Articles

Hereditary Maculopathies: The Outlook

Hereditary maculopathies represent a group of eye disorders that can severely impair vision, such as Stargardt's disease or retinitis pigmentosa. In recent years, remarkable scientific and technological advances have opened up new avenues in the treatment of these diseases, offering hope to many patients. Thanks to innovative gene therapies, stem cell transplants and advanced technologies, promising strategies are being developed to slow down the progression of these serious diseases.

Introduction to Hereditary Maculopathies

Hereditary maculopathies are complex ocular disorders characterised by degenerative processes affecting the macula.

The maculaalso known as the 'macula lutea' or 'yellow spot' due to its characteristic yellowish colour, is the central area of the retina responsible for sharp and detailed vision. It is, in fact, the portion of the retina that is most sensitive to light and colour, which enables us to distinguish details and colours, and is essential for reading, face recognition and other activities that require accurate vision.

There are two best-known types of inherited diseases affecting the macula the Stargardt's disease and the retinitis pigmentosaboth with a relevant genetic component.

Stargardt's disease

It is a rare ocular disease, characterised by progressive loss of central vision associated with irregular yellow-white macular and perimacular patches at the back of the eye, and a central macular atrophic lesion with a 'bronze beaten' appearance.

Prevalence and progression

Stargardt disease is the most common of the hereditary juvenile macular degenerations and its prevalence is estimated at 1 case per 8,000/10,000 individuals and is similar in both sexes. The disease begins in the first two decades of life, but symptoms can also occur in adulthood, up to the seventh decade.

Progression and severity are highly variable, but generally Stargardt's disease is characterised by progressive loss of central vision, associated with blurred vision and, occasionally, progressive difficulty adapting to darkness. Peripheral vision is usually normal. In most patients, colour vision is impaired. The disease may be associated with photophobia.

Central scotoma

Aetiology

The disease is caused by mutations in the ABCA4 gene, which encodes an adenosine triphosphate (ATP)-binding cassette transporter (ABCR) and is expressed in the cones and rods of the retina. Defects in ABCR function cause the accumulation of all-tranny-retinal and its cytotoxic derivatives, in particular lipofuscin pigments (e.g. diretinoid-pyridinium-ethanolamine) in photoreceptors and retinal pigment epithelium (RPE) cells, causing RPE cell death and subsequent loss of photoreceptors.

Transmission is either autosomal recessive or autosomal dominant, with a 25 or 50% chance of transmitting the disease to offspring, respectively.

Diagnosis

The diagnosis is based on the results of a series of examinations: visual acuity assessment, visual field, ophthalmoscopy, electroretinogram (ERG), fluorescein angiography (FA), fundus autofluorescence (FAF) and optical coherence tomography (OCT), which highlight abnormalities of the macula (progressive atrophy, often with a 'beaten bronze' appearance) and pisciform yellow-white patches that may be located only in the central portion of the macula, or extend beyond the vascular arcades. These patches are hyper-autofluorescent in images obtained with FAF. Fluorescein angiography shows the characteristic dark choroid ("choroidal silence") in approximately 85% of patients.

Prenatal diagnosis would be technically possible by screening the gene ABCA4but is not used in clinical practice.

Therapy

At present, therapy is based, first and foremost, on preventive measures aimed at slowing down the progression of the disease, e.g. wearing sunglasses to avoid excessive exposure to light, and on avoiding the use of vitamin A supplements. Regular ophthalmological check-ups are also recommended. Several treatment options are currently in development. These are generally oral therapies aimed at preventing lipofuscin accumulation. These treatments either inhibit the visual cycle by blocking the action of certain enzymes in the retina (RPE65/RBP4/LRAT/RDH5), replace vitamin A with its deuterated form (ALK001), or help remove lipofuscin by degrading it.

Prognosis

The course of the disease, given the marked clinical variability, depends on a number of parameters, including age at onset and electroretinogram results. In some cases, Stardgardt's disease can progress rapidly over a few months or gradually over several years, leading to a severe reduction in visual acuity. Peripheral vision is usually spared, but some patients may develop the cone-rod phenotype, which is associated with impaired peripheral retinal function.

Retinitis Pigmentosa

The retinitis pigmentosa is a hereditary dystrophy, affecting the retina, with onset usually before the age of 20.

Retinitis pigmentosa, fundus image showing typical features of the disease, such as pigmentary changes (arrows) and a pale colouration of the optic disc (asterisk).

Early symptoms include difficulty seeing in low light, such as at twilight, and a narrowing of the visual field, whereby one sees less and less to the sides, as if looking through a tunnel.

In some cases, retinitis pigmentosa not only affects vision, but may also be accompanied by other serious problems, such as deafness.

Symptoms can vary greatly between individuals, but early diagnosis is crucial to manage the progression of the disease, which in severe cases can lead to blindness.

Overall, retinitis pigmentosa is associated with more than 80 mutated genes, four of which are linked to the X chromosome, i.e. the sex chromosome.

Recently, a new IDH3G gene on the X chromosome, which could be a key element in the diagnosis and treatment of this complex eye disease.

The location of the IDH3G gene on the X chromosome could explain the hereditary transmission of retinitis pigmentosa within families affected by this condition and, moreover, imply a different approach in diagnosis and treatment, considering the different presentation in males and females.

Differential diagnosis

Stargard's disease typically manifests itself with a progressive loss of central vision, whereas in the case of retinitis pigmentosa there is a progressive reduction in peripheral vision due to degeneration of the rods.

