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Could inhibiting ceramide production in the eye be the universal solution to treat inherited retinal dystrophy?

The sense of sight is one of the five commonly known senses possessed by humans. Many of us would agree that vision plays a significant role in every aspect of daily life. Have you ever wondered what the main cause of inherited blindness in the Western world is [1]? I’ll give you a hint – it’s the same group of diseases that is second in line for causing reduced visual acuity in children [1] – inherited retinal dystrophy.  

Inherited retinal dystrophy

It is a group of disorders that affects an average of 1 in 1500-2000 individuals in the population, characterized by abnormal function of the retina cells and their progressive degeneration [1]. As Małgorzata Pacholec, the president of the Retina AMD Poland association, says, “People with retinal dystrophies know that everything they have is temporary because with the diagnosis, they are informed that they suffer from an incurable disease, so for as long as possible, they hold on to the world of the sighted” [2]. This is due to the nature of these disorders, during which vision impairment progresses until total loss of vision. Furthermore, due to their rarity, these diseases are not well known even among ophthalmology specialists, and therefore still do not have specialized diagnostic criteria, treatment principles, or methods [1].  

The most common form of retinal dystrophy is called retinitis pigmentosa, also known as pigmentary degeneration of the retina. This disease affects the light-sensitive cells of the retina – rods and cones – and, as mentioned earlier, leads to progressive vision loss [1]. The condition usually starts with difficulty seeing at night, narrowing of the visual field, and even photophobia [3]. To add some context: retinitis pigmentosa is an inherited disease that we are born with, affecting an average of 1 in 3500/4000 people [3]. The prognosis for pigmentary degeneration of the retina depends on the mode of inheritance. In individuals with autosomal dominant inheritance, sharp central vision should be maintained until around age 50, whereas in those with autosomal recessive/X-linked inheritance, visual acuity usually decreases before age 30 [3]. Like other forms of retinal dystrophy, there is currently no effective treatment for retinitis pigmentosa. 

Apoptosis, or programmed cell death (in this case of photoreceptor cells such as rods and cones), which occurs for example during retinitis pigmentosa, may have various pathophysiological causes. One of them is the pathological accumulation of ceramides. 

What are ceramides? 

Ceramides are simple sphingolipids belonging to the group of lipids that perform many functions, including regulation of cell division, cell differentiation, apoptosis (programmed cell death), and the aging process [4,8]. In the case of Alzheimer’s disease, high concentrations of ceramides can lead to the induction of mitochondria-dependent apoptosis, increased synthesis of reactive oxygen species, and decreased levels of ATP [4]. This suggests that the ceramide pathway present in this disease may directly stimulate changes in the brain in people with Alzheimer’s disease [8].

In the last decade, interest in the role of ceramides in the retina has increased, as studies have shown that ceramides affect many processes, such as proliferation (division), survival, migration, formation of new blood vessels, inflammation, and apoptosis of retinal cells [6,8]. Because impairment of these processes is associated with retinal degeneration-related disorders, ceramides are considered to be an important factor in the progression of these disorders [6,8].

Recently published research results from scientists at the University of California, Irvine, have shown that the accumulation of ceramides in the retina, caused by a lack of adiponectin receptor 1 (AdipoR1) – one of the main enzymes regulating ceramide homeostasis in the retina, leads to gradual death of photoreceptors and loss of vision [5]. One of the leading researchers in this scientific team who made this breakthrough discovery in early 2022 is Dr. Dominik Lewandowski.

Pharmacological decrease in ceramide levels 

Dr. Dominik Lewandowski is a scientist at the University of California, Irvine in the Department of Ophthalmology. The aforementioned results of the research team, led by Dr. Lewandowski, were published in the prestigious Journal of Clinical Investigation Insight. The researchers demonstrated that pharmacologically reducing the level of ceramides in the retina (through administration of desipramine and L-cycloserine) protects photoreceptors from apoptosis, helps maintain the structure and function of the retina, and improves vision [5]! Accumulation of ceramides in the retina, most likely due to insufficient activity of the enzyme ceramidase, led to the death of photoreceptor cells. However, after treatment of mice with a combination of desipramine and L-cycloserine, drugs approved by the US Food and Drug Administration as safe for use in humans for over 30 years, ceramide levels were reduced. Furthermore, the researchers observed an improvement in their daytime vision.

Dr. Dominik Lewandowski emphasizes that the proposed non-invasive pharmacological treatment is much easier to achieve in humans and much cheaper than gene therapy. Gene therapy, which is considered a promising future treatment for some cases of retinitis pigmentosa, is invasive and requires complicated procedures, significantly increasing its costs.

