The Use of Umbilical Cord-Derived Mesenchymal Stem Cells in Patients With Muscular Dystrophies: Results From Compassionate Use in Real-Life Settings

Major Points and Findings:

This Polish report describes 22 patients with several types of muscular dystrophy who received repeated doses of donor umbilical cord (Wharton’s jelly) mesenchymal stem cells under a compassionate-use arrangement, in most cases one intravenous infusion followed by intrathecal injections every two months. The cell type, the mixed route and the repeated dosing resemble the way cells are given in many clinics, including ours.

The evidence is weak by design. There was no control group, no blinding and no trial registration, and the outcomes were largely the investigators’ own dynamometer and gait tests. Average muscle strength rose at several joints, but the response varied widely, and six of 22 (27.3%) showed a change large enough to alter gait or a functional scale. Two of the four authors are employees of the company that made the cells, and the same company funded the work.

Aim:

To describe the safety and clinical outcomes of Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) given as an advanced therapy medicinal product to patients with muscular dystrophy outside a formal trial, under the Polish “medical experiment” rules for compassionate use.

Methods:

This was a single-arm, open-label medical experiment at Klara Medical Center in Częstochowa, Poland, between October 2016 and February 2018, approved by the local bioethics committee but not registered as a clinical trial. Inclusion criteria were age 3 to 85 years and a diagnosis of dystrophy of any type. Exclusion criteria were pregnancy or breastfeeding, infectious disease, severe psychiatric disorder, cancer, penicillin intolerance and unstable cardiovascular disease.

Twenty-two patients were treated, 11 men and 11 women, median age 33 years (range 4 to 63). The text reports 10 with limb-girdle muscular dystrophy, six with facioscapulohumeral dystrophy (FSHD), one with myotonic dystrophy, one with Becker dystrophy and four with an unspecified type. The per-patient table (Table 2) lists a different breakdown: eight limb-girdle, six FSHD, two myotonic, two Becker, one Duchenne (a 29-year-old woman) and three unspecified. The paper does not explain the difference. Only one patient was a child, a 4-year-old boy with myotonic dystrophy.

The cells were made under Good Manufacturing Practice by Polski Bank Komórek Macierzystych (FamiCord Group), Warsaw, from cord explants expanded to no more than passage 5, with viability above 90%, standard MSC surface markers (CD73, CD90, CD105 positive; CD34, CD45, CD14, CD19, HLA-DR negative), sterility and infection testing, and cryopreservation in 10% dimethyl sulfoxide with 5% human albumin.

Four standard doses of 10, 20, 30 or 40 million cells per injection were chosen by body weight, giving roughly 1 million cells per kg per injection. Injections were given every two months, one to five per course, with up to two courses allowed. The first injection was always intravenous for safety; later ones were intravenous or intrathecal. The text says two patients had only intravenous injections, four had only intrathecal after the first dose, and 16 had one intravenous injection then intrathecal ones. Table 2 shows 5 to 10 injections per patient (one FSHD patient had one intravenous and nine intrathecal). No immunosuppression was given.

Assessments were done the day before each injection: a 26-item dynamometer strength test (hand grip plus flexion, extension, adduction and abduction at shoulder, elbow, hip and knee, best of three attempts, in Newtons), a filmed 2-metre walk for sideways lean, a 6-metre walk for step length and speed, the Brooke and Vignos scales, and the investigator’s and patient’s opinion of change. A qualitative tendency was noted at 6 months. Change was tested with the Friedman test and Dunn’s post hoc comparison.

Results:

Muscle strength (Table 3, n = 22): Comparing baseline with the end of the course, median strength rose significantly at 14 of the 26 measures. The largest gains were right elbow extension (16.0 to 25.5 N, p below 0.0001), right shoulder adduction (7.0 to 10.0 N, p below 0.0001), right hip adduction (7.5 to 10.0 N, p below 0.0001), left shoulder abduction (26.5 to 39.5 N, p = 0.003), left shoulder flexion (14.0 to 20.5 N, p = 0.001) and right hip flexion (18.0 to 25.5 N, p = 0.002). Smaller significant gains were seen in right hand grip (175.5 to 179.5 N, p = 0.049), left hip extension and adduction, right hip extension, right knee extension, left shoulder extension, and right shoulder abduction and flexion.

Several cautions apply. Twelve measures did not change significantly, including left hand grip, knee flexion on both sides and left knee extension. For some significant items the overall test across all five visits was not significant (right hand grip, right knee extension, right shoulder abduction), and the percentage change from baseline was significant for only two measures (right shoulder adduction and right elbow extension). Right elbow flexion fell from a median of 29.0 to 24.0 N (p = 0.038), a change in the wrong direction that the text does not comment on.

Individual response (Table 2): Measured strength improved in 12 of 22 patients (54.5%). The investigator judged 11 (50.0%) improved and 14 patients (63.6%) felt improved; by interview, walking improved in 13 (59.1%) and self-care in 10 (45.5%). On the filmed gait analysis, only 3 patients (13.6%) improved in sideways lean, step length and walking speed. The Brooke scale improved by one grade in 3 patients (13.6%); the Vignos scale improved in 1 patient (4.5%, from 7 to 5) and worsened by one grade in 3. At 6 months the qualitative tendency was upward in 7 patients (31.8%), unchanged in 13 and downward in 2. The authors state that 6 of 22 (27.3%) had a benefit large enough to change gait or a functional scale, and that outcome was not associated with dystrophy type, sex or route. The best case stopped using a crutch, ended rehabilitation and returned to full-time work. The discussion mentions one patient with partial deterioration in the lower limbs.

Safety: The authors write that administrations were well tolerated and that “only one patient experienced transient headache and lower back pain after the last administration” (a 38-year-old man with limb-girdle dystrophy, one intravenous and four intrathecal injections). Table 2 also records weight gain as an adverse event in a second patient (a 31-year-old woman with limb-girdle dystrophy); the other 20 rows say “No”. No serious adverse events, infections or immune reactions were reported. The paper does not describe systematic laboratory safety monitoring.

Creatine kinase, spirometry, the 6-minute walk test, timed tests and the North Star Ambulatory Assessment were not measured.

Conclusions:

The authors call WJ-MSCs a reasonable experimental option in Poland under hospital exemption and describe the results as “cautiously encouraging”, while stating that it is far too early to define the place of MSCs in dystrophy and that the duration of any effect is unknown. They suggest a paracrine mechanism may require cyclical repeat treatment.

The limitations they list are: an open, uncontrolled design; no measurement of what the injected cells secreted; no blood biomarkers or standard clinical tests (6-minute walk, time to stand, North Star); and short, qualitative follow-up. Added to that, the disease types were mixed, only one Duchenne patient and one child were included, the eligibility criteria were very broad, and the abstract’s “intravenous and/or intrathecal” simplifies a schedule that varied from patient to patient.

Background Information:

The authors argue that cells cannot correct the mutation but may soften its consequences, chiefly inflammation (they cite an eight-fold rise in TNF-alpha and a two-fold rise in IL-6 in Duchenne boys). The intrathecal route was justified by the presence of dystrophin in Schwann cells and by an earlier uncontrolled series in India. The dose and the three-injection minimum came from the manufacturer’s experience in other neurological conditions, not from dystrophy data. The manufacturer funded editorial support and employs two of the four authors; the other two hold leadership posts at the treating clinic.