Stem Cell Research: AMD

• Estimated Start Date: April 2022
• Estimated Completion Date: December 2026
• Recruitment Status: The trial is currently ongoing, with the next group of patients (the mid-dose cohort) being treated.

Participants

• Estimated Sample Size: A total of 18 participants will be enrolled across all dose levels. This report covers the first 6 participants.
• Ages: 71 to 86 years old.
• Eligibility Focus: Participants must have vision loss due to dry AMD with geographic atrophy.
• Separated into two groups:
  • Group A: Worse vision (20/200–20/800)
  • Group B: Better vision (20/100–20/200)

Cell Type Used: RPESC-RPE-4W

• The therapy uses a unique cell product derived from adult donor tissue.
• These cells start as adult Retinal Pigment Epithelium (RPE) stem cells, sourced from the RPE layer of eyes donated to qualified eye banks.
• These adult stem cells are then grown and matured in a lab for four weeks to a specific “progenitor” stage.
• Goal: Replace the RPE cells that have died off due to dry AMD and support photoreceptor cells to restore or improve sight.

Delivery Method

• Subretinal Injection: Cells are injected directly under the retina in a one-time procedure.
• Control: The patient’s untreated eye acts as the control (no placebo).

Cell Dosage

• Low-dose group: 50,000 cells (covered in this report).
• Future groups: Medium dose (150,000 cells) and high dose (250,000 cells).

Schedule

• Single injection followed by 12 months of monitoring.

Follow-up Schedule

• Patients monitored at 1 week, 1 month, 3 months, 6 months, 9 months, and 12 months post-procedure.

What They Are Measuring

• Effectiveness (Safety Perspective): Ensuring that patients do not experience significant vision loss.
• Safety: Monitoring for tumor formation, inflammation, or other adverse events related to the cell product.

Other Outcomes

• Vision Improvement: Measuring changes in sharpness of vision using a standard eye chart.
• Retinal Health: Using OCT scans to assess the size of damaged retinal areas and thickness of the retina.
• Structural Evidence: Looking for imaging evidence that transplanted cells have successfully engrafted.

Cell Type Used: iPSC-Derived RPE

• The therapy uses a highly personalized cell created from the patient’s own body.
• What they are:
  • The process starts with a patient’s own blood cells.
  • In the lab, these cells are turned into induced pluripotent stem cells (iPSCs).
  • The iPSCs are then guided to become new, healthy Retinal Pigment Epithelium (RPE) cells — the exact type of cell lost in dry AMD.
• The Goal: This autologous therapy aims to replace the dead RPE cells with a patch of new ones, rescuing overlying vision cells from further degeneration.

Delivery Method

• Subretinal Transplantation: The lab-grown RPE cells are grown as a single layer on a thin, biodegradable scaffold. This patch is surgically transplanted into the subretinal space in a one-time procedure.
• The Control: This is a single-arm study with no placebo group. The patient’s untreated eye may be used for comparison.

Cell Dosage

• The total number of cells delivered on the scaffold is not specified in the current trial documents.

Schedule

• The treatment is a one-time surgery. Patients receive immunosuppressive medications to prevent rejection.

Follow-up Schedule

• The trial includes a long-term follow-up period with at least 14 study visits over the first 5.5 years after surgery.
• After the main study, participants will be contacted yearly for up to 15 years to monitor long-term safety.

What They’re Measuring

• Main Goal (First 12 Months): Determine if the therapy is safe.
• Effectiveness (from a safety perspective): Measuring any changes in visual acuity to ensure the procedure doesn’t cause harm.
• Safety: Tracking the number and severity of all adverse events in the first year after surgery.

Other Outcomes

• Vision Function: Measuring changes in retinal sensitivity and gaze stability (fixation) using microperimetry.
• Retinal Health: Using high-resolution imaging (OCT, fundus autofluorescence, fluorescein angiography) to assess structural changes in the macula and transplanted cells.

• Actual Start Date: April 1, 2015
• Estimated Final Completion Date: January 31, 2031
• Recruitment Status: Active, not recruiting

Participants

• Sample Size: 24 participants enrolled across four cohorts.
• Ages: 50 years and older.
• Eligibility Focus: Participants had advanced dry AMD with geographic atrophy. The first three cohorts included legally blind patients, while the final cohort (Cohort 4) included patients with better vision and less advanced disease.

