Human Cone Research Articles

ATF6 is essential for human cone photoreceptor development

Endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) signaling promote the pathology of many human diseases. Loss-of-function variants of the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital vision loss diseases such as achromatopsia by unclear pathomechanisms. To investigate this, we generated retinal organoids from achromatopsia patient induced pluripotent stem cells carrying ATF6 disease variants and from gene-edited ATF6 null hESCs. We found that achromatopsia patient and ATF6 null retinal organoids failed to form cone structures concomitant with loss of cone phototransduction gene expression, while rod photoreceptors developed normally. Adaptive optics retinal imaging of achromatopsia patients carrying ATF6 variants also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the defect in cone formation observed in our retinal organoids. These results establish that ATF6 is essential for human cone development. Interestingly, we find that a selective small molecule ATF6 signaling agonist restores the transcriptional activity of some ATF6 disease-causing variants and stimulates cone growth and gene expression in patient retinal organoids carrying these variants. These findings support that pharmacologic targeting of the ATF6 pathway can promote human cone development and should be further explored for blinding retinal diseases.

Toward Sustainable, Colorless, and Transparent Photovoltaics: State of the Art and Perspectives for the Development of Selective Near‐Infrared Dye‐Sensitized Solar Cells

AbstractDye‐sensitized solar cell (DSSC) is one of the promising photovoltaic (PV) technologies for applications requiring high aesthetic features combined with energy production such as building integration PV (BIPV). In this context, DSSCs have the ability to be wavelength selective, thanks to the development of new sensitizers by molecular engineering. The long history of dye research has afforded is technology different colorations for reaching panchromatic light absorption. However, nearly 45% of radiation from sunlight lies in the near‐infrared (NIR) region, where human cones are not sensitive. This review provides the reader with key information on how to selectively exploit this region to develop colorless and transparent PV based on DSSC technology. Besides selective NIR absorbers, the triptych photoanode, counter‐electrode, and redox mediator are together contributing to reach high aesthetic features. Details of all the components, interplay, and an opinion on the technological limitations to reach colorless and transparent NIR‐DSSC are herein discussed in relationship with BIPV applications.

Cone photoreceptor reflectance variation in the northern tree shrew and thirteen-lined ground squirrel.

In vivo images of human cone photoreceptors have been shown to vary in their reflectance both spatially and temporally. While it is generally accepted that the unique anatomy and physiology of the photoreceptors themselves drives this behavior, the exact mechanisms have not been fully elucidated as most studies on these phenomena have been limited to the human retina. Unlike humans, animal models offer the ability to experimentally manipulate the retina and perform direct in vivo and ex vivo comparisons. The thirteen-lined ground squirrel and northern tree shrew are two emerging animal models being used in vision research. Both models feature cone-dominant retinas, overcoming a key limitation of traditional rodent models. Additionally, each possesses unique but well-documented anatomical differences in cone structure compared to human cones, which can be leveraged to further constrain theoretical models of light propagation within photoreceptors. Here we sought to characterize the spatial and temporal reflectance behavior of cones in these species. Adaptive optics scanning light ophthalmoscopy (AOSLO) was used to non-invasively image the photoreceptors of both species at 5 to 10 min intervals over the span of 18 to 25 min. The reflectance of individual cone photoreceptors was measured over time, and images at individual time points were used to assess the variability of cone reflectance across the cone mosaic. Variability in spatial and temporal photoreceptor reflectance was observed in both species, with similar behavior to that seen in human AOSLO images. Despite the unique cone structure in these animals, these data suggest a common origin of photoreceptor reflectance behavior across species. Such data may help constrain models of the cellular origins of photoreceptor reflectance signals. These animal models provide an experimental platform to further explore the morphological origins of light capture and propagation.

