Muscle Derived Cell Therapy for Bladder Exstrophy Epispadias Induced Incontinence

Bladder exstrophy patients who have undergone primary bladder closure, but have a bladder
capacity too low for bladder neck reconstruction (Group 1), have limited additional surgical
options that permits urethral voiding and urine storage within a native bladder. Previous
studies have demonstrated a positive correlation between bladder capacity and success of
bladder neck reconstruction. Likewise, patients who have undergone bladder neck
reconstruction but continue to have urinary incontinence (Group 2) are also faced with
limited options. Often, both groups are considered for augmentation cystoplasty with closure
of the bladder neck requiring intermittent catheter voiding through a surgically constructed
continent catheterizable channel. Such major reconstruction has significant associated short
and long-term morbidities. Endoscopic injection of MDCs for the treatment of urinary
sphincter insufficiency is a potential alternative therapy for these patients. By increasing
the outflow resistance and rhabdosphincter contractility, MDC injection may permit more
efficient bladder cycling and bladder expansion in Group 1 patients allowing them to proceed
on to bladder neck reconstruction. This same increase in resistance and sphincter
contractility may allow Group 2 patients to attain urinary continence and avoid any further
reconstructive surgical procedures.

Eligible and consented patients would undergo rectus muscle biopsy and immediately
transferred to the Cell Therapy Lab for tissue processing and MDC expansion.The MDC expansion
process takes approximately 21 days after which cells are harvest and cryopreserved for
future injection.Each vial will be filled with cells at a concentration of approximately 2.0
x 107 cells/ml. At the time of planned MDC injection, enrolled patients will return for
cystoscopy under anesthesia. At that time, aliquots of MDCs will be removed from the freezer
and be allowed to thaw passively in the 30 minutes preceding the time of planned injection.
MDC product will be endoscopically injected using an FDA approved DEFLUX™ needle at the level
of the external urethral rhabdosphincter and bladder neck. Patients would be assessed for
toxicity and adverse events postoperatively at day 1 and 40 followed by semiannual visits for
36 months. variables measured are:

group 1: Bladder capacity, detrusor leak point pressure, bladder filling pressure, post-void
residual urine volume, urodynamics, periurethral electromyographic activity, renal - Bladder
Ultrasound, cystoscopy.

Group 2: Detrusor leak point pressure, bladder filling pressure, maximum cystometric
capacity, post-void residual urine volume, periurethral electromyographic activity, 24 hour
pad / diaper weight assessment, voiding diary including incontinence grade and maximum
daytime dry interval, renal - Bladder Ultrasound, cystoscopy

Inclusion Criteria:

1. Group 1 - Males and females at least 2 years of age with:

- Classic bladder exstrophy with successful primary, secondary, or delayed primary
closure and subsequent epispadias repair.

- Cystography done with 90 days preceding participant identification and at least
12 months after successful bladder closure demonstrating a bladder capacity less
than 100cc.

2. Group 2 - Males and females greater than 5 years of age with:

- Classic bladder exstrophy with successful primary, secondary, or delayed primary
closure and subsequent epispadias repair.

- Previous bladder neck reconstruction.

- At the time of participant identification, urinary incontinence defined as
leakage of urine at night or leakage of urine at an interval of less than 3 hours
in the daytime persisting at least 2 years after bladder neck reconstruction.

3. Screening labs obtained less than 30 days prior to MDC injection meeting the following
criteria:

- Urinalysis and urine culture demonstrating either no bacterial growth or growth
of an organism that can be treated with an appropriate oral antibiotic for 7 days
preoperatively. Participants with a positive urine culture should have the
urinalysis and urine culture repeated after completion of antibiotics and prior
to MDC injection. A negative urine culture must be demonstrated prior to MDC
injection.

- Serum creatinine in normal range for age (Infant: 0.2-0.4 mg/dl; Child 0.3-0.7
mg/dl; Adolescent 0.5-1.0 mg/dl).

- Negative Study Donor Virology Panel (Hep B surface antigen, HIV 1 / 2 antibody,
Hep B core antibody, Rapid Plasma Reagin (RPR), Human T-cell Lymphotrophic Virus
(HTLV) I / II antibody, Hep C antibody). This panel is only done during the
screening process and is not repeated during study follow-up.

4. Parent or legal guardian who is, in the opinion of the investigator, reliable and
willing to make themselves and patient available for the duration of the study and are
willing to follow study procedures and unit policies.

5. Parent or legal guardian able to complete and sign the informed consent document.

6. Negative pregnancy test for sexual active female teenagers. If able to conceive and
sexually active, participants must agree to use barrier contraceptives from the time
of study enrollment until 6 months after the last MDC injection. Male participants who
are able to conceive and are sexually active must agree to use protection as well from
the time of study enrollment until 6 months after the last MDC injection.

Exclusion Criteria:

1. Urodynamic study demonstrating severe uninhibited bladder contractions.

2. Severe urethral or bladder neck stricture demonstrated during screening cystoscopy or
cystogram

3. Cystography at the time of screening demonstrating Grade IV vesicoureteral reflux
(high-grade reflux with dilation of the renal pelvis and blunting or the fornices) or
Grade V vesicoureteral reflux (Grade IV findings plus loss of the papillary impression
and ureteral tortuosity).

4. Any degree of renal scarring at the time of screening as demonstrated by DMSA or MAG3
renal scintigraphy in the presence of any grade of vesicoureteral reflux (VUR)

5. Renal ultrasound demonstrating Society of Fetal Urology Grade III hydronephrosis
(widely split renal pelvis, renal calices uniformly dilated, no parenchymal thinning)
or Grade IV hydronephrosis (Grade III dilation plus parenchymal thinning). See
Appendix D.

6. Previous injection of bulking agents at the level of the bladder neck (bovine collagen
or DEFLUX™)

7. Positive urine culture resistant to preoperative oral antibiotic therapy

8. Need for chronic or pulse steroids or history of other congenital or acquired
condition that results in immunocompromise

9. Previous adverse reaction to anesthesia