Stem Cell Treatment for Optic Nerve Atrophy (ONA)

The optic nerve is the nerve supplying the retina – the neurological part of the eye receiving different visual images to transmit them to the brain. Optic nerves, therefore, transmit visual images from the eye (retina) to the brain to be processed and analyzed. Optic nerve atrophy (ONA) is basically the death or gradual degeneration of the optic nerve. It could occur due to hereditary causes, endocrine/metabolic causes, brain/eye tumors (ex. pituitary tumors), neurological diseases (ex. multiple sclerosis), head trauma, or due to different retinal disorders – as will be discussed below. Optic nerve atrophy is usually an irreversible chronic condition, and it occurs only following a period of reversible optic nerve abnormality (1).  Retinal disorders are a separate group of disorders that could actually lead to optic nerve atrophy in the long term. The most-commonly encountered retinal disorder is age-related macular degeneration (AMD) which is responsible for almost 10% of all cases of blindness. Different risk factors often increase one’s risk of developing macular degeneration including smoking, diabetes mellitus, and cardiovascular diseases (2). Despite both conditions being separate when it comes to the causes, they both follow the same pathway of degeneration and symptoms and will therefore be discussed together in relation to stem cell therapy.

Given that optic atrophy occurs due to nerve degeneration, its treatment options are limited similar to other neurological conditions. Once the original cause of damage causes the optic nerves to atrophy, the damage is usually irreversible and doesn’t respond to conventional treatments.  Therefore, current treatment usually focuses on reducing/removing the insult damaging the retina or optic nerve prior to entering the stage of actual optic atrophy. Such treatments include (1, 2, 4-6):

• Corticosteroids: Steroids are strong anti-inflammatory drugs that might reduce the optic nerve or retinal inflammation occurring due to trauma or tumors.
•  Lifestyle modifications: These include adopting a healthy diet, exercising, smoking and alcohol cessation…etc.
• Anti-VEGF drugs and other anti-angiogenic drugs: These drugs are beneficial only in one type of macular/retinal degeneration known as “wet age-related macular degeneration” which occurs due to overproduction of “defective” blood vessels within the retina. Therefore suppressing the production of these blood vessels delays the retinal degeneration rate and the development of blindness. There are currently three approved anti-VEGF drugs for this use; namely ranibizumab, aflibercept, and brolucizumab. However, these drugs require prolonged, and maybe life-long, intraocular (within the eye) injections at close intervals; which might be inconvenient for many patients – especially given that it is merely a way to delay the disease progression and not a permanent curative treatment.
• Photodynamic therapy (Using Verteporfin dye): This treatment is also used in wet AMD to slow the progression of the disease by targeting the abnormal blood vessels within the retina. However, this therapy doesn’t improve visual outcomes and it simply delays disease progression.

As you can see, treatment options are limited, and none of the mentioned treatments address the issue of retinal and/or optic nerve atrophy. Current treatments only aim to reduce the damage and/or delay disease progression. This is where stem cell therapy has been emerging in the past few years as a possible hope for the treatment of retinal degeneration and/or optic nerve atrophy after its success in improving a multitude of other neurological disorders such as cerebral palsy and autism.

To date, there has not been a single study – to our knowledge – that has compared different types of stem cells, concerning safety and efficacy, particularly in patients with retinal or optic nerve disorders. However, we can summarize different stem cell sources that have been tested in these disorders. Each form of stem cells has its own benefits and drawbacks as will be mentioned. Different stem cell sources that have been tested in ONA include (11):

• Mesenchymal Stem Cells: These are stem cells obtained from adipose tissues, bone marrow, or umbilical cord tissues – which we actually use at Beike. These cells can be easily produced in larger numbers to accommodate higher number of patients and allow better efficacy, have better response in neurological diseases – including ONA and retinal disorders – have better differentiation capacity into retinal cells, and have better anti-cell death effect in case of degenerative conditions like ONA that already have an ongoing destructive process – compared to other stem cells.
• Embryonic Stem Cells: Another type of stem cells includes embryonic stem cells. These cells can also differentiate into photoreceptors; yet they are difficult to obtain and have ethical concerns regarding their sources. 
• Adult Pluripotent Stem Cells: These are another source that can be produced in large numbers; yet their differentiation abilities are once again limited.

After carefully reviewing all of the benefits and risks of each type, we have decided to use mesenchymal umbilical cord-based stem cells that have been most extensively studied; with the least reported side effects.

In addition to the source of stem cells, there are also multiple routes of stem cell administration. Most clinical trials testing stem cell therapy in ONA and retinal disorders use combined routes of administration including (11):

• Intravenous (Into the blood)
• Intrathecal (Into the CSF surrounding the brain)
• Retrobulbar (Behind the eye where the optic nerve resides)
• Intraocular (Into the eye)
• Intravitreal routes (Into the vitreous of the eye)

At Beike, we use combined intravenous and intrathecal routes; with some patients being eligible for two additional retrobulbar injections depending on different factors.

