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a. Human RPE Transplant. The success of the RPE and IPE transplants in animal models has prompted several pilot studies in AMD and RP patients. A surgical team of ophthalmologists at the Johns Hopkins Medical Institute recently attempted a Phase 1 clinical trial aimed at restoring vision with fetal human neural retinal transplants (36). Patients selected for the transplant had advanced cases of retinitis pigmentosa and neovascular age-related macular degeneration. The objective of the pilot study was to determine the safety of the surgical procedure, the patient's tolerance for the grafted tissue, and the visual outcome. The procedure involved surgically grafting small healthy fragments of fetal human neural retina sheets into the subretinal space of eight patients with RP and one with AMD. Recipients of the allografts were not given postoperative systemic immunosuppressive drugs. Several criteria were used to assess visual improvement after the procedure. These included, pre- and postoperative fundus photography, flourescein angiography, scanning laser ophthalmoscope (SLO), macular microperimetry, electroretinogram (ERG) recordings, and visual function testing. Safety of the procedure was demonstrated in all nine subjects, and graft-versus-host complications were not severe in any of the patients involved in the clinical trial. An improvement in light sensitivity was recorded for three of the patients in the study. However, any positive changes in the quality of vision were shortlived and disappeared a few months after the transplant procedure. Only one individual in the group, an RP patient, developed new blood vessels at the graft site. It was difficult to determine a statistically significant effect of the transplants from this initial trial since only a small cohort was tested. However, a high tolerance for grafte retinal tissue in humans was clearly demonstrated. The procedure is still in its experimental stages, but with careful modifications in surgical procedures and types of tissue selected for transplant, it may prove to be a feasible biopharmaceutic approach for preventing the loss of vision caused by degeneration of key retinal cells (36).

Adjuvant therapy using RPE transplants is another approach currently being evaluated in retinal disorders requiring surgical removal of neovascular membranes. Surgical removal of choroidal neovascular membranes is a technique used to slow down the progression of degeneration in the retina, but it can also result in a loss of RPE cells and subsequent disruption of the blood-retinal barrier. Under those conditions, vision is further compromised by additional leakage and bleeding from the choroidal blood vessels into the retinal tissue. Prior to the Johns Hopkins study, a research team from Sweden reported that disruption of the blood-retinal barrier in advanced AMD cases is highly likely to increase allograft rejection. They showed in their preliminary study that subretinal human RPE transplants were rejected in 75% of the recipients treated. Tissue rejection appeared to occur sooner (within 3 months after transplant procedures) in all cases of neovascular AMD where the blood-retinal barrier was disrupted by surgical removal of neovascular membranes. Long-term tolerance (6-20 months) of the grafted tissue was only seen in AMD patients with intact blood-retinal barrier function (37). In 1994, the same group reported that RPE transplants were well tolerated in the fovea or parafoveal regions of AMD recipients who were subjected to surgical removal of subretinal neo-vascular membranes. While macular edema was observed, the fetal human RPE cells survived and were capable of replacing lost RPE cells and repairing the damage caused to the retina by surgical intervention (19). While these studies were preliminary, adjuvant transplant therapy is an interesting concept worthy of more research effort. It is possible that administration of

Figure 3 (A) Control: normal monkey retina; (B) autologous IPE transplant: light microscopic examination. (Courtesy of Dr. Toshiaki Aloe, Tohoku University, Sendai, Japan.)

immunosuppressive drugs after removal of CNV membranes may increase the adjuvant potential of RPE grafts.

b. Human IPE Transplant. The clinical efficacy of autologous IPE to improve vision after subretinal removal of neovascular membranes was evaluated in AMD patients as well. Evidence accumulated from animal studies indicated that iris pigment epithelium is easy to isolate, can integrate into the retina and substitute for RPE function, and is not associated with graft-versus-host complications. For these reasons, a pilot m

Figure 3 (C) Autologous Dil-labeled IPE transplant seen in cryostat section. Intensely fluorescent IPE cells are seen between the photoreceptors and RPE layers. (Courtesy of Dr. Tokashi Aloe, Tohoku University, Sendai, Japan.)

study was conducted using human autologous IPE to improve vision. A cohort of 20 who had neovascular membranes removed was used in this clinical trial. The transplant procedure was successful, and visual improvement was recorded for 5 patients. Thirteen individuals showed stable visual acuity, and 2 of the 20 patients experienced reduced vision with the autologous IPE transplants. Rejection of the graft and other immunologi-cally related complications were not observed in any of the AMD recipients (38). The clinical trial points to the use of IPE transplants as a more feasible treatment option than RPE cells for retinal degenerations or for those conditions associated with a loss of RPE cells after surgery.

