Heywood M. Petry

Vision Improvement in Retinal Degeneration Patients by Implantation of Retina Together with Retinal Pigment Epithelium

PURPOSE To demonstrate efficacy and safety of the implantation of neural retinal progenitor cell layers (sheets) with its retinal pigment epithelium (RPE) in retinitis pigmentosa (RP) and dry age-related macular degeneration (AMD) patients with 20/200 or worse vision in the surgery eye. DESIGN Interventional nonrandomized clinical trial. METHODS Ten patients (six RP, four AMD) received retinal implants in one eye and were followed in a phase II trial conducted in a clinical practice setting. Early Treatment Diabetic Retinopathy Study (EDTRS) was the primary outcome measure. All implant recipients and nine of 10 tissue donors were deoxyribonucleic acids typed. RESULTS Seven patients (three RP, four AMD) showed improved EDTRS visual acuity (VA) scores. Three of these patients (one RP, two AMD) showed improvement in both eyes to the same extent. Vision in one RP patient remained the same, while vision in two RP patients decreased. One RP patient has maintained an improvement in vision from 20/800 to 20/200 ETDRS for more than five years; at the six-year examination, it was still maintained at 20/320 while the nonsurgery eye had deteriorated to hand motion vision. This patient also showed a 22.72% increase in light sensitivity at five years compared to microperimetry results at two years; the other patients showed no improved sensitivity. Although no match was found between donors and recipients, no rejection of the implanted tissue was observed clinically. CONCLUSIONS Seven (70%) of 10 patients showed improved VA. This outcome provides clinical evidence of the safety and beneficial effect of retinal implants and corroborates results in animal models of retinal degeneration.

Transplantation of intact sheets of fetal neural retina with its retinal pigment epithelium in retinitis pigmentosa patients.

PURPOSE To show the safety of transplanting sheets of fetal neural retina together with its retinal pigment epithelium (RPE) to patients with retinitis pigmentosa. DESIGN Interventional case series. METHODS Sheets of fetal neural retina and RPE were transplanted together into the subretinal space near the fovea unilaterally in the eyes of five patients with retinitis pigmentosa who had only light perception in both eyes. The patients were followed for 6 months. The main outcome measures were tissue typing of both donors and recipients, fluorescein angiography, multifocal electroretinogram (mfERG) testing, and clinical examination. No immunosuppressive medications were given. RESULTS No evidence of rejection was observed. Up to 6 months there was no evidence of tissue disintegration, retinal edema, or scarring. There was no change in vision both by Snellen acuity and with mfERGs. Growth of the transplant was noted in two of five patients at 6 months vs. 2 weeks. All patients typed were HLA mismatched with donor tissue. CONCLUSIONS This study indicates that fetal retina can be transplanted together with its RPE and survive for at least 6 months without evidence of rejection. However, no improvements in vision were observed, possibly due to the severe retinal degeneration of the patients.

Pulvinar projections to the striatum and amygdala in the tree shrew.

Visually guided movement is possible in the absence of conscious visual perception, a phenomenon referred to as “blindsight.” Similarly, fearful images can elicit emotional responses in the absence of their conscious perception. Both capabilities are thought to be mediated by pathways from the retina through the superior colliculus (SC) and pulvinar nucleus. To define potential pathways that underlie behavioral responses to unperceived visual stimuli, we examined the projections from the pulvinar nucleus to the striatum and amygdala in the tree shrew (Tupaia belangeri), a species considered to be a prototypical primate. The tree shrew brain has a large pulvinar nucleus that contains two SC-recipient subdivisions; the dorsal (Pd) and central (Pc) pulvinar both receive topographic (“specific”) projections from SC, and Pd receives an additional non-topographic (“diffuse”) projection from SC (Chomsung et al., 2008). Anterograde and retrograde tract tracing revealed that both Pd and Pc project to the caudate and putamen, and Pd, but not Pc, additionally projects to the lateral amygdala. Using immunocytochemical staining for substance P (SP) and parvalbumin (PV) to reveal the patch/matrix organization of tree shrew striatum, we found that SP-rich/PV-poor patches interlock with a PV-rich/SP-poor matrix. Confocal microscopy revealed that tracer-labeled pulvino-striatal terminals preferentially innervate the matrix. Electron microscopy revealed that the postsynaptic targets of tracer-labeled pulvino-striatal and pulvino-amygdala terminals are spines, demonstrating that the pulvinar nucleus projects to the spiny output cells of the striatum matrix and the lateral amygdala, potentially relaying: (1) topographic visual information from SC to striatum to aid in guiding precise movements, and (2) non-topographic visual information from SC to the amygdala alerting the animal to potentially dangerous visual images.