Emulated retinal image capture (ERICA) to test, train and validate processing of retinal images

High resolution retinal imaging systems, such as adaptive optics scanning laser ophthalmoscopes (AOSLO), are increasingly being used for clinical research and fundamental studies in neuroscience. These systems offer unprecedented spatial and temporal resolution of retinal structures in vivo. However, a major challenge is the development of robust and automated methods for processing and analysing these images. We present ERICA (Emulated Retinal Image CApture), a simulation tool that generates realistic synthetic images of the human cone mosaic, mimicking images that would be captured by an AOSLO, with specified image quality and with corresponding ground-truth data. The simulation includes a self-organising mosaic of photoreceptors, the eye movements an observer might make during image capture, and data capture through a real system incorporating diffraction, residual optical aberrations and noise. The retinal photoreceptor mosaics generated by ERICA have a similar packing geometry to human retina, as determined by expert labelling of AOSLO images of real eyes. In the current implementation ERICA outputs convincingly realistic en face images of the cone photoreceptor mosaic but extensions to other imaging modalities and structures are also discussed. These images and associated ground-truth data can be used to develop, test and validate image processing and analysis algorithms or to train and validate machine learning approaches. The use of synthetic images has the advantage that neither access to an imaging system, nor to human participants is necessary for development.

Restoration of visual function in advanced disease after transplantation of purified human pluripotent stem cell-derived cone photoreceptors.

SummaryAge-related macular degeneration and other macular diseases result in the loss of light-sensing cone photoreceptors, causing irreversible sight impairment. Photoreceptor replacement may restore vision by transplanting healthy cells, which must form new synaptic connections with the recipient retina. Despite recent advances, convincing evidence of functional connectivity arising from transplanted human cone photoreceptors in advanced retinal degeneration is lacking. Here, we show restoration of visual function after transplantation of purified human pluripotent stem cell-derived cones into a mouse model of advanced degeneration. Transplanted human cones elaborate nascent outer segments and make putative synapses with recipient murine bipolar cells (BCs), which themselves undergo significant remodeling. Electrophysiological and behavioral assessments demonstrate restoration of surprisingly complex light-evoked retinal ganglion cell responses and improved light-evoked behaviors in treated animals. Stringent controls exclude alternative explanations, including material transfer and neuroprotection. These data provide crucial validation for photoreceptor replacement therapy and for the potential to rescue cone-mediated vision.

AAV Induced Expression of Human Rod and Cone Opsin in Bipolar Cells of a Mouse Model of Retinal Degeneration

Vision loss caused by inherited retinal degeneration affects millions of people worldwide, and clinical trials involving gene supplementation strategies are ongoing for select forms of the disease. When early therapeutic intervention is not possible and patients suffer complete loss of their photoreceptor cells, there is an opportunity for vision restoration techniques, including optogenetic therapy. This therapy provides expression of light-sensitive molecules to surviving cell types of the retina, enabling light perception through residual neuronal pathways. To this end, the bipolar cells make an obvious optogenetic target to enable upstream processing of visual signal in the retina. However, while AAV transduction of the bipolar cells has been described, the expression of human opsins in these cell types within a model of retinal degeneration (rd1) has been less successful. In this study, we have expanded the optogenetic toolkit and shown successful expression of human rhodopsin driven by an ON-bipolar cell promoter (Grm6) in the rd1 mouse model using modified AAV capsids (AAV2.4YF, AAV8.BP2, and AAV2.7m8) delivered via intraocular injection. We also show the first presentation of ectopic expression of human cone opsin in the bipolar cells of rd1 mice. These data provide evidence of an expansion of the optogenetic toolkit with the potential to restore useful visual function, setting the stage for future trials in human patients.

Zebrafish Models of Photoreceptor Dysfunction and Degeneration.

Zebrafish are an instrumental system for the generation of photoreceptor degeneration models, which can be utilized to determine underlying causes of photoreceptor dysfunction and death, and for the analysis of potential therapeutic compounds, as well as the characterization of regenerative responses. We review the wealth of information from existing zebrafish models of photoreceptor disease, specifically as they relate to currently accepted taxonomic classes of human rod and cone disease. We also highlight that rich, detailed information can be derived from studying photoreceptor development, structure, and function, including behavioural assessments and in vivo imaging of zebrafish. Zebrafish models are available for a diversity of photoreceptor diseases, including cone dystrophies, which are challenging to recapitulate in nocturnal mammalian systems. Newly discovered models of photoreceptor disease and drusenoid deposit formation may not only provide important insights into pathogenesis of disease, but also potential therapeutic approaches. Zebrafish have already shown their use in providing pre-clinical data prior to testing genetic therapies in clinical trials, such as antisense oligonucleotide therapy for Usher syndrome.

Single-cell RNA sequencing in vision research: Insights into human retinal health and disease.

