A New Outlook for Ocular Diseases Thanks to Gene Therapy Developments

Inherited optic neuropathies (IONs) are a group of ocular diseases that result from genetic disorders that cause damage to the optic nerve. The optic nerve is the nerve that connects the eye to the brain and carries visual information. IONs can affect the optic nerve in different ways, depending on the type and cause of the disorder. Over time, damage to the optic nerve leads to visual impairment and vision loss. These ocular diseases can affect both adults and children, severely reducing quality of life. Although there are no effective treatments available for most IONs, gene therapy for ocular diseases has seen significant advances in recent decades and the results from new clinical trials give us hope for the near future.

Ocular Diseases With A Genetic Component

There are two main types of IONs: dominant optic atrophy (DOA) and Leber hereditary optic neuropathy (LHON). Both are mitochondrial cytopathies, which means they are caused by defects in the mitochondrial DNA, the part of the cell that produces energy.

Dominant Optic Atrophy (DOA)

DOA is inherited in an autosomal dominant fashion, which means that one copy of the mutated gene (OPA1) from either parent is enough to cause the disorder. It is thought to be the most common of the IONs, with a prevalence of 1 in 10,000 to 1 in 50,000 people. It causes progressive vision loss that usually starts in childhood and may be associated with nystagmus (involuntary eye movements) and hearing loss. The optic nerve appears pale and thin on examination.

Leber Hereditary Optic Neuropathy (LHON)

LHON is inherited in a maternal fashion, which means that it can only be passed on by mothers to their children. It affects mostly males (80 to 90% of cases) and causes sudden or gradual vision loss that usually starts between 15 and 35 years of age. The vision loss is painless and often affects both eyes within weeks or months. The optic nerve may show swelling, abnormal blood vessels and leakage on examination.

How Gene Therapy Developments Can Transform Treatment

Gene Therapy For Dominant Optic Atrophy (DOA)

Gene therapy for autosomal DOA aims to restore the normal expression and function of OPA1 in retinal ganglion cells and optic nerve fibers. There are different strategies for gene therapy, depending on the type and location of the mutation. Some of the current developments include:

Gene Replacement Therapy: This involves delivering a functional copy of OPA1 to the target cells using a viral vector, such as an adeno-associated virus (AAV). This can potentially compensate for the loss of OPA1 expression due to haploinsufficiency (reduced gene dosage) or dominant negative effects (interference with normal protein function) of the mutant OPA1.
Gene Editing Therapy: This involves correcting the mutation in OPA1 using a molecular tool that can precisely target and modify the DNA sequence. This can potentially restore the normal splicing and expression of OPA1 and prevent further accumulation of the abnormal gene.
Antisense Oligonucleotide (ASO) Therapy: This involves delivering a synthetic nucleic acid that can bind to and modulate the expression of OPA1. This can potentially correct the splicing defects or reduce the expression of mutant OPA1 that causes DOA.

Gene Therapy For Leber Hereditary Optic Neuropathy (LHON)

Gene therapy for LHON aims to deliver a normal copy of the mutated gene to the target cells, with the most common mutation in LHON being G11778A. This affects the ND4 gene that is involved in mitochondrial energy production. Some of the current developments in gene therapy for LHON include:

Lenadogene Nolparvovec: This is a recombinant adeno-associated virus (AAV) vector that carries a normal ND4 gene and delivers it to the cells in the eye and the optic nerve. This can help restore the energy production and prevent further cell death. Lenadogene nolparvovec is injected into one eye of the patient and can improve the vision in both eyes.
Mitochondrial Base Editing: Mitochondrial base editing uses a molecular tool, such as CRISPR-Cas9, that can precisely target and modify the DNA sequence of ND4. This can potentially restore the normal function of ND4 and prevent further cell death. Mitochondrial base editing for LHON is still in its early stages and has been shown to work in patient-derived cells.

The Future Of Gene Therapy For Inherited Ocular Diseases

There are a few concerns with regard to the use of gene therapy for genetic ocular diseases because of the costs associated with developing such technologies and the critical role of timing a treatment to maximize therapeutic effect. It should also be noted that these therapies are currently undergoing clinical trials, although study results have so far been encouraging. Most of the challenges to gene therapy for ocular disease can be overcome with advances in therapy and improved access to rapid genetic testing on the horizon.