There is no specific timing for stem cell treatment; but like many other neurological conditions, we generally recommend seeking stem cell therapy early after diagnosis. This is because the earlier the stem cell intervention, the easier it is to prevent further damage of the present cells and to be able to restore normal retinal or eye functioning before permanent damage – or involvement of the fovea – takes place. We still need to report that clinical benefit is not 100% guaranteed as is the case with any intervention, and consulting our specialists prior to undergoing the procedure is of utmost importance in order to gain more insight on the procedure and the estimated possibility of treatment success for your individual case.

Of course, no treatment is without complications, and stem cell therapy is the same. However, despite its novelty, stem cell therapy has limited side effects if used properly, with comparable general side effects to those experienced with regular blood transfusion or foreign organ transplantation (ex. allergic reactions, cell rejection, or fever). Additionally, in studies specifically studying stem cell therapy in the optic nerve and retinal diseases, no significant side effects were reported and none were life-threatening or had life-long consequences. They were also easily managed medically at the time of their occurrence (11).

The following factors might affect a patient's response to stem cell therapy, and how we at Beike Technology address each factor to ensure that we provide you with the highest efficacy using the safest procedure possible.

• Dose/Number of stem cells: The higher the dose of stem cells – within limits of course – the better the response. At Beike Technology, we administer an optimum dose of around 120-400 Million Cells (depending on the person’s weight and age) for people with different eye disorders.
• Route/Method of administration: As previously mentioned, studies have shown that combining intrathecal injection (through lumbar puncture directly within the brain’s CSF) with the traditional intravenous route provides a better response than administering intravenous injections alone (which causes stem cells to go to other organs than the brain before reaching the brain). Multiple studies found benefits of other routes injecting stem cells directly into the affected eyes; including: Retrobulbar, intraocular, and intravitreal routes. Therefore, at Beike Technology, we use both intravenous and intrathecal routes concomitantly. In some selected patients, we might additionally recommend additional retrobulbar injections in order to obtain maximal efficacy; while ensuring the least possible side effects or toxicity.
• Type of Stem Cells used: As previously mentioned, both umbilical cord-based stem cells, which we use at Beike Technology, and bone marrow stem cells have better-proven efficacy in the optic nerve and retinal disorders compared to other types of stem cells.
• Timing of stem cell transplantation: As explained before, early intervention is crucial for people with optic diseases. Therefore, we recommend early intervention soon after diagnosis depending on the time one develops symptoms.
• Follow-up Time: Significant benefits from stem cell therapy in patients with optic nerve and retinal diseases begin appearing around 4 weeks after stem cell therapy, and most people reach their full potential around 6 to 12 months after treatment – where the effects then plateau. At Beike Technology, even after discharge, we provide you with a full follow-up program beginning as early as one month and up to one year after transplantation. You have complete access to our professional team even after you leave our center.

The cause of ONA is dependent upon the type of atrophy present:

• Demyelinating ONA, also known as optic neuritis, occurs in conditions such as multiple sclerosis and other demyelinating and inflammatory conditions. Patients often present with rapid loss of vision in one eye, which may be loss in part or all of the visual field.
• Ischemic ONA results from occlusion of blood vessels supplying the optic nerve and can occur in conditions such as vasculitis, giant cell arteritis, granulomatosis with polyangiitis, and rheumatoid arthritis. Patients with ischemic ONA develop rapidly progressing loss of vision, often in the superior aspect of their visual field.
• Traumatic ONA results from direct injury to the optic nerve, often from blunt force or accidents such as motor vehicle collisions.
• Inflammatory ONA, also known as infiltrative neuropathy, results in the destruction of the optic nerve from locally invading tumors, infection, and autoimmune processes such as sarcoidosis.

ONA is diagnosed by extensive ophthalmological investigation which may include:

1. Visual field testing: visual field defects in optic neuropathies can take several patterns including central, diffuse, arcuate, and altitudinal defects. The pattern of visual field defect is not specific to any etiology and almost any type of field defect can occur with any optic neuropathy. However, altitudinal defects are more common in ischemic optic neuropathies and central, or cecocentral defects frequently accompany toxic/nutritional and hereditary optic neuropathies.
2. Electrophysiological testing: Visual evoked potential (VEP) are often abnormal in optic neuropathies. Although VEP is not necessary for the diagnosis of optic neuropathy, it can be useful in patients with early or sub-clinical optic neuropathy who may have normal pupillary responses and no discernible optic disc changes on clinical examination
3. Optical coherence tomography: a relatively new technique that uses low coherence light to penetrate tissue and a camera to analyze the reflected image. By performing circular scans around the optic nerve head, the peripapillary nerve fiber layer can be analyzed. This has been useful in the follow-up of patients with optic neuritis, traumatic optic neuropathy, and Leber’s hereditary optic neuropathy

Symptoms of ONA often include tunnel vision (also known as scotoma), blurred vision, and loss of other visual fields. These defects are diagnosed on further investigation using the aforementioned techniques.

The mechanisms by which stem cells deliver their regenerative action are :

• Secretion of neurotrophic factors before or after differentiation. MSCs release certain neurotrophic growth factors including brain-derived neurotrophic factor (BDNF) which may offer neuroprotection.
• Injection of MSC may result in anti-inflammatory effects, thereby increasing the regeneration of neurons located within the optic nerve.