Understanding and reprogramming developmental visual disorders: from anophthalmia to cortical impairments

A large part of mammalian behavior depends on visual perception and thus on the establishment of appropriate afferent and efferent connections among the different CNS regions that together form the visual system.  The visual system is primarily composed of three structures: the eye (with its neural component, the retina), the thalamus and the visual cortex, which are precisely connected: the retina is wired to the thalamic lateral geniculate nucleus (LGN) by the axons of the retinal ganglion cells, which extend along the optic nerve, chiasm and tract (proximal visual pathway). The LGN neurons, in turn, project to the primary visual cortex, forming the optic radiation (secondary pathway). The primary visual cortex projects back to the LGN and forms extensive circuits with other cortical areas, sustaining the coordination between visual perception and other behaviors. The resulting integrative network provides optimal computing for responding to the external visual information that surrounds us. Failure in specification of the brain regions involved in receiving or processing this information as well as alterations in their connectivity lead to neurodevelopmental visual disorders (NDVD), which are largely incurable. The poor therapeutic success is, at least in part, associated with their most common origin: the impairment of gene function during embryonic development. Symptoms, and thus diagnosis, however manifest after birth or in childhood/adolescence, when the brain has already reached a consolidated organization, making therapeutic approaches so far unfeasible. NDVD are rare diseases with a frequency of about 2.4 per 10,000 newborns but are impairing to the point that they often perturb the general development of affected infants. They have heterogeneous genetic origins that nevertheless often lead to common morphological features, such as reduction in neuronal numbers, heterotopias, defects in neuronal branching and connectivity, as well as to strong neurological defects that may include, besides poor or absent vision, epilepsy, intellectual deficits, or abnormal social behavior, a commonality to other rare diseases with neurodevelopmental origin. Thus, NDVD represent an important but poorly studied and unresolved societal burden. 

There are two classes of NDVD, classified according to their primary anatomical origin. The first class includes disorders that affect the anterior visual pathway. Prominent examples are severe malformations of the eye leading to partial or total loss of vision, known as microphthalmia, anophthalmia and coloboma (MAC). In many instances, genetic analyses of MAC have identified heterozygous mutations in genes fundamental for nervous system development but that result in restricted disease phenotypes. The second class of NDVD, collectively termed cerebral visual impairment (CVI), is composed of heterogeneous (restricted/mild to widespread/severe) conditions affecting the posterior visual pathway, in the absence of anterior defects. Inheritable congenital prosopagnosia (the inability to recognize familiar faces) is an example of a mild CVI, whereas severe forms show developmental delays and/or intellectual disabilities. Unfortunately, beyond the identification of a few genetic causes and a partial description of the related phenotypes, we are far from understanding how a defect in any one of the visual structures impacts on the remaining visual territories and on the brain as a whole. It is also unclear how the brain adapts to these defects and how we can make use of this plasticity. A limitation for finding answers to these problems is the availability of suitable animal models. 

In the latter years, coordinated European-funded research has begun to fill this gap identifying new potential gene candidates to explain NDVD and designing new animal models that allow to study the above questions, providing information on overall brain reorganization after genetic alterations in specific brain region. This research has also fostered studies in human samples and opened avenues to therapeutic approaches through in vitro and in vivo cell reprogramming. The proposed workshop is designed to be a forum for discussing recent progress on NDVD and to draw the attention of the society to this class of neglected rare diseases. The workshop will navigate around two of the fundamental columns supporting the formation of visual circuits: 1) the existence of conserved modules of genetic networks that instruct the specification of the different visual territories and the coordinated assembly of their circuits; 2) the possibility of brain repair through the latest advancements in in vivo lineage reprogramming that may allow to replace defective or even missing circuitry components and boost neural plasticity, to possibly finally treat NDVD in the future. Leaders in different fields of neurobiology will provide a comprehensive view of the current state-of-the-art covering aspects such as mouse models of NDVD, molecular specification of visual networks, system biology defining neuronal models, electrophysiological assessment, and cell reprogramming, with particular attention to translational aspects. The goal is to generate fruitful forum of discussion on the full consequences that a genetic defect in one visual structure has on the rest of the connected CNS areas and on how to correct the impaired circuits and the lost functions. 

In a broader perspective, this workshop should attract the attention of individuals interested in the understanding and managing other rare neurodevelopmental diseases, given that NDVD represent just one of the many examples of how defects in the assembly of human brain circuits during embryonic/childhood development has devastating consequences in the affected individuals. We thus believe that the proposed workshop should attract the attention of different researchers and stockholders, hopefully increasing society awareness on a set of poorly understood congenital rare diseases, bringing this important discussion closer to our national communities. Most importantly, this workshop intends to contribute to the setting of novel grounds of interactions and knowledge to improve the prognosis and treatment of patients with rare diseases.