Cell Type Used: OpRegen (RG6501)

• The therapy uses a specialized “off-the-shelf” cell product derived from human embryonic stem cells (hESCs).
• What they are:
• The cells begin as human embryonic stem cells.
• Researchers guide them into becoming healthy Retinal Pigment Epithelium (RPE) cells.
• The final product, called OpRegen, is a liquid suspension of these lab-grown RPE cells.
• The Goal: To replace the RPE cells that have died off in the back of the eye, providing essential support to surviving vision cells and improving overall retinal health and function.

Delivery Method

• Subretinal Injection: The cells are injected once into the subretinal space in the back of the eye as a liquid suspension.
• Control: This is a single-arm study. The patient’s untreated fellow eye serves as the comparison.

Cell Dosage

• Dose-escalation design with targeted doses ranging from 50,000 to 200,000 cells per injection.

Schedule

• A single treatment injection followed by long-term monitoring for safety and vision changes.

Follow-up Schedule

• The main study follow-up period is 12 months, but participants will be monitored for over 10 years to track long-term safety and durability.
• Estimated Final Completion: 2031.

What They’re Measuring

• Safety: Tracking the percentage of participants who experience adverse events related to treatment.
• Intraocular Pressure: Monitoring any changes in eye pressure from baseline to Month 12.

Other Outcomes

• Vision Improvement: Assessing how well patients can read a standard eye chart with best correction.
• Retinal Health: Measuring the size of the damaged area using Fundus Autofluorescence imaging to assess whether degeneration has slowed or reversed.
• Quality of Life: Using a 25-question standardized survey to evaluate how vision impacts daily life and well-being.

Cell Type Used: OpRegen (hESC-RPE)

• This therapy uses an “off-the-shelf” cell product that is not made from the patient’s own cells.
• What they are:
• Retinal Pigment Epithelium (RPE) cells — the type of support cells lost in dry AMD.
• Created in a lab by starting with human embryonic stem cells (hESCs) and guiding them to become a pure population of RPE cells.
• The Goal:
• To surgically place new, healthy RPE cells in the back of the eye to replace those that have died.
• This aims to support remaining vision cells and improve retinal structure and function.

Delivery Method

• Subretinal Surgical Delivery: The OpRegen cells are administered as a liquid suspension and surgically delivered into the subretinal space in the back of the eye.
• This is a one-time surgical treatment.

Cell Dosage

• Dose per Injection: Up to approximately 200,000 cells.
• Schedule: The treatment is a single, one-time procedure.

Follow-up Schedule

• The primary follow-up period for the main study goals is 3 months after surgery.
• The total study duration, including long term follow up, continues until 2031.

What They Are Measuring

• Surgical Success: Measuring the proportion of patients where OpRegen cells were successfully delivered to the target regions of the eye.
• Safety: Tracking the incidence and severity of any adverse events related to the procedure within the first 3 months.

Other Outcomes

• Retinal Structure: Measuring the proportion of patients showing qualitative improvement in retinal structure (via OCT scans) within the first 3 months.

Delivery Method

• The study used three different treatment plans (“Arms”) that combined several injection methods:
• IV: Into the bloodstream
• Retrobulbar: Behind the eyeball
• Sub-tenons: Into the tissue surrounding the eyeball
• Intravitreal: Into the gel-like substance inside the eye
• Subretinal: Under the retina (used for the most severe cases)

Cell Type & Source

• The treatment used autologous Bone Marrow-Derived Stem Cells (BMSCs).
• This is a concentrate of multiple cell types, including mesenchymal stem cells, taken from the patient’s own bone marrow.

Cell Preparation

• The cells were not cultured or expanded in a lab.
• The procedure was performed on the same day. Bone marrow was harvested, processed immediately using an FDA-cleared device and then administered back to the patient.

Dosage

• The total concentrate contained an average of 1.2 billion total nucleated cells.
• The number of cells varied depending on the injection site:
• Approximately 4 million cells for intravitreal injection.
• Up to 240 million cells for retrobulbar injection.

Safety

• The procedure was conducted safely with no complications observed.
• Because the treatment used the patient’s own cells, no immunosuppression was required.

Clinical Improvements

• 63% of treated eyes (20 of 32) showed an improvement in visual acuity.
• The average improvement in these eyes was 27.6% on the LogMAR vision scale.
• 34% of treated eyes (11 of 32) remained stable over the one-year follow-up period.
• The overall improvement in vision was highly statistically significant.