So far, the therapeutic efficacy of retinal transplants to improve and maintain vision remains nebulous. A significant sustained positive effect on visual function has not yet been demonstrated by any single transplantion procedure. The results from animal and human studies indicate a reasonable degree of success in graft tolerance, tissue integration, and function of the transplanted tissue, but the data are still inconclusive and the procedure is open for debate. Although these findings are promising for future efforts in the field, several technical and biological concerns still need to be addressed for the procedure to emerge as a successful and clinically relevant therapeutic approach for retinal degenerative diseases (20,23,36,39,40). Some of these concerns include:

1. Choice of tissue: As yet, retinal tissue from other species cannot be used for human transplantation purposes. Finding suitable human alternatives that are easily accessible and functional limits current efforts in the field. Human fetal retina tissue is, perhaps, the most successful transplant treatment option for improving human vision. The cells from these tissues are not well differentiated and may contain stem cell populations with high survival potential in the eye. However, there is much controversy over the use of human fetal tissue for clinical applications, even though they may provide the best therapeutic outcomes. Adult neurons, on the other hand, are highly differentiated, do not survive as well as fetal neurons after transplant, and are not easily accessible. Autologous iris pigment epithelium has now emerged as a very attractive alternative treatment approach for retinal degenerations, but more clinical trials using this tissue need to be carried out. Neuronal cell lines may have potential because they are easy to culture and manipulate, but their high tumori-genic potential eliminates them as a viable transplant option at this time.

2. Surgical and mechanical considerations: During surgical implantation, tissues are directly grafted into the subretinal space through a small retinotomy made in a posterior incision of the sclera, underlying choroid, and peripheral retina. Retinal detachment and damage to the lens and vitreous can occur during this procedure. Severe visual loss or other ocular complications can result from the surgery. In this regard, the technique used should allow for retinal reattachment in the area of transplant in a relatively short period and small peripheral excisions that can heal without suturing. Transplantation procedures are also often followed by ocular infection, vasculitis, inflammation, and hemorrhaging in the eye (20). If substrates are used during the procedure, as shown in some animal models, they should be nontoxic, improve site-specific integration, and facilitate correct orientation of the transplants. Thickness, degradability, malleability, and permeability of the substrates are some features that affect the success of the transplant. For example, rigid substrates can introduce tears in the host tissue, leading to excessive bleeding or retinal detachment. Thin biodegradable sheets of polyglycolic and polylactic acid are reported to be optimal substrates for RPE grafts in rat retinas. They degrade easily, leaving well-established sheets of RPE cells in the correct orientation in the host retina. Transplant procedures, therefore, should seek to minimize the risk of retinal detachment, ocular injuries, or other complications that could have severe negative effect on vision.

3. Graft rejection: Rejection of grafted tissue accounts for a significant percentage of unsuccessful retinal transplants. Loss of integrity of the RPE-retina complex and the blood-retinal barrier contributes to the rejection of transplants in the retina. It is believed that nonclassical mechanisms of tissue rejection may be operative in the retina, even though this tissue is considered an immunologically privileged site. In severe retinal degenerations, however, the retina may lose its immune protective status and elicit a strong response to allogeneic transplants, with the risks being higher in older patients. Immunosuppressive therapy for nonneuronal allografts is essential but is not a requirement for neural tissues. Where autologous transplants are not possible, the use of immuno-suppressive drugs in cases of severe retinal degenerations may be essential to provide increased tissue tolerance.

4. Functional retinal circuitry: Proper host integration and orientation of transplants into target retinal sites are key factors in predicting the efficacy of the transplant procedure. Improvement in vision depends on correctly integrated grafts that develop normal retinal lamination and functional synapses with the host retina. Pigmented epithelial cells are polar in nature, with specific apical and basal characteristics that are important to their function of phagocytosis and trophic influence. Transplanted dissociated RPE cells often integrate randomly into the host retina with little structural or functional polarity. They frequently wander into the subretinal space where their proliferation can promote retinal detachment or inhibit visual transduction processes. Where degeneration of the retina is localized, transplantation procedures must be refined to promote tissue integration with correct orientation and rapid reestablishment of the host retina to achieve positive visual outcome. It is difficult to determine the success of transplant integration in humans without histopathological information. So far, integration of grafted tissue and restoration of retinal circuitry have only been examined and confirmed in histological preparations of animal retinas. For morphological and histochemical evaluations, the eyes are monitored ophthalmoscopically after the transplant procedure and eyes are enucleated at various time points. Integration of tissue and expression of biological test markers are visible in the preparations using light microscopy and immunocytochemistry techniques. Lack of this information results in somewhat speculative data regarding morphological and functional connections of human retinal transplant. Visual improvement correlates of type, site, and number of transplants, as well as sham effects on vision, are useful in determining the success of the technology.

5. Trophic influence: Growth factors, upregulated after mechanical stress to ocular tissues, have resulted in a temporary delay of retinal degenerations and a positive, transient effect on vision. In this regard, surgically induced trophic influence may account for differentiation and survival of the grafts and does not accurately reflect the clinical efficacy of the transplanted tissue. In addition, these factors may also promote neovascularization, leading to complications that further compromise vision and reduce the beneficial effects of the transplant. Therefore, appropriate measures must be taken to evaluate the secondary effects of trophic factors, induced by surgical manipulation, to obtain conclusive results to validate the efficacy of a specific transplant approach.

6. Visual improvement and stabilization: Transplanted tissues must have the ability to improve vision. Grafts must integrate, restore retinal circuitry, and perform functions required for long-term visual therapy. Morphological or biochemical alterations in the phenotype of the grafted cells can hinder the therapeutic effects of the transplant on vision recovery. Long-term survival of the grafted tissue must be ensured to maintain stabilized vision.

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