Gene Therapy for Male Patients With Danon Disease Using RP-A501; AAV9.LAMP2B

The study is a non-randomized open-label Phase I clinical trial to characterize the safety
and toxicity associated with infusion of a recombinant adeno-associated serotype 9 (rAAV9)
capsid containing the human lysosome-associated membrane protein 2 isoform B (LAMP2B)
transgene (investigational product (IP), RP-A501) in male patients with Danon Disease (DD).

During the course of the study, approximately 12-24 subjects will receive a single
intravenous (IV) infusion of the IP, with up to 4 specific cohorts receiving RP-A501 at
sequentially higher dose levels. Two dose levels are planned to be investigated in 4 distinct
cohorts:

- Cohort 1: Adult and age 15-17: Low Dose (n=3-6 subjects)

- Cohort 2: Adult and age 15-17: High Dose (n=3-6 subjects)

- Cohort 3: Pediatric age 8-14: Low Dose (n=3-6 subjects)

- Cohort 4: Pediatric age 8-14: High Dose (n=3-6 subjects)

Pending determination of safety in Cohort I, concomitant enrollment in Cohorts 2 and 3 is
permissible.

The study will also enable an initial evaluation of whether or not the investigational
therapy results in cardiomyocyte and skeletal muscle transduction and gene expression and
preliminary assessment of the extent of cardiomyocyte and histologic correction.
Additionally, a preliminary evaluation of clinical stabilization following infusion will also
be made.

Inclusion Criteria:

1. DD diagnosis with any confirmed LAMP2 mutation(s).

2. Cardiac involvement as documented by at least one abnormal finding on
electrocardiogram (ECG), echocardiogram, gadolinium-enhanced cardiac magnetic
resonance imaging (MRI) or electrophysiology study.

3. Age ≥15 years for cohorts 1 and 2; 8-14 years for cohorts 3 and 4.

4. Male gender.

5. New York Heart Association (NYHA) Class of II or III. Patients with NYHA Class I are
eligible if unable to walk ≥450 meters during the 6-Minute Walk Test (6MWT).

6. Adequate hematologic function as defined by:

1. Hemoglobin ≥10 g/dL (6.2 mmol/L; Grade ≤ 1 anemia, per National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI CTCAE), version 5.0).

2. Absolute neutrophil count ≥1500/mm^3 (1.5×10^9/L; Grade ≤1 neutropenia).

3. Platelet count ≥75,000/mm^3 (75×10^9/L; Grade ≤1 thrombocytopenia).

7. Hepatic function as defined by:

1. AST and ALT ≤7×ULN (transaminase elevations in DD are considered largely to
result from muscle injury; hence the relatively high upper limit for these
parameters, and the presence of additional hepatic eligibility markers of
bilirubin and PT/INR).

2. Serum bilirubin ≤1.5×ULN (i.e., Grade ≤1 bilirubin increase).

3. PT/INR ≤1.5×ULN (in the absence of anticoagulation).

8. Renal function as follows: creatinine ≤1.5×ULN; (if creatinine is >1.5×ULN, then
creatinine clearance ≥50 mL/min/1.73m^2 is required, as calculated by Modification of
Diet in Renal Disease equation (Stevens 2006), the revised Schwartz formula (for
patients under 18 years old) (Schwartz 2009), or 24-hour urine collection).

9. Ability to provide informed consent (for adult patients and parents/legal guardians of
pediatric patients) and assent (for patients age 15-17).

10. Ability to comply with study procedures including investigational therapy and
follow-up evaluations.

11. Able to walk >150 meters unassisted during the 6MWT.

Exclusion Criteria:

1. IV therapy with positive inotropes, vasodilators or diuretics within the 30 days prior
to enrollment (i.e. patient must be stable on oral medical therapy).

2. Prior cardiac transplantation or prior transplant of other organ (lung, liver, other).

3. Cardiac surgery, percutaneous cardiac intervention or valvuloplasty within 30 days
prior to enrollment.

4. Presence or requirement of a LVAD.

5. Myocardial infarction, unstable angina, stroke or transient ischemic attack (TIA)
within 90 days prior to enrollment.

6. Significant (greater than moderate) valvular stenosis or regurgitation on
echocardiogram.

7. Requires mechanical ventilation.

8. Anti-AAV9 neutralizing antibody titer >1:5.

9. Concurrent enrollment in any other clinical investigation involving use of an
investigational agent for the treatment of congestive heart failure or cardiomyopathy.

10. Active hepatitis B or C infection (including patients with positive HBsAg, HBeAg or
detectable HBV or HCV viral load). Patients with previous, adequately resolved HBV or
HCV are eligible.

11. Significant medical conditions including documented HIV infection, active viral or
other hepatitis, poorly-controlled hypertension or diabetes, poorly controlled cardiac
arrhythmia or uncontrolled viral, bacterial or fungal infection.

12. Any concomitant medical or psychiatric condition that in the opinion of the
investigator renders the patient unfit for study participation or at higher than
acceptable risk for study participation.

13. Active hematologic or solid organ malignancy, not including non-melanoma skin cancer
or other carcinoma in situ. Patients with previously resected solid organ malignancies
or definitively treated hematologic malignancies may be eligible if there has been no
evidence of active malignancy during the prior 3 years.