Author: mbanach-orlowska@ichf.edu.pl

This disease manifests itself in the cloudy lens, less sharp vision and severely affects life quality causing among others difficulties in reading. Cataract which can lead to complete loss of vision more frequently affects individuals over the age of 60. However, the number of younger patients is also pessimistic.

The International Centre for Translational Eye Research, ICTER conducts intense research in a field of eye diseases. Among them there is cataracts, which according to the recent WHO report (World report on vision; https://www.who.int/news-room/fact-sheets/detail/blindness-and-visual-impairment, published in 2019) affects 65.2 million people globally. In #Poland, the number of patients is also alarmingly high – exceeding 800,000. In 2019 only there were more than 300,000 cataract removal surgeries.

Cataract can be categorized by its age-at-onset: congenital (or infantile) developed within the first year of life; juvenile within the first decade of life; presenile before the age of 45 years; and senile (or age-related) thereafter.

The factors predisposing to cataract pathogenesis include: age, heavy alcohol use, smoking, obesity, high blood pressure, previous eye injuries a family history of cataracts, extensive exposure to UV (sun), diabetes, and to radiation from X-rays and cancer treatments.

In addition to environmental or life-style related factors, there are numerous mutations found to be connected with cataract pathogenesis. In approximately 10% of mapped loci there were no causative gene identified. About 50% are mutations in genes encoding lens crystallins, 10% in transcription factors, 15% in connexins, 5% each in intermediate filaments or aquaporin 0, and 10% in a variety of other genes [doi: 10.1111/cge.12182]. Inheritance of particular mutation in different families or even within the same family can lead to radically different cataract phenotype (morphologies and severities), which indicates that additional genetic or environmental factors might be involved in progression of disease [doi: 10.1111/cge.12182].

The only effective treatment for cataract is surgery. In most cases it is recommended when disease begins to affect quality of life or interfere with an ability to perform normal daily activities. As in every diseases, regular medical controls and self-discipline of patients are crucial in proper management of treatment including timing of cataract surgery.

We believe that the results of the everyday work of scientists in ICTER will help many people around the world. Thanks to the interdisciplinary character of our team we do our best to construct new diagnostic tools, modern surgical instruments, search for new pharmacological and gene therapies, discover connections between cells of the visual tract and finally search for unknown molecular mechanisms of pathogenesis.

*Among people suffering from cataract there were many famous individuals including French painter and founder of impressionist painting, Claude Monet (1840–1926;) or living in our time John Goodman, an Academy Award winning actor.

Author of the text: dr Magdalena Banach-Orłowska, Coordinator of the Computational Genomics Group.

February 4th is World Cancer Day. It gives an opportunity to improve public awareness of this serious and difficult-to-treat disease affecting millions of people around the world.

Cancer is the general name for a group of malignant neoplasms originating from epithelial tissue, although it is commonly used to refer to all malignant tumors that develop in different parts of the body.

As a scientific unit, ICTER (International Centre for Translational Eye Research) has a special interest in malignant neoplasms that develop within the ocular organ. The most common include melanoma, lymphoma, squamous cell carcinoma, and retinoblastoma which affects children.

Melanoma of the eye, as well as the more common melanoma that develops on the skin, originate from melanocytes (pigment cells) which divide rapidly in an uncontrolled manner-. Ocular melanomas are located in various areas of the eyeball and also on the eyelids.

Predisposing factors include light color of the eyes and skin, presence of irregularly shaped nevi on the skin, abuse of sunbathing (including tanning beds), and age (over 50). Research on genetic determinants of uveal melanoma (UM) – one of the eye melanomas performed by many teams identified a number of genes which lead to the development of the tumor when mutated. Among them are: GNAQ, GNA11, PLCB4,CYSLTR2, BAP1, SF3B1, EIF1AX and recently identified MBD4, which encode proteins  involved in many biological processes. Eye melanoma diagnosed at early stages of growth can be successfully treated. In contrast, metastasis from the primary tumor to other parts of the body, which is observed in about half of patients, leads to death in 20-30% of cases within 5 years and in as many as 45% within 15 years of diagnosis. Metastasis is the greatest challenge in the treatment of cancers not only of the organ of vision.

To treat melanoma, doctors use radiation therapy, laser treatments and surgery to remove the cancer while preserving the eye. There are also reported cases giving hope for success in the treatment of UM with  PD1 inhibitors – compounds used in a promising and relatively new therapy  targeting programmed cell death control point. In addition to this therapy, other solutions are being tested in various stages of clinical trials. Apart from immunotherapy, potential drugs are being tested for so-called targeted therapy (targeting e.g. a specific enzyme acting in a cell), epigenetic therapy (targeting DNA modifying proteins), or liver-specific treatment, since it is the main organ where eye melanoma metastases develop. The search for effective drugs continues unabated, many studies have failed, many are still hopeful and others are in the early stages and recruiting volunteers is ongoing.

The same is true for the less common intraocular lymphoma of the eye. Primary intraocular lymphoma is a “variant” of central nervous system lymphoma, whereas secondary ocular lymphoma develops outside the nervous system and occupies the eye through metastasis. The etiology of primary lymphoma is still mysterious. The development of the neoplasm inside the eye is thought to follow the “luring” of appropriate cells circulating in the choroid to the retinal pigment epithelium by chemoattractant such as B-lymphocyte chemoattractant (BLC) or stromal cell-derived factor-1 (SDF-1) present in the choroid. Most primary lymphomas of the eye arise from B-lymphocytes and only a few arise from T-lymphocytes. According to another theory – proposed for patients with compromised immune systems, e.g., AIDS – infectious agents such as Epstein-Barr virus (EPV) cause uncontrolled proliferation of B lymphocytes in the absence of suppressor T lymphocytes.