The multidimensionality of the discovery

High levels of ceramides are also present in other medical conditions such as Alzheimer’s disease, cancer, type 2 diabetes, multiple sclerosis, cardiovascular diseases, and non-alcoholic fatty liver disease, as well as severe cases of COVID-19 infection [7]. Therefore, it is worth noting that the strategy proposed by Dr. Lewandowski’s team may have broad applications.

Dr. Dominik Lewandowski is not resting on his laurels, but rather continues to work on improving the method of reducing ceramides by using other strategies. He is exploring new therapeutic possibilities for retinitis pigmentosa by targeting three different nodes of ceramide metabolism – inhibiting two key enzymes that generate ceramides and stimulating ceramide degradation through AdipoR1 to reduce pathologically elevated levels of these lipids. Huge congratulations to Dr. Lewandowski and the entire research team for such a groundbreaking discovery!


  1. Polska RA. Entry – IRD – The major cause of inherited blindness in Western World. (www.retinaamd.org.pl). Available from: http://retinaamd.org.pl/informator-badania-genetyczne/wstep-ird-glowna-przyczyna-dziedzicznej-slepoty-w-zachodnim-swiecie/
  2. Matusewicz K. Retinal Dystrophy – saving the vision is priceless. 2021. (www.pulsmedycyny.pl). Available from: https://pulsmedycyny.pl/dystrofie-siatkowki-ocalenie-wzroku-jest-bezcenne-1110675
  3. Starzyk lek. med. K. Retinitis Pigmentosa. Przeglad okulistyczny. 2010. Available from: https://www.przegladokulistyczny.pl/zwyrodnienie_barwnikowe_siatkwki
  4. Car H, Zendzian-Piotrowska M, Fiedorowicz A, Prokopiuk S, Sadowska A, Kurek K. The role of ceramides in selected brain pathologies: Ischemia/hypoxia, Alzheimer disease. Postepy Hig Med Dosw. 2012. Available from: https://pubmed.ncbi.nlm.nih.gov/22706115/
  5. Lewandowski D, Foik AT, Smidak R, Choi EH, Zhang J, Hoang T, et al. Inhibition of ceramide accumulation in AdipoR1–/– mice increases photoreceptor survival and improves vision. JCI Insight. 2022. Available from: https://insight.jci.org/articles/view/156301 
  6. Simón MV, Prado Spalm FH, Vera MS, Rotstein NP. Sphingolipids as Emerging Mediators in Retina Degeneration. Front Cell Neurosci. 2019. Available from: https://www.ncbi.nlm.nih.gov/pubmed/31244608
  7. Khodadoust MM. Inferring a causal relationship between ceramide levels and COVID-19 respiratory distress. Sci Rep 11, 20866 (2021). Available from: https://www.nature.com/articles/s41598-021-00286-7
  8. Lewandowski D, et al. Dynamic lipid turnover in photoreceptors and retinal pigment epithelium throughout life. Progress in Retinal and Eye Research. 2022. Available from: https://www.sciencedirect.com/science/article/pii/S1350946221000987
Dominik Lewandowski
Dr. Dominik Lewandowski is a Project Scientist at the University of California, Irvine. He has a background in multiple disciplines, including biochemistry, molecular biology, and ophthalmology. In 2016 he defended his Ph.D. thesis, where he characterized molecular mechanisms underlying interactions between Lyme disease bacteria and its tick vector. These findings are of interest in the Lyme disease field and can be used to find preventative measures to limit the transmission of pathogenic bacteria. For his doctoral dissertation, he received multiple distinctions, including the prestigious award for best Ph.D. thesis granted by Polish Prime Minister. In 2017, Dr. Lewandowski successfully switched fields from Lyme disease research to vision science, starting post-doctoral research in Prof. Krzysztof Palczewski's lab – one of the top vision scientists in the world. Since then, he has been fascinated by eye research, focusing on deciphering the mechanisms of retinal degenerative diseases and establishing novel strategies for preventing and treating these disorders. Recently, Dr. Lewandowski discovered that adiponectin receptor 1 is one of the principal enzymes regulating ceramide homeostasis in the retina, and its dysfunction in mice leads to an accumulation of ceramides, resulting in photoreceptor cell death and, ultimately, vision loss. He also found that pharmacological lowering of ceramide levels protected photoreceptors, helped preserve the retina's structure and function, and improved vision, published in a prestigious medical journal JCI Insight in 2022. Lately, being nominated by co-workers and awarded Outstanding Postdoctoral Fellow 2022 by the University of California Irvine, he continues to explore the roles of ceramides and other lipids in retinas' health and disease.
Wiktoria Bulik

A graduate of the University of Bedfordshire in Biomedical Sciences. Strongly passionate about science, entrepreneurship and medical innovations. She adores broadening her knowledge and learning new things. On a daily basis, she works in a bio-tech industry, is socially active and takes part in many interesting projects both in Poland and abroad.

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Wiktoria Bulik

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