Gene expression provides valuable insight into cell function. As such, vision researchers have frequently employed gene expression studies to better understand retinal physiology and disease. With the advent of single-cell RNA sequencing, expression experiments provide an unparalleled resolution of information. Instead of studying aggregated gene expression across all cells in a heterogenous tissue, single-cell technology maps RNA to an individual cell, which facilitates grouping of retinal and choroidal cell types for further study. Single-cell RNA sequencing has been quickly adopted by both basic and translational vision researchers, and single-cell level gene expression has been studied in the visual systems of animal models, retinal organoids, and primary human retina, RPE, and choroid. These experiments have generated detailed atlases of gene expression and identified new retinal cell types. Likewise, single-cell RNA sequencing investigations have characterized how gene expression changes in the setting of many retinal diseases, including how choroidal endothelial cells are altered in age-related macular degeneration. In addition, this technology has allowed vision researchers to discover drivers of retinal development and model rare retinal diseases with induced pluripotent stem cells. In this review, we will overview the growing number of single-cell RNA sequencing studies in the field of vision research. We will summarize experimental considerations for designing single-cell RNA sequencing experiments and highlight important advancements in retinal, RPE, choroidal, and retinal organoid biology driven by this technology. Finally, we generalize these findings to genes involved in retinal degeneration and outline the future of single-cell expression experiments in studying retinal disease.

Optoretinography of individual human cone photoreceptors.

Photoreceptors mediate the first step of vision, transducing light and passing signals to retinal neurons that ultimately send signals along the optic nerve to the brain. A functional deficiency in the photoreceptors, due to either congenital or acquired disease, can significantly affect an individual's sight and quality of life. Methods for quantifying the health and function of photoreceptors are essential for understanding both the progression of disease and the efficacy of treatment. Given that emerging treatments such as gene, stem cell, and small molecule therapy are designed to operate at the cellular scale, it is desirable to monitor function at the commensurate resolution of individual photoreceptors. Previously, non-invasive imaging methods for visualizing photoreceptor mosaic structure have been used to infer photoreceptor health, but these methods do not assess function directly. Conversely, most functional techniques, such as ERG and conventional microperimetry, measure function by aggregating the effects of signals from many photoreceptors. We have previously shown that stimulus-evoked intrinsic changes in intensity can be measured reliably in populations of cone photoreceptors in the intact human eye, a measurement we refer to more generally as the cone optoretinogram. Here we report that we can resolve the intensity optoretinogram at the level of individual cones. Moreover, we show that the individual cone optoretinogram exhibits two key signatures expected of a functional measure. First, responses in individual cones increase systematically as a function of stimulus irradiance. Second, we can use the amplitude of the functional response to middle wavelength (545 nm) light to separate the population of short-wavelength-sensitive (S) cones from the population of middle- and long-wavelength-sensitive (L and M) cones. Our results demonstrate the promise of optoretinography as a direct diagnostic measure of individual cone function in the living human eye.

Proteostasis Modulation Prevents Photoreceptor Pathology in Retinal Organoids

Dysregulation of the endoplasmic reticulum (ER) Unfolded Protein Response (UPR) is implicated in the pathology of many human diseases associated with ER stress. Inactivating genetic variants in the UPR regulator Activating Transcription Factor 6 (ATF6) cause severe congenital heritable vision loss in patients by an unknown pathomechanism. To investigate this, we generated retinal organoids from patient iPSCs carrying ATF6 disease-causing variants and ATF6 null hESCs generated by CRISPR. Interestingly, we found that cone photoreceptor cells in ATF6 mutant retinal organoids lacked inner and outer segments concomitant with absence of cone phototransduction gene expression; while rod photoreceptors developed normally. Adaptive optics retinal imaging of patients with disease-causing variants in ATF6 also showed absence of cone inner/outer segment structures but preserved rod structures, mirroring the phenotypes observed in our retinal organoids. These results reveal that ATF6 is essential for the formation of human cone photoreceptors, and associated absence of cone phototransduction components explains the severe visual impairment in patients with ATF6 -associated retinopathy. Moreover, we show that a selective small molecule ATF6 activator compound restores the transcriptional activity of ATF6 disease-causing variants and stimulates the growth of cone photoreceptors in patient retinal organoids, demonstrating that pharmacologic targeting of ATF6 signaling is a therapeutic strategy that needs to be further explored for blinding retinal diseases.