Many methods are used in imaging lymphoma, or retinoblastoma (described below), including the optical coherence tomography (OCT) – a method developed by the founder of ICTER.

The treatment of lymphoma includes both local solutions – injection of the eye with drugs (Methotrexate, Rituximab), radiation therapy or vitrectomy (surgery performed in the back of the eyeball, on the vitreous body and retina) and systemic solutions. Currently, single-drug chemotherapy and a combination version, where the patient receives mix of different drugs, are used. It is becoming common to combine chemotherapy with radiation. Despite the fact that several medications are approved in the clinic, new ones – more effective and safer – are still being developed.

Another example of eye cancer is retinoblastoma. Patients are young children under the age of 5 who develop cancer in the retina of one or both eyes. Early diagnosis and proper treatment give a chance for full recovery. It is estimated that 40% of cases are caused by genetic factors – inherited or acquired due to somatic mutations. Among genes, mutated in retinoblastoma patients are: RB1, BCOR, MDM4, KIF14, MYCN, DEK, E2F3, CDH11 or RBL2, which encode proteins involved in various biological processes. Moreover, changes in methylation of some genes (e.g. SYK) and dysregulated levels of certain micro RNAs (miR-17~92 and miR-106b~25 cluster) are the cause of retinoblastoma development. The treatment of retinoblastoma depends on the size of the tumor. For small sizes, cryotherapy or laser photocoagulation or thermotherapy is used. Larger tumors are treated with brachytherapy, radiation therapy and chemotherapy – systemic or administered directly to the eye. In extreme cases, when the tumor reaches a significant size, surgery (by removing the entire eye) is required. Untreated retinoblastoma can grow and metastasize to lymph nodes, bone, bone marrow, and the central nervous system. In addition, in the case of genetically affected patients – with mutations in the RB1 gene, there is an increased risk of developing other primary tumors. Such individuals may develop bone, lung, bladder cancer or melanoma, later in life.

Squamous cell carcinoma that develops in various parts of the human eye – usually on the surface of the eyeball – is less invasive than the cancers discussed above and usually does not metastasize to other organs. If left untreated, it can spread within the eye and lead to its loss.

In the fight against eye tumors, it is important to detect them quickly and apply appropriate treatment which, thanks to the achievements of science, are still being improved. For ICTER scientists, this is one of the most important goals.

Author: Magdalena Banach-Orłowska, PhD

Sources:

https://www.zwrotnikraka.pl/swiatowy-dzien-walki-z-rakiem/

https://www.nhs.uk/conditions/eye-cancer/

https://www.cancerresearchuk.org/about-cancer/eye-cancer/treatment/decisions

https://academic.oup.com/jnci/article/113/1/80/5814932?login=false

https://www.nature.com/articles/s41467-018-04322-5

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5824910/

https://www.ncbi.nlm.nih.gov/books/NBK576390/#article-140272.s2

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774148/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6034991/

https://www.nhs.uk/conditions/retinoblastoma/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774148/

The International Centre for Translational Eye Research, ICTER was created to actively fight a battle between eye diseases and numerous patients, doctors and scientists around the world. Thanks to the interdisciplinary character of the centre we are able to operate on diverse fronts.

We construct new diagnostic tools, modern surgical instruments, we search for new pharmacological and gene therapies, we study connections between cells of the visual tract in a healthy and diseased system, we build tools supporting vision in people with severe visual disorders, and we search for unknown molecular mechanisms of eye diseases development. The achievements of our scientists will help in diagnosing, preventing, and curing diverse diseases or other eye conditions that lead to impairment and even loss of vision.The list of diseases and conditions investigated in ICTER includes relatively rare: eye cancers (retinoblastoma, primary intraocular lymphoma, uveal melanoma), Stargardt’s disease and Leber congenital amaurosis; more frequent e. g. retinitis pigmentosa and finally the most common: glaucoma, cataracts, age-related macular degeneration, diabetic retinopathy, and presbyopia.

According to the recent WHO report (World report on vision; https://www.who.int/news-room/fact-sheets/detail/blindness-and-visual-impairment), in 2019 there were 65.2 million people suffering from cataracts globally. This disease more frequently affects individuals over the age of 60 years old which can lead to complete loss of vision. It manifests itself in the cloudy lens, less sharp vision, and difficulties in reading or TV watching. WHO report says about 10.4 million of people all over the world suffer from age-related macular degeneration in which the damage of the central part of the retina leads to vision impairment, distortion of shapes and lines, or presence of shadows and dark patches within a field of vision. Another high-ranked eye disease is glaucoma which affects 6.9 million people globally. Initially, non-symptomatic, glaucoma causes worsening of edge-seeing and – finally in extreme cases -total loss of vision. The main cause of glaucoma is increased pressure inside the eye that leads to pain and redness of the eye, blurry vision upon waking, and vertigo. The WHO world report on vision informs about 4 million individuals suffering from corneal opacity, which is caused by damages and infections of the cornea as well as vitamin A deficiency in childhood.

Diabetic retinopathy (3 million cases reported by WHO in 2019) is yet another eye disease investigated in ICTER. It is caused by damage of small vessels in the retina in response to a long-term increase of glucose level in the blood of a diabetic. Severe vision deterioration, blurry image, dark patches in the field of vision, difficulty seeing in the dark, and progressing loss of vision are the consequences of impaired blood circulation in the eye, bleeding into the vitreous, and detachment of the retina. One of the common methods used for the diagnosis of diabetic retinopathy and many other eye diseases and defects is OCT tomography developed by the founder of ICTER.

We believe that the results of the everyday work of scientists in ICTER will help many people around the world. Not only those suffering from eye diseases, but also healthy individuals experiencing the natural process of age-related vision impairment.

Author: Magdalena Banach-Orłowska, PhD