2008 Annotation: RP is a progressive disease (similar to temporal lobe epilepsy), rather than a focal event that scissors off photoreceptors. Framing the discussion in that manner properly brings understanding of the molecular and structural mechanisms of negative CNS neuroplasticity to bear on the problem of vision restoration.

• Cell transplant technologies presume substantial survival of retinal outflow channel architectures.
  The retina is complex and forms approximately 14 patterned outflow channels, realized as ganglion cells. The mammalian retinal parts list includes 1 rod class, 1 rod horizontal cell, 1 rod bipolar cell, 2-3 cone classes, 1-3 cone horizontal cells, 9+ cone bipolar cells, 27 amacrine cells, and about 15-20 ganglion cells. Thus, about 60-70 cellular devices form the outflow channels. Our next challenge will be to trace the wirings that create outflow channels; resolve synaptic transduction assemblies in terms of molecular signaling and electromorphology; reconcile wiring models with physiological data; and produce a complete, validated model of retinal vision.

  There are four broad classes of cell-based retinal degeneration therapies: (1) RPE or RPE-surrogate trans- plants; (2) photoreceptor transplants; (3) embryonic retina transplants; (4) stem cell or neuroprogenitor transplants. RPE and RPE/surrogate transplants are designed to replace failed RPE or provide survival factor delivery. These are the simplest and most promising therapies, but must be introduced prior to cone loss and remodeling onset. All other therapies depend explicitly upon the survival of normal architecture in the neural retina and proper syn- aptic patterning of all transplanted elements. Rod transplants are a popular model system, but have poor prospects for restoring photopic vision. Embryonic systems represent large-scale replacements that must seri- ally connect with ganglion cells or replace them. Finally, injections of naïve stem cells require an unknown guidance to activate proper transcriptions of coordinate gene arrays, morphing extrinsic cells into phenotypes proper for retinal function.

  2008 annotation: Recently very exciting studies on rod or cone progenitor/surrogate cell therapies show much promise [MacLaren et al, 2006 and Oskada et al, 2008] but are (i) limited to rods (loss of cones in RP is the real issue); (ii) display low efficiency in vivo (<0.1% so far); and/or (iii) must be executed during remodeling phase I or mid-phase II, which is when most patients still have cone vision. Phase III, when patients are blind, appears to be completely intractable for all cell-based therapies so far.

  • Neural retinal topology is corrupted in retinal degenerations. After loss of the cones, all Müller cells enter a hypertrophic response phase where the perikarya migrate throughout the retina and their processes hypertrophy to form distal and proximal seals, as well and columns or walls of glia that transect the neural retina. The distal glial seal obliterates the subretinal space and there is no place to transplant new cells without creating traumas that trigger further remodeling. All glial surfaces appear to be guides for unregulated neuronal migration and transplanted cells will also migrate. Spatial patterning is key to visual processing, and no control of de-patterning is offered by any transplant design to date.

    2004 annotation: These concerns remain unaltered. Indeed, circumstances are likely even more complex in AMD, as we now know that Muller glia can perforate Bruch's membrane, invade the choroid, and trigger concurrent exodus of neurons from the retina.

  • Neuronal cell death is extensive in retinal degenerations. Though many neurons persist after death of the sensory retina, all are susceptible to cell death in varying fractions and patterns. Focal depletion of the inner nuclear layer is common and some genetic types of photoreceptor degenerations express massive ganglion cells loss in large patches of retina.There is no evidence that transplanted cells are better survivors or can delay intrinsic death events. In some studies, it appears that transplantation triggers more death and remodeling.

    2004 annotations: Again, cell death can be even more aggressive in AMD and many prior studies of cell loss used counts of retina that still possessed ONL somas (which inhibits much neuronal cell death) and did not use validated neuronal markers.

  • Aberrant rewiring attends retinal degenerations. The most dramatic changes in remodeling retinas include the elaboration of new neurite fascicles and the formation of new circuitry in microneuromas across the retina, next to the distal glial seal. New circuitry includes aberrant re-entrant bipolar cell circuits and extensive changes in synaptic architecture. Modeling of new circuits shows that all are corruptive and many form resonant circuits. Thus, the remnant neural retina is no longer an effective image processor. Insertion of any transplant system into this architecture offers no basis for recovery of proper wiring.
    

    2004 annotations: This doesn't include the clearly corruptive neurite retraction by bipolar cells, signal transduction phenotype decomposition, horizontal cell remodeling and partial cell loss, and changes in ganglion cell signaling that occur early in retinal degenerations. It is unlikely that any retinal cell remains normal following the onset of most retinal degenerations.

    2008 Annotations: Our recent work now shows that remodeling goes beyond rewiring and morphological change and includes molecular reprogramming. Passive anatomy alone will not reveal the scope of neural revisioning in response to retinal diseases such as RP.

  • Cell fusion, improper rewiring, and co-opting prevent restoration of a normal retina. Certain transplantation schemes may slow some forms of retinal degeneration when implemented before degeneration of the sensory retina is complete and remodeling becomes dominant. This is not a viable strategy for most hu- man disease. Further, transplantation studies often do not report failure rates or study transplant fate properly. It is likely that the outcomes of most transplants will be impacted by cell fusion, improper rewiring, and co- opting of transplanted cells into defective or non-functional forms by resident neurons and glia.
    • Fusion. Many reports of transplanted stem cells assuming phenotypes of host cells are now known to be in- stances of cell fusion. When sufficient trauma attends the delivery of exogenous cells, aberrant protein and DNA uptake can also alter host and guest phenotypes, confounding analysis.
    • Improper rewiring Remodeling retinas engage in corruptive local and global rewiring and have lost patterning restrictions as well. Naïve cells do not carry this developmentally proffered structuring and cannot induce re- patterning. Moreover, transplanted photoreceptors or any other fragments of retina will certainly en- gage in wide-area neurite extensions if they survive, and degenerating retinas already engage in pro- fuse generation of aberrant neurites. There is no evidence that any of these processes make proper connections.
    • Co-opting What phenotype should an uncommitted stem cell assume and how will it be transcriptionally guided in forming that phenotype? Published data demonstrate that most transplant studies fail to properly phe- notype cells; that any emergent phenotypes, if informed by local signaling from negatively remodeling cells, will most likely be co-opted into an aberrant phenotype; and that most cells slowly lose their own mature phenotypes after transplantation. The key error in transplant designs is a belief that the neural retina is normal. It is not – there is hardly a cell type that evinces normality.
      
      
• Summary: The basic assumptions of transplant technologies (intactness, receptivity and instructional ca- pacity of the host neural retina) are false for most retinal degenerations. Moreover, expectations that cells transplanted into negatively remodeling environments will restore normalcy to host cells, maintain mature phe- notypes or assume proper phenotypes seem baseless and, as yet, untested.

  2004 annotations: Circumstances are not much different today. Although appreciation of these issues is more common, open acknowledgment is rare.