Hereditary maculopathies: genes & C

Hereditary maculopathies constitute the most genetically heterogeneous group of inherited diseases in humans. They can be inherited via:
– autosomal recessivewhen two copies of the same gene are altered
– autosomal dominantwhen one copy of a gene is normal and the other mutated)
– X-linkedwhen the defect is localised on the X sex chromosome and the male is sick with XY, while the female XX is a healthy carrier.

Hereditary maculopathies result in progressive vision loss due to abnormal development or dysfunction or degeneration of the photoreceptors or retinal pigment epithelium. The worldwide prevalence is 1:1,380 individuals, with approximately 5.5 million people possibly affected.

The first gene causing hereditary maculopathy was identified in 1990, then an average of 9 genes per year were discovered between 1990 and 2021, and at present there are 280 genes identified and a plateau has been reached, indicating that there may still be a few genes that have not yet been identified, but most are included in the mutations already identified.

The genetic alterations identified manifest themselves with varying degrees of severity, ranging from blindness or low vision in childhood and early adolescence to progressive vision loss during adult life.

The most common form of hereditary retinal disease is retinitis pigmentosa, followed by cone/rod degeneration, Leber congenital amaurosis and hereditary macular dystrophies. In most cases hereditary maculopathies result exclusively in ocular manifestations, i.e. they are 'non-syndromic', but around 70 types of syndromic forms have also been described, of which Usher syndrome is the most common.

Therapy: current events and perspectives

The development of comprehensive and effective therapeutic options for hereditary maculopathies is certainly a great challenge for scientists and researchers, and in recent years important progress has been achieved in approaches based on the replacement of defective genessuch as gene therapy and targeted pharmacological agents, or on the correction of mutationssuch as translational read-through therapy and antisense oligonucleotides (ASOs: artificial DNA chunks constructed for the purpose of binding and blocking a specific messenger RNA).

Non-gene approaches based on neuroprotection and regeneration, such as stem cell therapy and surgical retinal implants, are also under development.

As far as gene therapy is concerned, antiretroviral vector (AAV)-based approaches present very promising horizons, although they cannot be used for very large genes. Furthermore, unfortunately, neutralising antibodies against AAVs can also form that can attenuate the efficacy of anti-retroviral vector-based therapies.

In a study recently published in the New England Journal of Medicine, "Gene Editing for CEP290-Associated Retinal Degeneration", researchers tested the safety and efficacy of EDIT-101, an experimental gene editing therapy using CRISPR technology in patients born with a form of retinal degeneration associated with CEP290. CRISPR-Cas9 makes it possible to treat mutations in genes larger than those for which viral adenovector therapy would be usable, and CEP290 is too large to fit within a typical AAV.

CRISPR-Cas9 offers a set of advantages over other gene editing technologies, so much so that this approach is one of those that can actually be used. It must, however, be borne in mind that this is not a treatment that restores the patient's previous visual function, but it does allow for major improvements. In the study, carried out by a pool of American universities, 12 adults aged between 17 and 63 and two boys aged between 9 and 14 were treated with EDIT-10 injections. Compared to baseline 6 of the participants reported a significant improvement in photopic, cone-mediated vision, and of these patients 5 reported an improvement in at least one other significant visual parameter. Compared to baseline, nine participants (64%) reported a significant improvement in best corrected visual acuity, red light sensitivity, and mobility test score. In addition, a significant improvement in the vision-related quality-of-life score was found in six patients.

On the subject of maculopathies see also:

• Stargardt's disease: new hope for patients - Oculista Italiano
• Geographical atrophy & AI - Oculist Italiano

• Pierce EA, Aleman TS, Jayasundera KT, et al. Gene Editing for CEP290-Associated Retinal Degeneration. N Engl J Med. 2024 Jun 6;390(21):1972-1984. doi: 10.1056/NEJMoa2309915. Epub 2024 May 6. PMID: 38709228.
• Ben-Yosef T. Inherited Retinal Diseases. Int J Mol Sci. 2022 Nov 3;23(21):13467. doi: 10.3390/ijms232113467. PMID: 36362249; PMCID: PMC9654499.
• Del Pozo-Valero, M.; Riveiro-Alvarez, R.; Martin-Merida, I.; et al. Impact of Next Generation Sequencing in Unraveling the Genetics of 1036 Spanish Families With Inherited Macular Dystrophies. Investig. Opthalmology Vis. Sci. 2022, 63, 11.