The Spatial Frequency Content of Urban and Indoor Environments as a Potential Risk Factor for Myopia Development.

PurposeTo examine the hypothesis that the spatial frequency spectra of urban and indoor environments differ from the natural environment in ways that may promote the development of myopia.MethodsA total of 814 images were analyzed from three datasets; University of California Berkeley (UCB), University of Texas (UT), and Botswana (UPenn). Images were processed in Matlab (Mathworks Inc) to map the camera color characteristics to human cone sensitivities. From the photopic luminance images generated, two-dimensional spatial frequency (SF) spectra were calculated and converted to one-dimensional spectra by rotational averaging. The spatial filtering profile of a 0.4 Bangerter foil, which has been shown to induce myopia experimentally, was also determined.ResultsThe SF slope for natural scenes followed the recognized 1/fα relationship with mean slopes of −1.08, −0.90, and −1.04 for the UCB, UT and UPenn image sets, respectively. Indoor scenes had a significantly steeper slope (−1.48, UCB; −1.52, UT; P < 0.0001). Urban environments showed an intermediate slope (−1.29, UCB; −1.22, UT) that was significantly different from the slopes derived from the natural scenes (P < 0.0001). The change in SF content between natural outdoor scenes and indoors was comparable to that induced by a 0.4 Bangerter foil, which reduced the SF slope of a natural scene from −0.88 to −1.47.ConclusionsCompared to natural outdoor images, man-made outdoor and indoor environments have spatial frequency characteristics similar to those known to induce form-deprivation myopia in animal models. The spatial properties of the man-made environment may be one of the missing drivers of the human myopia epidemic.

The optoretinogram reveals the primary steps of phototransduction in the living human eye.

Photoreceptors initiate vision by converting photons to electrical activity. The onset of the phototransduction cascade is marked by the isomerization of photopigments upon light capture. We revealed that the onset of phototransduction is accompanied by a rapid (<5 ms), nanometer-scale electromechanical deformation in individual human cone photoreceptors. Characterizing this biophysical phenomenon associated with phototransduction in vivo was enabled by high-speed phase-resolved optical coherence tomography in a line-field configuration that allowed sufficient spatiotemporal resolution to visualize the nanometer/millisecond-scale light-induced shape change in photoreceptors. The deformation was explained as the optical manifestation of electrical activity, caused due to rapid charge displacement following isomerization, resulting in changes of electrical potential and surface tension within the photoreceptor disc membranes. These all-optical recordings of light-induced activity in the human retina constitute an optoretinogram and hold remarkable potential to reveal the biophysical correlates of neural activity in health and disease.

Optoretinogram: optical measurement of human cone and rod photoreceptor responses to light.

Noninvasive, objective measurement of rod function is as significant as that of cone function, and for retinal diseases such as retinitis pigmentosa and age-related macular degeneration, rod function may be a more sensitive biomarker of disease progression and efficacy of treatment than cone function. Functional imaging of single human rod photoreceptors, however, has proven difficult because their small size and rapid functional response pose challenges for the resolution and speed of the imaging system. Here, we describe light-evoked, functional responses of human rods and cones, measured noninvasively using a synchronized adaptive optics optical coherence tomography (OCT) and scanning light ophthalmoscopy (SLO) system. The higher lateral resolution of the SLO images made it possible to confirm the identity of rods in the corresponding OCT volumes.

Saliency-based image correction for colorblind patients

Improper functioning, or lack, of human cone cells leads to vision defects, making it impossible for affected persons to distinguish certain colors. Colorblind persons have color perception, but their ability to capture color information differs from that of normal people: colorblind and normal people perceive the same image differently. It is necessary to devise solutions to help persons with color blindness understand images and distinguish different colors. Most research on this subject is aimed at adjusting insensitive colors, enabling colorblind persons to better capture color information, but ignores the attention paid by colorblind persons to the salient areas of images. The areas of the image seen as salient by normal people generally differ from those seen by the colorblind. To provide the same saliency for colorblind persons and normal people, we propose a saliency-based image correction algorithm for color blindness. Adjusted colors in the adjusted image are harmonious and realistic, and the method is practical. Our experimental results show that this method effectively improves images, enabling the colorblind to see the same salient areas as normal people.

