Stem Cell Ophthalmology Treatment Study (SCOTS): bone marrow derived stem cells in the treatment of Dominant Optic Atrophy

Major Points and Findings:

This paper reports six adults with dominant optic atrophy, an inherited disease of the optic nerve, who were treated with their own bone marrow cells in the Stem Cell Ophthalmology Treatment Study (SCOTS) in the United States. The cells were placed behind the eye, beside the eye and inside the eye, and the rest were given into a vein.

Five of the six patients (83.3%) had better visual acuity afterwards, in both eyes each time, with gains of one to four lines on the eye chart. The sixth patient was judged unchanged. The study had no control group, the patients and examiners knew what treatment had been given, and the paper does not report side effects in a systematic way. It shows that vision improved after treatment in a very small group. It cannot show how much of that improvement was caused by the cells.

Aim:

To report visual acuity results in patients with dominant optic atrophy (also called Kjer’s optic neuropathy) treated under the SCOTS and SCOTS 2 protocols.

Methods:

SCOTS and its follow-on study SCOTS 2 are registered with the US National Institutes of Health (NCT01920867 and NCT03011541) and were approved by an Institutional Review Board. They are open-label and non-randomised. There is no placebo or sham group. The comparison is the natural history of the disease, meaning the expectation that vision in these conditions does not improve by itself.

To be included, patients had to be at least 18 years old, have optic nerve or retinal disease that was progressive or unlikely to improve, have best corrected vision of 20/40 or worse or an abnormal visual field, and be medically fit for anaesthesia and surgery.

Bone marrow was taken from the back of the hip bone. A bone marrow concentrate was separated from it in a device cleared by the FDA as a Class II medical device. The concentrate averaged 1.2 billion nucleated cells, including mesenchymal stem cells, in about 14 to 15 millilitres. The cells were the patient’s own, so no immune-suppressing drugs were used. All procedures were carried out under anaesthesia by one investigator at one surgical centre.

The protocol has three treatment arms:

• Arm 1: retrobulbar injection (behind the eye, 3 ml) and sub-Tenon injection (beside the eye, 1 ml), followed by the remaining concentrate intravenously.
• Arm 2: the same, with an added intravitreal injection (into the gel inside the eye, 0.05 ml).
• Arm 3: for the worse eye, surgical removal of the vitreous followed by injection under the retina or into the optic nerve itself (about 0.1 ml), with the better eye receiving Arm 1 or Arm 2.

Eleven of the twelve eyes in this report received Arm 2. One eye received Arm 3.

The six patients were three men and three women aged 39 to 62. The paper states that genetic testing confirmed the diagnosis in four of them. Where the paper gives it, the history of visual loss or the diagnosis went back between 3 and 30 years. Eye examinations were required at 1, 3, 6 and 12 months, and the follow-up reported for each patient ranges from 8 to 24 months.

Visual acuity was measured on Snellen and ETDRS charts and converted to logMAR, a scale on which lower numbers mean better vision. Before and after values were compared with a paired t-test, counting each eye separately.

Results:

Visual acuity: Five of six patients (83.3%) improved, and in each of them both eyes improved, giving 10 of 12 eyes. The gains in those ten eyes ranged from one to four Snellen lines. Average logMAR across all twelve eyes went from 0.84 before treatment to 0.59 afterwards, a change of about 0.25, which the authors express as a 29.5% improvement (33.3% in the eyes that improved). The change was statistically significant (p below 0.001).

Individual patients:

• A 62-year-old man improved from 20/80 and 20/100 to 20/40 in each eye at 18 months.
• A 39-year-old woman improved from 20/60 and 20/80 to 20/40 in each eye at 4 months. At 12 months she was 20/50 and 20/40.
• A 54-year-old woman improved from 20/200 and 20/400 to 20/100 and 20/250 at 12 months. Her left eye was the one treated under Arm 3, and the authors note it benefited slightly less.
• A 40-year-old woman improved from 20/200 in each eye to 20/100 in each eye at one year. She reported better colour and depth perception, and her visual field test results improved between the 3-month and 6-month visits. A possible mild epiretinal membrane (a thin layer of scar tissue on the retina) was noted in both eyes.
• A 42-year-old man did not improve. His vision measured slightly worse than on the day before treatment, but matched the measurements his own eye doctor had recorded for several years, so the authors judged it unchanged. The cells injected into his eyes had cleared within two months. The authors say they usually remain visible for about four months.
• A 43-year-old man improved from 20/200 and 20/400 to 20/80 and 20/150 at about 4 months, and was stable at 8 months.

Safety: The abstract states that there were no surgical complications. The paper has no separate section on side effects. Two observations appear in the case descriptions and the discussion: the possible mild epiretinal membrane in both eyes of one patient, and, in the patient who did not improve, a “minimal decrease in vision in one eye” that the authors attribute to leftover debris in the vitreous.

The paper contains some inconsistencies. The abstract gives the median improvement as 2.125 Snellen lines (about 10.6 letters), and the results section gives 2.456 lines (about 12.3 letters). A few visual acuity values in the table differ from those in the case descriptions.

Conclusions:

The authors conclude that bone marrow cells given under the SCOTS protocols led to statistically significant improvements in visual acuity in patients with dominant optic atrophy, maintained for up to 24 months. They suggest that the cells may help by passing healthy mitochondria to damaged nerve cells and by releasing protective substances, because dominant optic atrophy is a disease of the mitochondria. They did not test this in the study.

The authors do not list limitations. The following points come from the paper itself:

• There were six patients and no control group.
• Neither patients nor examiners were blinded, and visual acuity depends on patient effort.
• The patient judged unchanged shows that measurements of the same eyes differed between two examination rooms by about half a line.
• Each eye was counted as a separate observation in the statistics, although two eyes of one person are not independent.
• Follow-up differed from patient to patient, from 8 to 24 months.
• The same two authors run the study and report its results. They declare no conflicts of interest.

Background Information:

Dominant optic atrophy is the most commonly diagnosed inherited optic neuropathy, affecting about 1 in 50,000 people. In about 60% of affected families it is caused by a fault in the OPA1 gene, which is needed for the normal working of mitochondria. It usually begins in early childhood with loss of sharpness and colour vision in both eyes. According to the paper, between 13% and 46% of patients are registered as legally blind.

The treatment in this study differs from umbilical cord stem cell therapy in two ways. The cells were the patient’s own bone marrow concentrate, a mixture of cell types that was not grown or characterised in a laboratory. And 11 of 12 eyes received an injection into the eye itself, a route that has caused retinal detachment in other studies.