Safety and Preliminary Efficacy of ULSC in Facioscapulohumeral Muscular Dystrophy (FSHD)

• ULSC (Biological): Allogeneic umbilical-cord lining stem cells (ULSC) are cryopreserved and supplied in vials to be thawed and prepared for infusion at point of use. Each dose of 1 x 10\^8 ULSC will be added into 250 sterile saline for infusion (total volume of 260 mL volume).
• Placebo (Biological): The Placebo will consist of 250 ml of sterile saline with sterile diluent solution added (total volume of 260 mL) for IV administration.

Primary outcomes

• Adverse Events (AE) and Serious Adverse Events (SAEs) that begin during or following treatment infusion. [Baseline, during each infusion, 7 days, 30 days, and 3 months after each infusion, as well as 6 months and 12 months after the final dose.]: Cumulative listing of all AEs/SAEs with descriptive statistics for categorical variables and count variables with emphasis on all SAEs and AEs/SAEs suspected to be treatment infusion-related.

Secondary outcomes

• Balance and Mobility Assessment of Timed Up and Go (TUG) [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: Individuals are asked to rise from a chair, walk 3 meters, turn around, return to the chair, and sit. The time that it takes to complete the task will be recorded. The TUG will be performed at a comfortable pace and at a maximum pace. Assistive devices, orthoses, and ankle braces will be allowed. This test involves walking only, not running or skipping. This test is a timed test, and it will use Stanford-created OPENCAP video capture system.
• Leg Function Assessment of Timed Sit to Stand [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: Timed sit to stand tests proximal lower extremity strength and core strength by having subjects stand from a standard height chair. This will be performed and timed one time and five times; the latter using Stanford-created OPENCAP video capture system.
• Leg Function Assessment of 10 Meter Walk (10MWT)/Run (10MWRT) [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: From a standing start, the participant will be asked to go 10 meters either walking at normal speed (10MWT) or as quickly as possible, whether by walking or running (10MWRT). Orthotics and ankle braces are allowed. The time in seconds to complete the task will be recorded; these tests will use Stanford-created OPENCAP video capture system.
• Leg Function Assessment of Time to Ascend/Descend 4 Stairs [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: Participants will be asked to climb up and down (Timed as separate tests) 4 stairs as quickly as possible, using steps with a six-inch rise and ten-inch run. Quality grades will be captured for this test to record the use of railings and manner of ascent (i.e. step-to or step-over-step pattern). The time it takes to complete the task will be recorded.
• Leg Function Assessment of Toe Stand [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 (6 months after the final dose).]: Evaluate lower leg and balance by having participants rise onto tip toes as quickly as possible and try and hold it there for 30 seconds. This test will use Stanford-created OPENCAP video capture system.
• Leg Function Assessment of Jumping [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: To evaluate participant's ability to jump as high as possible. If unable to jump, the participant is instructed to simulate a jump by bending their knees and standing upright as fast as they can. This test will use Stanford-created OPENCAP video capture system.
• Shoulder and Arm Function Assessment Using Brooke Upper Extremity Scale (with and without weights) [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: The tasks are an adaptation of the activities contained in the Brooke upper extremity scale, to test straight arm abduction without compensation to lift hands above head, or to test ability to lift a weighted cup (200 g) to chin or alternatively, to lift an unweighted cup. This category tests proximal to mid arm tasks, and the ability to coordinate upper extremity function across a variety of muscle groups (shoulder abduction/flexion, elbow flexion/extension). Brooke score is assigned on scale from 2 (unable to lift unweighted cup from lap to chin) to 6 (hands lifted above head with no compensation). This test will use Stanford-created OPENCAP video capture system.
• Shoulder and Arm Function Assessment of Donning and Doffing a Coat [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: Measuring the time it takes participants to don and doff a coat, which is a more complex task that incorporates functional use of both proximal and mid-limb muscles.
• Shoulder and Arm Function Assessment of Stacking Heavy Cans [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: Assessing participant's ability and number to stack up to five (5) heavy cans.