Extra Visual Function of the Human Eye.

Abstract The eye is part of the sensory nervous system. However, there are a number of organ systems that also work with the eye. The retina is the only tissue in mammals that regulates photoreception due to the presence of photoreceptors, the rods and cones and performs both visual and non-visual functions Light plays a fundamental role in the behavior of almost all organisms. In addition to visual processes, light also induces important physiological responses. People with mild vascular disease that causes damage to the retina in the eye are more likely to have problems with thinking and memory skills. Everyone has a natural body clock that they are born with and all organs in the body operate according to biological rhythms. Our experiments with ophthalmic mutant rats also showed that the loss of vision also hampered their physiological activities and their rhythmicity was also disturbed. The menstrual cycle disturbances and age of menarche are regulated by many factors; nevertheless, blindness is one of the most impotent factors in regulating biological clock dependent functions. The human eyes are the only organs in the body capable of “seeing”- wavelengths of light and turning it into visual images. We can't “see” or get a visual image to the brain without eyes. The eye-like ability of skin to sense light by using a receptor (Cryptochrome) but failed to form image. Photoreceptors contain chemicals that change when they are hit by light. This causes an electrical signal, which is then sent to the brain along the optic nerve. Different types of photoreceptor allow us to see an enormous range of light and colours. There are two types of photoreceptors in the human retina, rods and cones. Rods are responsible for vision at low light levels (scotopic vision). They do not mediate colour vision and have a low spatial acuity. The blind: People who have lost their sight have different experiences. Some describe seeing complete darkness, like being in a cave. Some people see sparks or experience vivid visual hallucinations that may take the form of recognizable shapes, random shapes and colours, or flashes of light. An afterimage is an image that continues to appear in the eyes after a period of exposure to the original image. Afterimages occur because photochemical activity in the retina continues even when the eyes are no longer experiencing the original stimulus.

Dry Skulls and Cone Beam Computed Tomography (CBCT) for Teaching Orofacial Bone Anatomy to Undergraduate Dental Students.

Learning bone anatomy of the skull is a complex topic involving three-dimensional information. The impact of the use of human dry skulls and cone beam computed tomography (CBCT) imaging was investigated in the teaching of undergraduate dental students. Sixty-four first-year students in the University of Hong Kong were randomly divided into eight groups. Four teaching methods were tested: (1) CBCT followed by standard lecture, (2) CBCT followed by lecture with skulls, (3) standard lecture followed by CBCT, and (4) lecture with skulls followed by CBCT. After each, students were given a multiple-choice questionnaire to assess their objective learning outcome (20 questions) and a questionnaire for their subjective satisfaction (10 statements). Surveys were assessed with Cronbach's alpha, Kendall's tau-b, and principal components analysis. Data were analyzed with Student's t-test and a one-way ANOVA (significance α=0.05). Standard lecture followed by CBCT showed the highest learning outcome score (81.6%±14.1%), but no significant difference was present among four teaching methods. Cone beam computed tomography followed by lecture with skulls scored the highest overall subjective satisfaction (4.9±0.8 out of 6), but no significant difference was present among teaching methods. Nevertheless, students' perception of learning was positively influenced by the use of skulls (P=0.018). The timing of administration of the CBCT did not affect students' subjective satisfaction or objective learning outcome. Students perceived to learn more by using skulls, but their objective learning outcomes were not significantly affected. A discrepancy seems to exist between students' perception of learning and their effective performance.

SPATIALLY INFORMED CNN FOR AUTOMATED CONE DETECTION IN ADAPTIVE OPTICS RETINAL IMAGES.

Adaptive optics (AO) scanning laser ophthalmoscopy offers cellular level in-vivo imaging of the human cone mosaic. Existing analysis of cone photoreceptor density in AO images require accurate identification of cone cells, which is a time and labor-intensive task. Recently, several methods have been introduced for automated cone detection in AO retinal images using convolutional neural networks (CNN). However, these approaches have been limited in their ability to correctly identify cones when applied to AO images originating from different locations in the retina, due to changes to the reflectance and arrangement of the cone mosaics with eccentricity. To address these limitations, we present an adapted CNN architecture that incorporates spatial information directly into the network. Our approach, inspired by conditional generative adversarial networks, embeds the retina location from which each AO image was acquired as part of the training. Using manual cone identification as ground truth, our evaluation shows general improvement over existing approaches when detecting cones in the middle and periphery regions of the retina, but decreased performance near the fovea.

