Intravitreal Allogeneic Mesenchymal Stem Cells: A Non-Randomized Phase II Clinical Trial for Acute Non-Arteritic Optic Neuropathy

Major Points and Findings:

Very few properly regulated clinical trials of mesenchymal stem cells for an optic nerve disease have been published, and this is one of them. Five patients in Spain with a fresh “stroke of the optic nerve” (acute non-arteritic anterior ischaemic optic neuropathy, NA-AION) received a single injection of donor bone marrow stem cells directly into the eye and were followed for a year. Four of the five saw better afterwards. One developed scar tissue on the retina that led to a retinal detachment and lost all useful vision in that eye.

The authors document both benefit and harm in detail. Their experience identifies a risk with one specific route. Cells placed inside the eye itself (intravitreal injection) can clump and can trigger scarring. With five patients and no control group, the study cannot show that the treatment works.

Aim:

To assess the safety of a single intravitreal injection of allogeneic (donor) bone marrow-derived MSCs (a product called MSV) in acute NA-AION, and to record visual outcomes over 12 months.

Methods:

This was a prospective, non-randomized, single-arm trial run at the University of Valladolid eye institute (IOBA), approved by the Spanish medicines agency and registered as EudraCT 2016-003029-40 and NCT03173638. The agency classified it as phase II, although the authors say its purpose was mainly safety.

Eligible patients were adults aged 50 or over with NA-AION in one eye, presenting within two weeks of symptom onset, with at least two of the following: sudden painless loss of vision in one eye, swelling of the optic nerve head, and a clear relative afferent pupillary defect. People were excluded if they had:

• Blood tests or a history suggesting giant cell arteritis
• Any other cause of optic neuropathy, even in the other eye
• Systemic vasculitis, multiple sclerosis, collagen disease or previous cancer treatment
• Uveitis, glaucoma, or an eye pressure of 24 mmHg or more in either eye
• Other retinal disease in the affected eye, or eye surgery in the previous three months

The product consisted of donor bone marrow MSCs expanded under Good Manufacturing Practice. The cells were at least 97% positive for CD105, CD73, CD90 and CD166 and no more than 1% positive for CD34, CD45, CD14 and HLA-DR, with viability of at least 93%. Two of the five patients received cells from the same donor.

Procedure: In an operating room, under anaesthetic drops, 0.05 mL of cell suspension at 1.5 × 10⁶ cells per mL (roughly 75,000 cells) was injected with a 25-gauge needle through the pars plana. Antibiotic drops were used five times a day for five days. From the dates in the paper’s table, injections took place 8 to 17 days after the onset of symptoms.

Patients were seen over 12 months. Each visit included best-corrected visual acuity (ETDRS letters), eye pressure, slit-lamp and fundus examination, lens grading, OCT of the nerve fibre and ganglion cell layers, and visual evoked potentials. The primary endpoint was the absence of significant inflammation inside the eye at 12 months.

Results:

The five patients were aged 59 to 85. All had typical NA-AION and starting vision between 0 and 25 letters. Two had previously had NA-AION in the other eye. The text describes three men and two women. The paper’s own table lists three women and two men.

Vision: ETDRS letters from baseline to 12 months were as follows.

• Patient 1: 17 to 27
• Patient 2: 0 to 54 (63 at six months)
• Patient 3: 24 to 0
• Patient 4: 25 to 67 (80 at three and six months)
• Patient 5: 14 to 57

Most of the gain appeared in the first one to three months. Vision in patients 2 and 4 slipped back between six and twelve months, which the authors link to cataract progression.

On electrophysiology and OCT, the P100 amplitude on pattern visual evoked potentials improved in three patients, and the flash response improved in three. The nerve fibre and ganglion cell layers thinned in all five as swelling resolved and partial optic atrophy set in. The authors only speculate that thinning after six months was milder than in natural history series.

Safety:

• No patient developed acute or chronic inflammation inside the eye, and eye pressure did not change significantly.
• Epiretinal membrane occurred in 1 of 5. Patient 3 developed a membrane on the retinal surface between the one-month and three-month visits. The patient at first declined surgery, a tractional retinal detachment followed, and a year later cataract surgery and vitrectomy with silicone oil were needed. A large macular hole could not be closed. Final vision was 0 letters.
• A cell clump behind the lens occurred in 1 of 5. Patient 2 developed an aggregate behind the lens shortly after injection. It faded over months but left a significant posterior subcapsular cataract.
• Cataract progression was recorded in all four eyes that still had a natural lens (the fifth patient already had an artificial lens). The authors write that lens opacities progressed “with a possible relation to the injection procedure”.

Conclusions:

The authors conclude that intravitreal donor MSCs were well tolerated and that the risk-benefit balance justifies a larger trial, now planned in four Spanish centres. They acknowledge that the study was designed to assess safety and not efficacy, that five patients allow no conclusions, and that NA-AION often improves on its own. In the Ischemic Optic Neuropathy Decompression Trial, about 30% of untreated patients regained three or more lines and about 20% lost three or more.

They call the epiretinal membrane “the most serious complication” and judge it probably related to the injection. For the next trial they have added an exclusion criterion (vitreous still adherent to the retina) and closer monitoring of the retinal surface.

Background Information:

Timing: The trial borrowed the idea of a therapeutic window from stroke medicine, meaning treatment within days while damaged nerve cells can still be rescued. The authors criticise the earlier SCOTS reports of bone marrow cells for optic nerve disease on this point. Average visual loss there had lasted 9.8 years (range 1 to 35), and several delivery routes and unrelated diseases were mixed. The present trial provides no information about long-standing optic atrophy.

On scarring, the discussion lists published reports of intravitreal MSCs causing epiretinal membranes, proliferative vitreoretinopathy, retinal detachment, secondary glaucoma and new vessel growth. MSCs left on the retinal surface can turn into scar-forming myofibroblasts. In the group’s earlier rabbit work the injected cells collected over the optic nerve head and behind the lens, matching what was seen in patient 2. The authors suggest cell-free MSC exosomes might be safer, because they cannot multiply.

The paper does not test intravenous, intrathecal or retrobulbar delivery and offers no evidence for or against them.