• Manual Muscle Testing (MMT) of Shoulder and Elbow Muscle Groups [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: These tests evaluate right and left separately tested movements including shoulder abduction, shoulder forward flexion, and elbow flexion. Tests will include use of a 5-pound weight and evaluate whether participant can perform movements with full range of motion (ROM) and no compensation for the best score on the scale. In each test, score is determined based on defined criteria, such as the ability to perform with compensation or without weight (antigravity), with or without compensation, or with limited degree of range of motion.
• Assessment of Arm Range of Motion (ArmRoM) [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: This task evaluates bilateral arm movement in six (6) directions, arm raises in different directions and horizontal sweeps at waist height or as high as able, to assess range of motion of shoulder muscle groups and ability to move arms in smooth controlled way while trying not to bend elbows. This test will use Stanford-created OPENCAP video capture system.
• Shoulder and Arm Function Assessment of Curls [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: This task evaluates elbow and wrist movement, including elbow full extension, elbow full flexion, and wrist supinated and pronated RoM while keeping elbows at 90° and moving in smooth controlled way. This test will use Stanford-created OPENCAP video capture system.
• Trunk Function Assessment of Picking up a Penny or Pencil from the Floor [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: Picking up a penny or pencil off the floor tests the ability to bend and straighten but also balance and the ability of lower extremity muscles to compensate for core weakness.
• Trunk Function Assessment of Sitting Up from Supine and Timed Supine to Sit [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 end of study (6 months after the final dose).]: The ability to sit up from lying supine and the timed supine to sitting at edge of bed test reflects core muscle strength and coordination. Functional axial strength will be assessed by instructing individuals to move from supine to sitting on the edge of a plinth as quickly as possible. The time that it takes to complete the task will be recorded, as well as the manner of sitting (e.g. using one or two hands to pull up).
• Quantitative Muscle Testing (QMT) with Hand-Held Dynamometry (HHD) [Baseline, and at 30 days and 3 months after each infusion, as well as at Month 15 (6 months after the final dose).]: QMT will be conducted by trained and study qualified clinical evaluator, with specific procedures as described in the Clinical Evaluator Manual, and using Microfet Handheld Myometer. Shoulder abductors, elbow flexors, elbow extensors, knee flexors, and hand grip force will be evaluated bilaterally and data (kg) will be recorded for each. Each assessment is obtained three times, for 5 seconds each attempt and 10 seconds of rest between each attempt. Every effort should be made to have the same evaluator conduct these tests for an individual participant during the study.
• Muscle Fat Fraction (MFF) [Baseline, Month 6 and Month 12.]: Change from baseline in Muscle Fat Fraction (MFF, %) as a measure of infiltration of fat in muscle; this is assessed by Musculoskeletal (MSK) Magnetic Resonance Imaging (MRI)
• Lean Muscle Volume (LMV) [Baseline, Month 6 and Month 12.]: Change from baseline in Lean Muscle Volume (LMV, cu cm or Liter) as a measure of infiltration of fat in muscle; this is assessed by Musculoskeletal (MSK) Magnetic Resonance Imaging (MRI).
• Physical Activity Monitor (Actigraphy Wearable Device) [After screening and before Day 1 (baseline), 30 days before Month 6 (cross-over), 30 days before Month 12, and 30 days before Month 15 (end of study).]: At prespecified times for at least 30 days, exercise and sleep activity is monitored using the Actigraphy wearable device, providing real-world assessment of physical activity, sleep, functional mobility, and vital signs.
• Ricci Clinical Severity Score [Screening, Day 1, Month 6, Month 12, and Month 15]: To assess clinical severity of disease on a 10-point scale score, 0 implying no muscle weakness and 10 implying wheelchair dependency.
• Patient-Reported Quality of Life Outcome Assessed by Activity Limitations for Patients with Upper and/or Lower Limb Impairments (ACTIVLIM) [Between baseline and timepoints up to Month 6 (prior to first dose at cross-over), between Month 6 and timepoints up to Month 12, and at Month 15 end of study (6 months after final dose).]: Change in patient-reported quality of life by using ACTIVLIM 18-item questionnaire (total score scale from 0 to 36) that assess activity limitations of daily living with higher score indicating better function.