Binocular interactions during establishment of McCollough effects.

In four experiments we have shown that a McCollough color aftereffect (CAE) built up through one eye may or may not be influenced by simultaneous stimulation of the other eye depending on the kinds of similarity and dissimilarity between the two views. Binocular rivalry-produced suppression is not effective per se. However, there is a specifically binocular component that contributes strength to the CAE, and true interocular transfer takes place when facilitated by homochromatic stimulation of the two eyes. The establishment of CAE strength can also be impeded under certain conditions of dichoptic viewing.

Preliminary report: indications of improved visual function after retinal sheet transplantation in retinitis pigmentosa patients

PURPOSE To report indications of new visual function after retinal transplantation in two blind patients with retinitis pigmentosa. METHODS Intact sheets of fetal retina (15 and 17 weeks gestational age) were transplanted subretinally (between the neurosensory retina and the retinal pigment epithelium) near the fovea in the left eye of a 23-year-old white man (Patient A) and in the left eye of a 72-year-old white woman (Patient B), both with autosomal-recessive retinitis pigmentosa. RESULTS Postoperatively, at 6 and 5 months, respectively, both patients reported new visual sensation in the visual field corresponding to the transplant. In both patients, the visual sensation continued to be present after transplantation, at 12 and 8 months, respectively. In Patient A, a transient multifocal electroretinography (mfERG) response was observed in the transplant area 4 months postoperatively but was not detectable in Patient A at 6.0 and 9.5 months post-retinal transplantation. In Patient B, no positive mfERG responses were seen up to 5 months postoperatively. No rejection (presenting as cystoid macular edema, macular pucker, and extensive intraretinal edema with disrupted retinal pigment epithelium) to the transplanted tissue was seen up to 13 months in Patient A and 9 months in Patient B by fluorescein angiography. CONCLUSION Transplantation of intact sheets of fetal human retina in two patients with retinitis pigmentosa was not associated with evidence of transplant rejection. Subjective improvement and an indication of objective improvement 4 months postoperatively were seen in Patient A, and subjective improvement only was seen in Patient B.

Visual pigments of the tree shrew (Tupaia belangeri) and greater galago (Galago crassicaudatus): a microspectrophotometric investigation.

Optical density, linear dichroism and bleaching difference spectra were measured in photoreceptors from the cone-dominated retina of the tree shrew (Tupaia belangeri) and from the rod-dominated retina of the greater galago (Galago crassicaudatus) using a single-beam, wavelength-scanning, dichroic microspectrophotometer. In Tupaia, we obtained spectral records from 272 cone receptors (from 10 eyes), of which 264 were long-wave sensitive (lambda max = 555 +/- 6 nm) and 8 were short-wave sensitive (lambda max = 428 +/- 15 nm). Also, one anatomically-recognizable rod receptor was encountered and showed a peak absorption at approx. 496 nm. No mid-wave sensitive cone pigment was found, as would be expected in deutan-type dichromats like the tree shrew. Pre-retinal absorption by the cornea and lens was maximal at 370 nm and negligible beyond 430 nm. In Galago, all outer segments measured were rod-like in appearance (lambda max near 501 nm). Measurements of pre-retinal absorption yielded a single-peaked function with a maximum at 363 nm.