How the Cells Worked

• The cells appeared to work through supportive mechanisms rather than directly replacing lost tissue.
• Follow-up scans showed no major structural changes in the retina, suggesting the cells did not permanently engraft.
• The benefits are believed to result from paracrine effects ,the release of helpful substances such as neurotrophic factors and exosomes that:
• Provide neuroprotection
• Improve function of remaining retinal cells
• Reduce inflammation

What We Don’t Know

• The exact mechanism is not confirmed. It’s unclear whether the benefits come solely from paracrine effects or partial differentiation into new retinal cells, as suggested by some animal studies.
• The study was not randomized or controlled, and follow-up exams were conducted by local ophthalmologists, introducing possible data variability.

Conclusion

• The SCOTS trial demonstrated that treating dry AMD with a patient’s own bone marrow-derived stem cells can:
• Provide statistically significant improvement in visual acuity for most patients.
• Stabilize vision in others.
• The authors conclude that this approach is safe and warrants further clinical evaluation as a potential therapy to improve or delay vision loss from dry AMD.

Delivery Method

• Each participant received a one time subretinal transplantation of the implant during an outpatient surgical procedure.

Cell Type & Source

• The treatment uses an engineered implant called CPCB-RPE1.
• This implant is a patch of new, healthy eye cells designed to replace the ones that have died.

Cell Preparation

• The Cells: The new cells are Retinal Pigment Epithelium (RPE) cells grown in a lab from a line of human embryonic stem cells.
• Researchers guided embryonic stem cells to become fully developed RPE cells.
• The Structure: These RPE cells are grown as a single, organized layer (a “monolayer”). This organization is essential because it gives the cells a defined top and bottom,just like natural RPE cells in a healthy retina.

Dosage

• Each implant contained approximately 100,000 cells.

Safety

• The therapy met its primary endpoint and was confirmed to be safe and well tolerated at the one year mark.
• No unexpected serious adverse events were related to the implant itself.
• Eye adverse events such as retinal hemorrhage and edema occurred in four of the first six patients, but after surgical modifications, these events were significantly reduced in subsequent patients.
• No cases of implant migration, rejection, or tumor formation were observed.

Clinical Improvements

• Although the study was not statistically powered for efficacy, the results showed positive trends in vision improvement:
• 27% of treated eyes (4 of 15) gained more than 5 letters on an eye chart (improvements ranged from 6 to 13 letters).
• Only 7% of untreated fellow eyes gained more than 5 letters.
• Fewer treated eyes lost vision compared to untreated eyes (33% vs. 47%).

How the Cells Worked

• The therapy aims to support the patient’s remaining functional vision cells rather than replace all lost cells.
• The implant is believed to work in two main ways:
• Supporting Nearby Cells: The patch of healthy RPE cells provides vital support to photoreceptor cells above and around it, helping them survive and function better.
• Reactivating Dormant Cells: Within damaged areas, some photoreceptors may be “dormant” rather than dead. The new RPE patch may restore some of their function by rejuvenating the environment around them.

What We Don’t Know

• Although the safety profile was good, the study was small and lacked a control group, so the improvements are preliminary signals rather than conclusive evidence.
• It remains uncertain whether patients with less advanced disease might respond even better to this treatment.

Conclusion

• This was the first clinical trial of the CPCB-RPE1 implant.
• The study successfully demonstrated the safety of both the implant and the outpatient surgical procedure.
• The positive vision trends are encouraging, especially given the lack of available treatments for dry AMD.
• The researchers conclude that these findings justify further studies aimed at definitively proving the therapy’s effectiveness.

Cell Type & Source

• The treatment used Retinal Pigment Epithelium (RPE) cells derived from induced pluripotent stem cells (iPSCs).
• The cells were allogeneic, meaning they were grown from a single, established donor iPSC line rather than from the patients themselves.

Delivery Method

• The study used a new method called RPE strip transplantation:
• The new RPE cells are first grown in the lab into small, self-contained strips.
• During a standard vitrectomy, the surgeon creates a pocket under the retina and uses a fine needle to inject one or two strips into that space.
• The Goal: This approach is less invasive than transplanting a large patch but more controlled than a liquid injection because the strips are visible to the surgeon and remain in place. Once transplanted, the cells spread outward to form a new, functional RPE layer.

Dosage

• The AMD patient received one RPE strip; the two RP patients each received two strips.
• Each strip contained approximately 150,000 cells.

Safety

• Safety Confirmed: The RPE strip transplantation was completed with no serious adverse events.
• Notable Complications: Two manageable issues were reported:
• One patient experienced a mild immune reaction, successfully treated with anti-inflammatory therapy.
• Another developed an epiretinal membrane with macular edema, managed using a steroid injection.

