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e experiments, Li and colleagues identified cone outer segments by peanut agglutinin labeling or by antibodies against cone opsins. Moreover, antibodies against cone arrestin had been employed to identify the cell bodies of cone photoreceptors. Loss of COS, an early DBeQ sign of cone degeneration, was detected as early as PD12, at the peak of rod degeneration. The loss of COS was not evenly distributed. Rather, DBeQ it was concentrated in many small patches that had been negatively stained for PNA. The PNA negative places expanded with age, indicating progressive loss of COS. Intravitreal injection of recombinant CNTF protein dramatically changed the PNA negative places. They became substantially smaller and in quite a few instances entirely resolved. The reappearance of PNA staining in the prior PNA negative places suggests regeneration of COS.
To prove that CNTF therapy induces regeneration of COS, the investigators compared the COS densities just before and immediately after CNTF therapy. They demonstrated that COS density was greater in CNTF treated retina than just before the therapy, confirming that CNTF therapy did promote regeneration of COS. PluriSln 1 Since loss of COS is an early sign of cone degeneration, regeneration of COS may be regarded as reversal from the degenerative process. This result indicates that CNTF therapy may not only slow or quit degeneration, but might also reverse the degeneration process. Given that COS is part of the functional organelles of cone photoreceptors for light detection, the regeneration of COS could translate into functional improvement of cones.
In a different experiment, considerable long term protection of cone cells and cone ERG had been achieved by using CNTF secreting implants for sustained delivery of CNTF to the retina of S334ter rats. 6. 2. Protection of cones in Human musculoskeletal system human by CNTF As already described, the first indication of a neurotrophic effect of CNTF on cones came from a small open label clinical trial of CNTF secreting implants in patients with advanced RP. Though the trial objective was to determine the safety from the CNTF implants and the surgical procedure, the results showed that three patients skilled an increase of 10 15 letters over baseline in visual acuity whereas no boost was observed in the untreated fellow eyes among the seven study eyes that may be tracked for visual acuity.
The improvement of visual acuity is most likely to have resulted from the improvement of cone function, since visual acuity tests the function from the fovea, which has only cones, and in patients with advanced RP, virtually all rod photoreceptors have degenerated. PluriSln 1 The protective effect of CNTF on cone photoreceptors was objectively demonstrated in human patients making use of a effective imaging technology called the adaptive optics scanning laser ophthalmoscopy. Talcott and colleagues observed cones in three patients over a 2 year period and found a progressive cone density decreased in sham treated eyes. On the other hand, the cone density remained stable in CNTF treated eyes. Moreover, a recent clinical trial of CNTF secreting implants in patients with geographic atrophy showed a stabilization of visual acuity in eyes treated with high dose CNTF secreting implants.
Together, these findings indicate that CNTF is neuroprotective for cone photoreceptors. 6. 3. Restoration of cone function in dogs with CNGB3 mutations by CNTF Kom romy and colleagues DBeQ recently found that a single intravitreal injection of recombinant CNTF protein in adult dogs with CNGB3 mutations, which causes day blindness in dogs, induced a transient restoration of cone function and vision. The cone ERGs became detectable for up to 4 weeks immediately after injection. The treated animals also showed improved overall performance in navigating an obstacle course in bright light, indicating restoration of cone vision. There was in addition a transient reduce in rod ERG, which is consistent with all the prior findings in rat and mice.
There's no functional B subunit from the cone cyclic nucleotide gated channel in CNGB3 dogs and the mechanism from the restored cone function is unknown. The transient PluriSln 1 nature of these changes DBeQ is most likely due to the clearance from the injected CNTF protein. 7. CNTF and retinal ganglion cells 7. 1. Neuroprotection CNTF serves a neurotrophic function for RGCs. A single injection of CNTF protein into PluriSln 1 the vitreous substantially protected RGCs in an optic nerve axotomy rat model, whereas brain derived neurotrophic aspect did not. RGC protection by CNTF was also noticed in nitric oxide induced cell death. CNTF therapy 2 days prior to injection from the nitric oxide donor substantially protected RGCs from cell death. In culture, CNTF promoted the survival of purified rat RGCs in the presence of forskolin. CNTF gene transfer through Ad vectors also protects retinal ganglion cells from degeneration. RGC density in the eyes treated with intravitreal Ad CNTF 1 2 hours immediately after optic nerve axotomy was substantially higher than in the controls when examined 14 days later. Comparable protection