The differences between these conditions affect not only the diagnosis, but also the available treatments. It is therefore crucial to correctly identify the type of maculopathy in order to adopt an appropriate therapeutic approach.

Moreover, early diagnosis is crucial to effectively manage disease progression. Advanced imaging techniques and genetic testing are key tools in this process.

Impact on Quality of Life

Hereditary maculopathies profoundly alter patients' quality of life. Gradual vision loss causes severe difficulties in daily activities, such as reading or driving, and affects personal independence. The psychological impact is equally significant, with many patients experiencing anxiety and depression due to their condition.

It is also important to consider the social aspect. Interpersonal relationships and participation in social events may be limited, increasing the risk of isolation.

Psychological support and visual rehabilitation are essential tools to help patients manage the daily challenges these conditions bring and improve their overall well-being.

Progress in Gene Therapies

Gene therapies represent one of the most promising frontiers in the treatment of hereditary maculopathies. Through advanced techniques, it is possible to correct or replace defective genes that cause these diseases, offering new hope to patients.

Recent Successes and Challenges

In recent years, there have been several successes in gene therapy. For example, the FDA-approved Luxturna therapy has been a breakthrough for certain forms of retinitis pigmentosa. This treatment uses viral vectors to deliver functioning copies of a gene directly to retinal cells.

However, the genetic complexity of maculopathies requires customised approaches, and the high cost of treatment often limits access for many patients.

Ongoing research is crucial to overcome these barriers. New vectors and gene editing techniques, such as CRISPR, offer potential solutions to expand the effectiveness and accessibility of gene therapies.

Ongoing Clinical Studies

The clinical studies are crucial for verifying the safety and efficacy of gene therapies. Currently, numerous studies are underway exploring different strategies to treat hereditary maculopathies. These studies evaluate not only new viral vectors, but also CRISPR-based approaches to directly modify the DNA of retinal cells.

Researchers are also examining the use of nanoparticles to improve gene delivery and reduce the risks associated with viral vectors. These developments could radically transform the therapeutic approach to maculopathies.

Participating in a clinical trial offers patients the opportunity to access innovative treatments, but it is essential to carefully consider the potential risks and benefits.

Innovative Pharmacological Therapies

In addition to gene therapies, several pharmacological treatments are being developed to deal with inherited forms of maculopathies. These drugs aim to slow down retinal degeneration and protect visual function.

New Drugs in Development

Pharmacological research is focusing on new molecules capable of modulating degenerative processes in the retina. Some of these drugs aim to reduce oxidative stress, a key factor in the progression of maculopathies.

New developments include drugs that use peptides to protect retinal cells from damage. These treatments are still being tested, but preliminary results are promising.

In addition, combining drugs with other therapies, such as stem cell transplants, could offer a more effective integrated approach to slow down disease progression.

Personalised Approaches for Patients

Personalised medicine is an emerging trend in the treatment of hereditary maculopathies. This approach takes into account the specific genetic mutations, such as those associated with autosomal dominant inheritance, of the patient and their individual characteristics to develop tailor-made therapies.

Analysing the patient's DNA makes it possible to identify the mutations responsible for the disease and to select the most appropriate treatment. This method can significantly improve the effectiveness of therapy and reduce side effects.

Finally, the integration of big data and artificial intelligence helps predict the patient's response to treatments, further optimising therapeutic strategies.

Advanced Technologies and Devices

Advanced technologies are at the heart of innovations in the treatment of hereditary maculopathies. State-of-the-art devices and diagnostic tools are revolutionising the way these conditions are managed.

Retinal Lenses and Prostheses

Le lenses and retinal prostheses are essential tools for improving the vision of patients with maculopathies. Special lenses can amplify the image and improve visual quality, while retinal prostheses, such as the Argus II, can stimulate the cones and offer partial vision to those with complete vision loss.

These technologies require customised adaptation for each patient, taking into account specific visual needs and disease progression.

Retinal prostheses are particularly revolutionary as they use surgically implanted microchips to directly stimulate retinal cells, turning light stimuli into electrical signals that the brain can interpret.

Early Diagnosis Systems

I early diagnosis systems are crucial for detecting inherited maculopathies in the early stages, when therapies are most likely to be successful. The use of high-resolution imaging, such as optical coherence tomography (OCT), makes it possible to visualise minute details of the retina.

These diagnostic tools help monitor the evolution of the disease and evaluate the effectiveness of treatments. The integration of artificial intelligence algorithms further improves the accuracy and reliability of diagnoses.

Implementing regular screening programmes for people at risk is essential to detect changes in the visual field at an early stage and intervene promptly.

Future of Treatment for Maculopathies

The future of treatment for hereditary maculopathies is promising, thanks to ongoing advances in research and the development of new technologies. These developments offer new hope for more effective management of these conditions.

Long-Term Perspectives

Le long-term prospects for the treatment of hereditary maculopathies are optimistic. With the continued advancement of gene, drug and technology therapies, it is possible that the progression of hereditary dystrophies may be significantly slowed down in the future.

The combination of different therapies could offer more comprehensive and personalised solutions. The integration of digital technologies and genomic data promises to further improve the effectiveness and accessibility of treatments.

Ultimately, the future of maculopathy treatment will depend on the ability to translate scientific discoveries into practical and accessible treatments for all patients.

Among the most advanced studies published recently are:

 

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