Clinical Improvements

• Primary Goal Met: The study’s goal to reduce RPE damage was achieved in all three patients at 52 weeks.
• Vision (AMD Patient): The patient with dry AMD showed improved vision-related quality of life (VFQ-25 score) and better face recognition.
• Vision (RP Patients): The two patients with retinitis pigmentosa did not experience similar improvements and showed continued decline in some visual tests.

How the Cells Worked

• Engraftment and Expansion: Imaging confirmed the RPE strips successfully engrafted and expanded beneath the retina, forming a healthy hexagonal RPE cell layer.
• Mechanism: The therapy replaces diseased RPE cells with new ones that can support overlying photoreceptors (vision cells).

What This Means

• This first-in-human study demonstrates that RPE strip transplantation is a feasible and safe delivery method for retinal cell therapy.
• It provides a balance between invasive patch transplants and less controlled liquid suspensions.
• While vision improvement was only seen in one patient, successful engraftment in all participants provides critical proof of concept.

The Next Step

• Researchers recommend larger studies with more patients—particularly those with better baseline vision—to further evaluate safety and effectiveness.
• Longer-term follow-up will be needed to assess the durability of the transplanted cells and their impact on vision restoration.

• The main goal was to review the progress of the field and compare the different approaches being used to create and transplant RPE cells.
• How safe is this new type of therapy for patients? Have there been any serious side effects or complications like tumor formation?
• Has there been any evidence, even if preliminary, that these transplants can stop vision loss or even improve a patient’s sight?
• What are the major roadblocks still facing this technology and what is needed to move these therapies toward commercial approval?

1. Effectiveness (Clinical Evidence: Does it Work?)

• The trials were too small to make definitive conclusions about efficacy, but some positive signs were observed:
• Overall: In the 29 patients treated across six trials, none experienced a further decline in vision after the transplant.
• Wet AMD Patients: The three patients with “wet” AMD no longer required anti-VEGF injections after the transplant. The two patients with acute wet AMD experienced a significant improvement in visual acuity.
• Dry AMD Patients: At least one patient with “dry” AMD who received an RPE patch also showed an improvement in visual acuity.

2. How the Cells Work

• The goal of the therapy is for the new, lab-grown RPE cells to replace the old, degenerated ones.
• A healthy RPE transplant is expected to:
• Restore the RPE cell layer and provide functional support to the overlying photoreceptors (vision cells).
• “Patch” tears in the RPE layer to stop leaky blood vessels that cause wet AMD.
• Re-initiate nutrient exchange between photoreceptors and the blood supply.

3. Stem Cell Sources

• Embryonic Stem Cells (ESCs): Most of the trials (28 of 29 patients) used ESC-derived RPE cells. These are allogeneic (from a donor cell line).
• Induced Pluripotent Stem Cells (iPSCs): One trial used iPSC-derived RPE cells, which were autologous (created from the patient’s own cells).

4. Delivery Methods

• Cell Suspension: Simpler procedure where RPE cells are injected as a liquid suspension under the retina (22 of 29 patients).
• Cell Patch: More complex surgery where cells are grown on a scaffold and transplanted as a patch (7 of 29 patients).

5. Safety

• Safety was the primary goal, and results were positive:
• Overall Safety: All six trials confirmed the safety of RPE transplantation.
• Adverse Events: No severe side effects linked to the cells. Most side effects were due to surgery or immunosuppressants.
• Specific Issues: Some patients who received cell suspensions developed small, non-cancerous membranes (preretinal patches).

6. Limitations in the Studies Reviewed

• Small patient numbers (29 total).
• Most patients had very poor vision before treatment, limiting measurable improvement.
• Each trial used different manufacturing and surgical methods, making comparisons difficult.

• The authors state that the initial first-in-human trials have successfully confirmed the safety of transplanting PSC-derived RPE cells.
• While there are promising early signs of efficacy, the field has several roadblocks to overcome before it can be commercially approved.
• Future Phase 2 and 3 trials with larger patient populations will be required to prove efficacy.
• A key next step will be developing a way to cryopreserve (freeze) the cell patches so they can be easily distributed to clinics worldwide.

• The main goal was to summarize the existing evidence on the risks and benefits of stem cell transplantation for dry AMD.
• By combining the data from multiple small studies, could they determine if stem cell therapy, as a whole, leads to a statistically significant improvement in vision?
• How safe is the procedure? What are the common adverse events, and are they serious?
• Do different types of stem cells lead to different outcomes?

