal degenerative diseases that have a complex molecular etiology. About more than 100 mutations in a number of genes, together with rhodopsin, peripherin and phosphodiesterase (PDE)β, are supposed to be responsible for RP, even though the genotype of the bulk of RP patients are unknown. Typically the patient suffers from decrease night vision early in the life due to loss of rod photoreceptors. Although the genetic defect affects the rods, cones photoreceptor eventually degenerate, this leads to total blindness. The NT-501 device has been developed for intraocular delivery of CNTF for RP.

The principle experiments models of photoreceptor degeneration were conducted on the S334ter-3 transgenic rat and the rcd1 mutant dog. Pharmacokinetics studies were performed in the rabbits. The data from these studies indicate that CNTF delivered by NT-501 is not only effective in protecting photoreceptors, but also long-lasting. These preclinical studies of NT-501 paved the way for human clinical trial, which is currently ongoing.

The NT-501 Device effect on Photoreceptors in the rcd1 Dog RP Model

The device NT-501 was first investigated on rcd1 Dog model. These dogs were carrying the mutation on the PDEB gene encoding the β-subunit of the rod cGMP PDEβ. The degeneration of retina of this model is well characterised (45-46). In these animals the photo degeneration begins on 3.5 after the birth and continues for 1 yr, with about a loss of 50 % of photoreceptors at the age of 7 weeks. NT-501 devices secreting 1 to 2 ng/d of CNTF were surgically implanted into the left eye of each rcd1 dog at 7 wk of age, the earliest time point that the surgical procedure can be performed without disruption of the retina. In the normal dogs the ONL contains 10 to 12 layers of photoreceptor nuclei, but in these animals at 7 wk of age, only 5 to 6 layers of nuclei in the remain.

The contra lateral eye was not treated. At the endpoint of the experiment (14 wk of age), the devices were explanted and assayed for CNTF output and cell viability, and the eyes were collected and processed for histological evaluation. The ONL in untreated eyes contained only two to three rows of photoreceptor nuclei. In contrast, the ONL in the NT-501 treated eyes still had five to six rows remaining, similar to the number of nuclei rows present at the time when the treatment began (Fig. 2). The protection of photoreceptors was evenly distributed throughout the retina and not localized near the implant site. No apparent adverse effects were found in the retina. All explanted devices contained viable cells.

Fig. 3. Photoreceptor protection by CNTF secreting ECT device NT-501. Sections of retina from rcd1 dog model of retinitis pigmentosa were examined by light microscopy. A device was implanted into one eye at 7 wk of age and explanted at 14 wk of age. The contralateral eye was not treated. (A) Treated eye, (B) untreated eye. The ONL of treated retina contained five to six rows of nuclei. In contrast, the untreated retina had only two to three rows. Thus the NT-501device provided significant protection to photoreceptors in the rcd1 dogs. Brackets denote ONL.(Reproduced from ref. 12)

Conclusion

Preclinical development of ECT has demonstrated the therapeutic efficacy, long term delivery, and relative safety in the animal eyes. Based on this data, a clinical phase

I safety study of NT-501 has been initiated at the National Eye Institute to treat RP. If safety and consistent delivery are demonstrated in clinical trials, ECT could potentially serve as a Cedarbaum gave the pharmacokinetics of subcutaneously administered delivery system not only for RP, but also for a number of ophthalmic diseases for which no effective therapies are currently available.

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