A Gene Therapy Study for Homozygous Familial Hypercholesterolemia (HoFH)

Subjects will be asked to participate in an optional kinetics study. Subjects who agree will
be admitted to the research inpatient unit at University of Pennsylvania or selected sites
for the LDL kinetics study prior to vector administration.

The LDL kinetic assessment will be performed using a primed constant infusion of deuterated
leucine for 12 hours with repeated blood draws up to 48 hours. 2- 14 days following the start
of the leucine infusion, subjects will be admitted to the research inpatient unit at
University of Pennsylvania where the AAV8.TBG.hLDLR gene therapy vector will be administered.
Vital signs will be monitored frequently for 24 hours. Blood will be drawn for safety testing
daily for 3 days up to 72 hours and then weekly up to 12 weeks. More comprehensive assessment
of safety parameters will occur every 4 weeks up to 12 weeks. Twelve weeks after vector
administration, subjects that participated in the first optional kinetics study will be
re-admitted to the inpatient unit at University of Pennsylvania or selected sites for a
repeat LDL kinetics study. After this visit subjects will be permitted to resume LDL
apheresis and/or plasma exchange, and other lipid lowering treatments at the discretion of
their caring physician. Subjects will have a safety visit with blood draw every 12 weeks up
to 52 weeks, and will be followed with bi-annual telephone calls and annual lipid tests
thereafter up to 260 weeks.

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the
following criteria:

1. Male or female ≥ 18 years of age.

2. Untreated and/or treated LDL-C levels and clinical presentation consistent with the
diagnosis of homozygous FH

3. Molecularly defined LDLR mutations at both LDLR alleles.

4. Concurrent allowed lipid lowering medication must be stable for ≥ 4 weeks before the
baseline visit and must remain stable until 12 weeks after vector administration.
These include but are not limited to: statins, ezetimibe, bile acid sequestrants,
PCSK9 inhibitors, and LDL and/or plasma apheresis. Subjects on other lipid-lowering
medications are eligible for the study but must wash out of these medications for the
pre-specified time period.

5. Females of childbearing potential must have a negative pregnancy test at screening and
baseline visits and be willing to have additional pregnancy tests during the study.

6. Sexually active subjects (both female and male) must be willing to use a medically
accepted method of contraception from screening visit until 6 months after vector
administration

7. A baseline serum AAV8 NAb titer ≤ 1:10.

8. Subjects must be able to comprehend and be willing to provide a signed institutional
review board/ethics committee (IRB/EC) approved Informed Consent Form.

9. Subjects must be willing to comply with all study-related procedures and be available
for the duration of the study.

Exclusion Criteria

Subjects who meet any of the following exclusion criteria will not be eligible to
participate in the study:

1. Unwilling to wash out of the following lipid lowering therapies for the pre-specified
time period:

1. niacin > 250 mg/day: within 4 weeks of baseline

2. fibrates: within 4 weeks of baseline

3. Lomitapide: within 6 weeks of baseline

4. Mipomersen: within 24 weeks of baseline

2. Heart failure defined by the NYHA classification as functional Class III with history
of hospitalization(s) within 12 weeks of the baseline visit or functional Class IV.

3. History within 12 weeks of the baseline visit of a myocardial infarction (MI),
unstable angina leading to hospitalization, coronary artery bypass graft surgery
(CABG), percutaneous coronary intervention (PCI), uncontrolled cardiac arrhythmia,
carotid surgery or stenting, stroke, transient ischemic attack, carotid
revascularization, endovascular procedure or surgical intervention.

4. Uncontrolled hypertension defined as: systolic blood pressure > 180 mmHg, diastolic
blood pressure > 95 mmHg.

5. History of cirrhosis or chronic liver disease based on documented histological
evaluation or non-invasive imaging or testing.

6. Documented diagnosis of any of the following liver diseases:

1. Nonalcoholic steatohepatitis (biopsy-proven)

2. Alcoholic liver disease

3. Autoimmune hepatitis

4. Liver cancer

5. Primary biliary cirrhosis

6. Primary sclerosing cholangitis

7. Wilson's disease

8. Hemochromatosis

9. α1 anti-trypsin deficiency

7. Abnormal LFTs at screening (AST or ALT >2x upper limit of normal (ULN) and/or Total
Bilirubin of >1.5x ULN unless patient has unconjugated hyperbilirubinemia due to
Gilbert's syndrome).

8. Hepatitis B as defined by positive for HepB SAg, or Hep B Core Ab, and/or viral DNA

9. Chronic active Hepatitis C as defined by positive for HCV Ab and viral RNA.

10. History of alcohol abuse within 52 weeks.

11. Certain prohibited medications known to be potentially hepatotoxic, especially those
that can induce microvesicular or macrovesicular steatosis. These include but are not
limited to: acutane, amiodarone, HAART medications, heavy acetaminophen use (2g/day
more than 3 times a week), isoniazid, methotrexate, tetracyclines, tamoxifen,
valproate.

12. Current use of systemic corticosteroids or active tuberculosis, systemic fungal
disease, or other chronic infection.

13. History of immunodeficiency diseases, including a positive HIV test result.

14. Chronic renal insufficiency defined as estimated GFR < 30 mL/min.

15. History of cancer within the past 5 years, except for adequately treated basal cell
skin cancer, squamous cell skin cancer, or in situ cervical cancer.

16. Previous organ transplantation.

17. Administration of an investigational drug within 12 weeks or 5 half-lives of the drug
(whichever is longer) prior to the screening visit and until 52 weeks after receiving
AAV8.TBG.hLDLR.

18. Any major surgical procedure occurring less than 3 months prior to the screening
visit, or any planned future surgical procedure within 3 months of baseline.

19. Serious or unstable medical or psychological conditions that, in the opinion of the
investigator, would compromise the subject's safety or successful participation in the
study.

20. A baseline serum AAV8 NAb titer > 1:10.

21. Any other medical condition or finding that would make it not in the subject's best
interest to participate in the study

22. Study staff member or any direct family member.