Safety and Efficacy Study of Single Doses of TT-034 in Patients With Chronic Hepatitis C

This is a first-time use of a method of therapy designed to transfer anti-HCV genetic
sequences into the hepatocytes of subjects infected with HCV. The anti-HCV sequences will be
comprised of three different short hairpin RNAs (shRNA) that have the ability to directly
cleave the RNA genome of HCV by a process known as RNA interference. The transfer of the
anti-HCV sequences will be accomplished using a "vector" that was made from an
adenovirus-associated virus (AAV) by removing the viral genes and replacing them with a
non-replicating genetic sequence that produces three different shRNA that target three
different regions within the HCV genes. This type of vector has been used in other clinical
trials in order to transduce the hepatocytes of subjects who suffer from hemophilia.

Inclusion Criteria:

Subjects must a history of chronic HCV infection defined as documented HCV genotype 1
infection for at least 6 months.

- Subjects must have:

1. Documented failure to respond to prior treatment or relapse with a combination
of peg-interferon (peg-IFN), ribavirin (RBV), and either boceprevir or
telaprevir, OR a combination of peg-IFN and ribavirin or

2. Subject is ineligible or unwilling to receive a combination of peg-IFN, RBV, and
either boceprevir or telaprevir.

- Female subjects have to be of non-childbearing potential, defined as meeting any of
the following criteria:

1. Female subjects over the age 60.

2. Female subjects aged 45-60 years old must be amenorrhoeic for at least 2 years
and must have serum follicle stimulating hormone (FSH) levels > 30 IU/L.

3. Female subjects with hysterectomy or bilateral oophorectomy. All female subjects
must have a negative serum pregnancy test at Screening and a negative urine
pregnancy test at Baseline.

- Male subjects and their partners must be willing to comply with the following
requirements to use 2 methods of effective contraception: Male subjects with a
vasectomy must use a condom. Without a vasectomy, male subjects must use a condom.
The female must be sterile or willing to use an additional form of contraception.

- Baseline HCV RNA level of > 100,000 IU/mL and:

- No evidence of cirrhosis at Screening

- At least 3 months since prior therapy for HCV

- A willingness to enroll in a 5 year follow-up safety study

Exclusion Criteria:

- Body mass index < 18.5 or > 30

- Total body weight > 80 KG

- Female subjects of childbearing potential (including females with tubal ligation) or
women who are pregnant or nursing

- Male subjects who are unwilling to provide the required semen samples

- Presence of nAb levels to AAV8 that abrogate AAV8 transduction

- Severe Liver disease

- Hepatocellular carcinoma (HCC) or suspicion of HCC

- Coronary artery disease

- Platelet count of < 150 x 109/L or Creatinine ≥ 1.5 mg/dL at Screening

- Hypertension with systolic blood pressure consistently ≥ 130 mmHg or diastolic blood
pressure consistently ≥ 90 mmHg

- Screening examinations indicative of possible occult malignancy unless cancer has
been excluded

- Family history of colon cancer in any first-degree relative unless ruled out by
colonoscopy

- Positive for human immunodeficiency virus 1 (HIV1) or HIV2 antibody

- Co-infection with hepatitis B virus

- History of autoimmune disease

- Renal impairment

- Hospitalization for liver disease within 60 days of Screening

- Use of drugs of abuse in the prior 3 months

- Other concomitant disease or condition likely to significantly decrease life
expectancy or cancer

- Treatment with an investigational drug within 6 months preceding the first dose of
trial medication

- Received an AAV vector previously or any other gene transfer agent in the previous 6
months

- History of cardiac abnormalities, as assessed at the Screening Visit

- Twelve-lead ECG demonstrating QTcB > 465 ms at Screening

- Chronic hepatic diseases

- Evidence of clinically significant hematological, renal, endocrine, pulmonary,
gastrointestinal, cardiovascular, psychiatric, neurologic, or allergic diseases.

- Evidence of autoimmune disease or pre-existing autoimmune or antibody-mediated
diseases

- Use of immunosuppressive medications within 6 months before the entry into this
study, except for inhaled or topical corticosteroids