Hypothesis / aims of study
Interstitial cystitis (IC) is a chronic inflammatory disease with characteristic pelvic pain with varying degrees of accompanied lower urinary tract symptoms. Tiered therapy are recommended in guidelines but most them result in temporary alleviation of pain and have limited evidence strength, in other words, there is no definite cure for IC. Stem cell therapy is emerging as potent alternatives in chronic diseases and IC is one of the possible candidates considering its intractable nature. Here we report the first clinical application of human embryonic stem cell (ESC) derived mesenchymal stem cells (MSCs) on IC.
The therapeutic efficacy of autologous MSCs in stress urinary incontinence and detrusor underactivity patients have been introduced in the literature, but none in IC. Previously, we have reported the beneficial effects and non-tumorigenicity of multipotent-MSC (M-MSCs) derived from human ESCs in various preclinical voiding dysfunction models. In this regard, we developed clinical grade MSCs derived from hESCs into cell-type product with code name MR-MC-01, and investigated its potential in treating IC patients. The primary outcome was safety and tolerability of MR-MC-01 in human subjects and the secondary outcomes were efficacy of MR-MC-01 in clinical symptoms including pain, voiding profiles and characteristic of Hunner lesions on cystoscopy.
Study design, materials and methods
Three female patients with 1) symptom duration > 6 months, 2) visual pain analog scale (VAS) ≥ 4, and 3) 1–2 Hunner lesions < 2 cm on cystoscopy within 1 month were included. Patients unsuitable for participation based on criteria and investigators’ consideration were excluded. Under general anesthesia, participants received a cystoscopic submucosal injection of MR-MC-01 (2.0 × 107 /5 mL) at the center or margin of Hunner lesions and another part of the bladder wall (except trigone), at a volume of 1 mL. Follow-up was performed 1, 3, 6, 9, and 12 months post-procedure. Patients underwent scheduled work-ups, and symptoms were evaluated with validated questionnaires at each visit.
Results
The median age of patients were 71 years (range 68 – 77) with symptom duration more than one year. All patients had refractory symptom to oral medication including pentosan polysulfate. Two patients had previous history of intravesical instillation and endoscopic operation but had recurrent symptoms. All patients had negative urine cytology or bladder biopsy to rule out combined malignancy before screening. First two participants completed 12-month follow-up and third participant finished 6-month follow-up.
No MR-MC-01 related adverse events including immune reaction and abnormalities on laboratory tests and imaging work-ups were reported. Patient 1 reported temporary right-side suprapubic pain after stem cell injection but it was tolerable and did not require opioid analgesics, additional intervention or admission. Pain improved significantly at post-procedure 1 month, but changes differed afterwards. However, none of the patients required gabapentin or opioid analgesics and unexpected transiently aggravated pain was well-controlled with prn NSAIDs. There was no significant aggravation in subjective symptom questionnaires and voiding diaries. None of the patients presented de novo Hunner lesions or any abnormalities in the bladder. Except one Hunner lesion of Patient 1, which was not identifiable on 12-month cystoscopy, the extent of other lesions were similar or slightly decreased.
Interpretation of results
Main difference between previous clinical trials using hESC-derived cells and this study is the use of immunosuppressant. In clinical trials using hESC-RPE cells or patch, patients were prescribed a temporary systemic immunosuppression regimen such as oral tacrolimus, mycophenolate mofetil, or oral prednisolone to prevent rejection. These regimens led to a wide range of side effects including fatigue, diarrhea, stomach ache, uncontrolled diabetes, infection, and shortness of breath. We did not use a systemic immunosuppressant due to following reasons; First, injection site was submucosa of the bladder that transplanted cells were highly likely to be localized between submucosa and detrusor which might result in limited systemic response. Second, IC bladder present changes in immune responses like B-cell abnormalities that cyclosporine A which modulate immunity is recommended as fifth-line treatment for IC in American Urological Association (AUA) guidelines. Concurrent prescription of an immunosuppressant is most likely to overestimate the therapeutic efficacy of MR-MC-01 in future studies. Third, actual injected number of cells might be less than expected as needle injection result in a tiny defect of urothelium which could be route for cell spillage. In addition, human urinates regularly that spilled cells into the urinary bladder are immediately diluted by urine and get washed out during voiding.
The therapeutic efficacy of MR-MC-01 varied among study participants but VAS pain improved significantly (VAS ≤ 4) at post-procedure 1 month in all subjects. Size of Hunner lesion is not always proportional to the degree of pain, but initially large (nearly 2cm) Hunner lesions were more likely to persist throughout the follow-up. Meanwhile, extent of small Hunner lesions (<1cm) tended to decrease that one Hunner lesion of Patient 1 was not identifiable at 12-month follow-up. This trend was not applicable to Patient 3 who had initially smallest Hunner lesions. However, the subject had longest symptom duration (11 years), previous history of TURC four times and relatively decreased functional bladder capacity than other subjects. Disease duration of IC and extent of previous therapy might play a key role in variation of therapeutic efficacy.