Resolving Membrane Protein-Protein Interactions in Live Cells with Pulsed Interleaved Excitation Fluorescence Cross-Correlation Spectroscopy.

The cell plasma membrane (PM) contains thousands of proteins that sense and respond to the outside environment. These proteins have evolved sensitivity to a wide variety of physical and chemical signals and act as a delivery system across the PM. Membrane proteins are critical for information flow and decision making in the cell and thus are important targets in drug development. A critical aspect of membrane protein function is the way they interact with other proteins, often through the formation of dimers or small oligomers that regulate function at the protein, cell, and organism levels. Resolving membrane protein interactions in a live cell environment is challenging because of the chemical diversity and spatial heterogeneity of the PM. In this Account, we describe a fluorescence technique called pulsed interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS) that is ideally suited to quantify membrane associations in live cells. PIE-FCCS is a two-color fluorescence fluctuation method that can simultaneously measure the concentration, mobility, proximity, and oligomerization state of membrane proteins in situ. It has several advantages over two related approaches, single-molecule tracking (SMT) and Förster resonance energy transfer (FRET), including that it measures all of the properties listed above in a single measurement. Another advantage is that PIE-FCCS is most sensitive at the physiological expression levels for many membrane proteins rather than the very low or high levels typical in other techniques. Here, we review the history of FCCS as it has been applied to study membrane protein interactions in cells. We also describe PIE-FCCS and the advantages it has over biochemical approaches like coimmunoprecipitation (co-IP) and proximity ligation assays (PLA). Finally, we review two classes of membrane proteins that have been studied with FCCS and PIE-FCCS: receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCRs). For RTKs, ligand induced dimerization directly regulates the catalytic activity of the kinase, but higher order oligomerization and ligand-independent dimerization can complicate this historically simple paradigm. PIE-FCCS data have resolved a low population of EGFR dimers under basal conditions and assembly into multimers when stimulated with ligand. While GPCRs function primarily as monomers, dimerization has been hypothesized to regulate function for some receptors. PIE-FCCS data have established the dimerization potential of rhodopsin at low densities and were critical for the discovery of a novel dimerization interface in human cone opsins. This Account describes the how FCCS and PIE-FCCS can reveal the details of quaternary interactions in each of these receptor systems.

Empowering Retinal Gene Therapy with a Specific Promoter for Human Rod and Cone ON-Bipolar Cells

Optogenetic gene therapy holds promise to restore high-quality vision in blind patients and recently reached clinical trials. Although the ON-bipolar cells, the first retinal interneurons, make the most attractive targets for optogenetic vision restoration, they have remained inaccessible to human gene therapy due to the lack of a robust cell-specific promoter. We describe the design and functional evaluation of 770En_454P(hGRM6), a human GRM6 gene-derived, short promoter that drives strong and highly specific expression in both the rod- and cone-type ON-bipolar cells of the human retina. Expression also in cone-type ON-bipolar cells is of importance, since the cone-dominated macula mediates high-acuity vision and is the primary target of gene therapies. 770En_454P(hGRM6)-driven middle-wave opsin expression in ON-bipolar cells achieved lasting restoration of high visual acuity in the rd1 mouse model of late retinal degeneration. The new promoter enables precise manipulation of the inner retinal network and paves the way for clinical application of gene therapies for high-resolution optogenetic vision restoration, raising hopes of significantly improving the life quality of people suffering from blindness.

Blue-noise sampling for human retinal cone spatial distribution modeling

This paper proposes a novel method for modeling retinal cone distribution in humans. It is based on Blue-noise sampling algorithms being strongly related with the mosaic sampling performed by cone photoreceptors in the human retina. Here we present the method together with a series of examples of various real retinal patches. The same samples have also been created with alternative algorithms and compared with plots of the center of the inner segments of cone photoreceptors from imaged retinas. Results are evaluated with different distance measure used in the field, like nearest-neighbor analysis and pair correlation function. The proposed method can effectively describe features of a human retinal cone distribution by allowing to create samples similar to the available data. For this reason, we believe that the proposed algorithm may be a promising solution when modeling local patches of retina.