• Patient-Reported Quality of Life Outcome Assessed by 5-Level EQ-5D Version (EQ-5D-5L) [Between baseline and timepoints up to Month 6 (prior to first dose at cross-over), between Month 6 and timepoints up to Month 12, and at Month 15 end of study (6 months after final dose).]: Change in patient-reported quality of life by using EQ-5D-5L, which is a standardized measure of health status developed by the EuroQol Group. EQ-5D-5L covers the following five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression; the five levels of severity range from no problems to extreme problems. In addition, it provides Visual Analog Scale (VAS) for patient self-assessment of health with VAS 100 score ranging from 0 to 100. Scoring the EQ-5D-5L produces a health state profile index score in which 1 is the best possible health state.
• Patient-Reported Disease Activity & Quality of Life Outcomes Assessed by Domain Delta [Between baseline and timepoints up to Month 6 (prior to first dose at cross-over), between Month 6 and timepoints up to Month 12, and at Month 15 end of study (6 months after final dose).]: Change in level of disease activity as reflected by patient-reported disease and quality of life outcomes by using Domain Delta 14-item questionnaire, which inquires about the patient's self-assessed perception of change in 14 subdomains including overall health, quality of life, fatigue, pain, subdomains of physical function, and various subdomains that include thinking, satisfaction/performance in social situations, and communication. Participants evaluate their own perceived change on a 5-level scale with scores ranging from "a lot worse" to "a lot better". The Domain Delta is an instrument developed to assess quality of life and how disease has changed since last visit.
• Patient-Reported Quality of Life Outcome Assessed by PROMIS-57 [Between baseline and timepoints up to Month 6 (prior to first dose at cross-over), between Month 6 and timepoints up to Month 12, and at Month 15 end of study (6 months after final dose).]: Change in level of disease activity as reflected in patient-reported quality of life outcome assessed by using PROMIS-57. The PROMIS-57 is a questionnaire developed by the NIH PROMIS initiative that generates scores for physical function and the impact of physical limitations on daily life.
• Patient-Reported Pain Assessed by Visual Analogue Scale (VAS 10) [Between baseline and timepoints up to Month 6 (prior to first dose at cross-over), between Month 6 and timepoints up to Month 12, and at Month 15 end of study (6 months after final dose).]: Change in level of patient-reported pain using Visual Analogue Scale (VAS 10) with 0 being no pain and 10 being the worst pain.
• Patient-Reported Disease Activity & Quality of Life Outcomes Assessed by Upper Extremity Functional Index 15 (UEFI-15) [Between baseline and timepoints up to Month 6 (prior to first dose at cross-over), between Month 6 and timepoints up to Month 12, and at Month 15 end of study (6 months after final dose).]: Change in level of disease activity as reflected by patient-reported disease and quality of life outcomes by using UEFI-15. The UEFI-15 is a validated patient reported measure for adults with upper extremity dysfunction involving a 15-item questionnaire that assesses patient-reported level of difficulty in performing activities of daily living using upper extremities and provides a score ranging from 0.0 to 100.0 with 100.0 indicating the highest functional status.
• Patient-Reported Disease Activity & Quality of Life Outcomes Assessed by Facial Disability Index (FDI) for physical facial function [Between baseline and timepoints up to Month 6 (prior to first dose at cross-over), between Month 6 and timepoints up to Month 12, and at Month 15 end of study (6 months after final dose).]: Change in level of disease activity as reflected by patient-reported disease and quality of life outcomes by using FDI. The FDI physical score is a short 5 item questionnaire which assesses the physical impact of facial weakness. The responses are individually scored on a scale of 0 to 5 for physical function, and on a scale of 0 to 6 for social function; total scores that are then converted into a percentage scale. A score of 100% represents normal function with no difficulty or impact, and lower scores indicate increasing levels of disability with higher levels of difficulty and impact.
• Timed Motor Function Tests [Between baseline and timepoints up to Month 6 (prior to first dose at cross-over), between Month 6 and timepoints up to Month 12, and at Month 15 end of study (6 months after final dose).]: To evaluate changes from baseline in timed motor function tests.