Preliminary report: indications of improved visual function after retinal sheet transplantation in retinitis pigmentosa patients 1

PURPOSE To report indications of new visual function after retinal transplantation in two blind patients with retinitis pigmentosa. METHODS Intact sheets of fetal retina (15 and 17 weeks gestational age) were transplanted subretinally (between the neurosensory retina and the retinal pigment epithelium) near the fovea in the left eye of a 23-year-old white man (Patient A) and in the left eye of a 72-year-old white woman (Patient B), both with autosomal-recessive retinitis pigmentosa. RESULTS Postoperatively, at 6 and 5 months, respectively, both patients reported new visual sensation in the visual field corresponding to the transplant. In both patients, the visual sensation continued to be present after transplantation, at 12 and 8 months, respectively. In Patient A, a transient multifocal electroretinography (mfERG) response was observed in the transplant area 4 months postoperatively but was not detectable in Patient A at 6.0 and 9.5 months post-retinal transplantation. In Patient B, no positive mfERG responses were seen up to 5 months postoperatively. No rejection (presenting as cystoid macular edema, macular pucker, and extensive intraretinal edema with disrupted retinal pigment epithelium) to the transplanted tissue was seen up to 13 months in Patient A and 9 months in Patient B by fluorescein angiography. CONCLUSION Transplantation of intact sheets of fetal human retina in two patients with retinitis pigmentosa was not associated with evidence of transplant rejection. Subjective improvement and an indication of objective improvement 4 months postoperatively were seen in Patient A, and subjective improvement only was seen in Patient B.

Ultrastructural Examination of Diffuse and Specific Tectopulvinar Projections in the Tree Shrew

Two pathways from the superior colliculus (SC) to the tree shrew pulvinar nucleus have been described, one in which the axons terminate in dense (or specific) patches and one in which the axon arbors are more diffusely organized (Luppino et al. [1988] J. Comp. Neurol. 273:67–86). As predicted by Lyon et al. ([2003] J. Comp. Neurol. 467:593–606), we found that anterograde labeling of the diffuse tectopulvinar pathway terminated in the acetylcholinesterase (AChE)‐rich dorsal pulvinar (Pd), whereas the specific pathway terminated in the AChE‐poor central pulvinar (Pc). Injections of retrograde tracers in Pd labeled non‐γ‐aminobutyric acid (GABA)‐ergic wide‐field vertical cells located in the lower stratum griseum superficiale and stratum opticum of the medial SC, whereas injections in Pc labeled similar cells in more lateral regions. At the ultrastructural level, we found that tectopulvinar terminals in both Pd and Pc contact primarily non‐GABAergic dendrites. When present, however, synaptic contacts on GABAergic profiles were observed more frequently in Pc (31% of all contacts) compared with Pd (16%). Terminals stained for the type 2 vesicular glutamate transporter, a potential marker of tectopulvinar terminals, also contacted more GABAergic profiles in Pc (19%) compared with Pd (4%). These results provide strong evidence for the division of the tree shrew pulvinar into two distinct tectorecipient zones. The potential functions of these pathways are discussed. J. Comp. Neurol. 510:24–46, 2008.

Immunocytochemical identification of photoreceptor populations in the tree shrew retina

The presence and retinal distributions of short-wavelength-sensitive cones, long-wavelength-sensitive cones, and rods were assessed in the retina of the tree shrew Tupaia belangeri using visual pigment antibodies OS-2, COS-1 and anti-rhodopsin, respectively. Results demonstrated a clear immunocytochemical differentiation of the three photoreceptor types with each showing regional variation in density across the retina.

Retinal projections in the ground squirrel ( Citellus tridecemlineatus)

The retinal projections of the thirteen-lined ground squirrel were determined by tracing anterograde transport of intravitreally injected horseradish peroxidase (HRP) or wheat-germ conjugated horseradish peroxidase (WGA-HRP). Label was seen in the suprachiasmatic nucleus and adjacent anterior hypothalamic area, the accessory optic system (the medial, dorsal, and lateral terminal nuclei), the dorsal and ventral lateral geniculate nuclei, the intergeniculate leaflet, the pretectal nuclei (the anterior, posterior, and olivary pretectal nuclei and the nucleus of optic tract), and the superior colliculus. Most of these structures were labeled bilaterally, with dense contralateral label and sparse ipsilateral label, a pattern typical for animals with laterally placed eyes. However, the suprachiasmatic nucleus and the nucleus of the optic tract received input only from the contralateral eye. In contrast to previous degeneration studies, the sensitive HRP tracers (in conjunction with cytochrome-oxidase reactivity) revealed an elaborate organization within the lateral geniculate nucleus (dorsal LGN, ventral LGN, and intergeniculate leaflet) that is consistent with existing organizational schemes for other mammalian species.