1. Clinical Evidence: Does it Work?

• The combined data showed a significant improvement in vision after treatment:
• Overall Efficacy: Patients were 17 times more likely to have vision improvement at 6 months and 11 times more likely at 12 months after transplantation compared to before treatment.
• Cell Type Impact: Different stem cell types showed varying effectiveness. Adipose-Derived Stem Cells (ADSCs) produced the strongest vision improvements, followed by hESC-RPE and Bone Marrow Stem Cells.

2. Mechanism of Action (How the Cells Work)

• The review did not specifically analyze the mechanism, but noted that stem cells are believed to provide:
• Neuroprotective effects
• Anti-inflammatory effects
• Anti-apoptotic (anti–cell death) effects
• Overall promotion of survival and functional restoration of retinal cells

3. Stem Cell Sources

• The 10 studies used various stem cell types:
• hESC-RPE: Retinal Pigment Epithelium cells derived from human embryonic stem cells.
• Adipose-Derived Stem Cells (ADSCs): Mesenchymal stem cells sourced from fat tissue.
• Bone Marrow with CD34+ Stem Cells: Stem cells isolated from bone marrow.

4. Delivery Methods

• Subretinal: Injection under the retina.
• Suprachoroidal: Injection into the space between the sclera and the choroid.
• Intravitreal: Injection into the vitreous humor (the gel-like substance inside the eye).

5. Safety

• Overall Safety: The therapy was found to be relatively safe.
• Adverse Events: Only four related eye events were reported, including retinal hemorrhage and detachment.
• Systemic Events: No systemic (body-wide) adverse events were reported.
• The researchers believe the eye events were due to the injection procedure, not the cells themselves.

6. Limitations in the Studies Reviewed

• Small sample sizes across most studies.
• Only one randomized controlled trial among the 10 studies, increasing risk of bias.
• Incomplete reporting of adverse events, limiting full assessment of long-term safety.

• The authors conclude that their meta-analysis suggests stem cell transplantation may improve vision in patients with dry AMD.
• The therapy appears promising and relatively safe in the short term.
• However, the conclusion is preliminary due to the small number of studies and limited patient data.
• They emphasize that more evidence from large-scale, randomized controlled trials is needed to confirm long-term safety and effectiveness.

• The main goal was to combine all available data to see if cell therapy, as a whole, leads to a statistically significant improvement in vision for patients with AMD, SMD, and RP.
• Do different types of stem cells, the age of the patient, or the use of a scaffold have an impact on the treatment’s effectiveness?
• What does the overall evidence say about the potential of cell therapy for these currently incurable eye diseases?

1. Effectiveness (Clinical Evidence: Does it Work?)

• The combined data showed a statistically significant improvement in vision for all three diseases:
• AMD: Analysis of 12 studies (140 eyes) showed a significant improvement in vision, especially in patients with the “wet” form of AMD.
• SMD: Analysis of 7 studies (40 eyes) showed a significant improvement in vision.
• RP: Analysis of 2 studies (44 eyes) also showed a significant improvement in vision.

2. How the Cells Work

• The goal of cell replacement therapy is to generate new retinal cells to replace injured photoreceptors.
• Stem cells may also provide additional benefits including:
• Neuroprotection
• Immuno-regulation
• Inhibition of cell death
• Release of helpful growth and repair proteins

3. Stem Cell Sources

• The studies used a variety of stem cell sources, categorized as follows:
• RPE (Retinal Pigment Epithelium) Cells
• NSC (Neural Stem Cells)
• BMSC (Bone Marrow Mesenchymal Stem Cells)
• UMSC (Umbilical Cord Mesenchymal Stem Cells)
• ADSC (Adipose-Derived Stem Cells)

4. Which Cells Performed Better

• The meta-regression analysis for AMD patients found that:
• The use of RPE cells and NSCs had a significant positive effect on vision improvement.
• The use of BMSCs and UMSCs did not show a statistically significant effect.

5. Safety

• This meta-analysis did not include a formal analysis of adverse events.
• However, based on the reviewed studies, severe adverse events following stem cell therapy were infrequent.

6. Limitations in the Studies Reviewed

• Limited Number of Studies: Especially for RP and SMD, only a few studies were available.
• Inconsistent Reporting: Many studies reported only visual acuity, limiting analysis of retinal structure and other metrics.
• Lack of Long-Term Data: The review could not assess the long-term effects of treatment due to insufficient follow-up data.