Other outcomes

• Tissue Oxygenation Assessed by Near Infrared Spectroscopy (NIRS) during Cardiopulmonary Exercise Testing (CPET) [Between Screening, Day 1, Month 6 and Month 12.]: Change from baseline of tissue oxygenation during Cardiopulmonary Exercise Testing (CPET) using Near Infrared Spectroscopy (NIRS) to monitor regional tissue oxygenation (rSO2) by detecting differential light absorption by oxygenated and deoxygenated hemoglobin.
• Functional and Quantitative Assessments [At each clinical visit up to Month 15 end of study (6 months after final dose).]: Change from baseline for various functional and quantitative assessments.
• Inflammatory and Immune Markers [From baseline to 30 days and to 3 months after each infusion, up to Month 6 (prior to first dose at cross-over), and Month 12 (6 months after cross-over), as well as Month 15 end of study (6 months after final dose).]: Changes in the levels of cytokines and other inflammatory and immune biomarkers measured in plasma samples.

Sex: All, ages: 15 Years to any

Inclusion Criteria:

* Participants will be ≥15 years old.
* Diagnosis of genetically confirmed FSHD 1 or FSHD 2.
* Participants should have a Ricci clinical severity score of ≥1.5 (range is out of 0-10), at screening, and must be independently ambulatory at the time of the study.
* Participant will have the ability to comply with the requirements of the study, including MRI.
* All participants of reproductive age/capacity will be required to use adequate contraception, defined as two forms of highly effective contraceptives, with any partners during the study period and for at least three months beyond the study period for safety.
* Participant will have the ability to understand and provide written informed consent.
* For those participants who are on drug(s) or supplements that may affect muscle function, as determined by the Investigator, participants must be on a stable dose of that drug(s) or supplement for at least 3 months prior to the first dose of study drug and remain on that stable dose for the duration of the study.

  * This includes the following drug category: Immunomodulatory agents, including targeted biological therapies.
  * Exception is rapamycin. (See Exclusion Criteria #10.)
* Current and up-to-date immunizations.
* No contraindications to MRI.
* Hematocrit of ≤ 50%
* Prostate-specific antigen ≤ 4.0 ng/mL (or ≤ 3.0 ng/mL if the participant has a first-degree relative with prostate cancer)
* Fasting blood glucose <126 mg/dL

Exclusion Criteria:

* Hypersensitivity to study product components including history of hypersensitivity to dimethyl sulfoxide (DMSO).
* Active cancer or prior diagnosis of cancer within the past year (patients with basal and squamous cell cancer of skin will not be excluded).
* Any other condition that, in the judgment of the Investigator or Sponsor, would be a contraindication to enrollment, study product administration, or follow-up.
* Treatment with an investigational product within three months prior to randomization.
* Known active opportunistic or life-threatening infections including Human Immunodeficiency virus (HIV) and hepatitis B or C.
* Known active or inactive tuberculosis infection.
* Use of a product that putatively enhances muscle growth or activity on a chronic basis within 4 weeks before baseline
* Orally administered cytochrome P450 (CYP3A4) substrates and multidrug and toxin extrusion (MATE) and organic anion transporter (OAT)3 substrates are not permitted as concomitant therapy. In case of prior use, wash out period will need to be evaluated by investigator.
* Statin treatment initiation or significant adjustment to statin regimen within 3 months before baseline (stable, chronic statin use is permissible).
* Rapamycin treatment within 3 months before baseline.
* Evidence of an alternative diagnosis other than FSHD or a coexisting myopathy or dystrophy, based on prior muscle biopsy or other available investigations.
* Muscle biopsy within 30 days before baseline.
* A systolic blood pressure over 160 or a diastolic pressure over 100
* Heavy alcohol use (greater than 50g/day)
* Current testosterone or HGH use
* Current use of medications that interfere with the growth hormone or gonadal endocrine axis.
* Pregnant of lactating participants.
* Concomitant severe cardiac, pulmonary disease, active infection, or other conditions that preclude assessment of safety and efficacy of the study product.
* Anticipated need for surgery during the trial period.
* A history of prevalent noncompliance with medical therapy.
* Recipient of an organ transplant.
* Neutropenia (absolute neutrophil count <1,800/mm\^3 \[or <1,000/mm\^3 in African-American participants\]).
* Severe impairment in renal function (estimated glomerular filtration rate <30 ml/min/1.73m\^2).
* Recent of planned use of vaccination with live attenuated viruses.
* Condition that would impair an assessment of muscle strength, including neurological disorders such as Parkinson's disease or severe musculoskeletal condition.

• John W Day, MD, PhD, Principal investigator, Stanford University, School of Medicine, Neuromuscular Research Division