Dose-Escalation Study Of A Self Complementary Adeno-Associated Viral Vector For Gene Transfer in Hemophilia B

Hemophilia B is caused by an absence or abnormality in the gene that produces the factor IX
protein. Affected individuals cannot make a blood clot effectively and suffer from severe
bleeding episodes. Repeated bleeding episodes, specifically into joints, can cause chronic
joint disease and lead to disability. This research study will test the safety of giving an
affected individual a normal factor IX gene which can produce factor IX protein in his body.
We will give the normal gene for factor IX by using an inactivated (not able to function)
virus called "the vector." The vector used in this study was developed from an
adeno-associated virus that has been changed so that it is unable to cause a viral infection
in humans. This inactivated virus was further altered to carry the factor IX gene and to
locate within liver cells where factor IX protein is normally made.

Inclusion Criteria:

- Males ≥ 18 years of age with established severe HB (FIX:C<1u/dl),

- Treated/exposed to FIX products (e.g., concentrates or fresh frozen plasma) for at
least 10 years or 50 exposure days.

- A minimum of an average of 3 bleeding episodes per year requiring FIX infusions or
prophylactic FIX infusions because of frequent prior bleeding episodes

- Able to give informed consent and comply with requirements of the trial

- Currently free of inhibitor and have no history of inhibitors to FIX protein

- A negative family history for the development of an inhibitor,

- Willing to practice a reliable barrier method of contraception until 3 sequential
samples are negative for vector genomes using our PCR assay.

Exclusion Criteria:

- Evidence of active infection with Hepatitis B or C virus as reflected by HBsAg or NCV
RNA positivity, respectively. To be considered negative for active infection, two
negative assays at a minimum of a six month interval are required.

- Exposure to Hepatitis B or C who are currently on antiviral therapy.

- Serological evidence of HTLV or active HIV infection. Individuals who are effectively
being treated with antiretroviral therapy are eligible. Specific criteria for
effectiveness of treatment include the following:

- Documented CD4+ T-cell count of > 350 cells/mm^3.

- HIV-1 RNA viral load < 400 copy/ml for at least the past 12 months, including at
least 2 viral load test results of < 400 copy/ml during the immediate 12 month
interval prior to screening.

- Screening HIV-RNA viral load < 400 copies/ml.

- Stable HAART regimen (drugs of at least 2 different classes) for at least 12
months prior to study entry. Treatment regimen changes for dosing convenience and
in response to toxicity are permitted.

- Documented and confirmed (repeated) viral loads of ≥ 400 copies/ml during the 12
month time interval prior to screening are bases for exclusion although a single,
unconfirmed, "glimpse" of ≥ 400 copies/ml are permitted.

- Significant liver dysfunction as defined by an abnormal ALT (alanine transaminase),
bilirubin, alkaline phosphatase or INR. Potential participants who have had a liver
biopsy in the past 3 years will be excluded if they have significant fibrosis of 3 or
4 as rated on a scale of 0-4.

- Coronary artery disease as a co-morbid condition

- Platelet count of <50 x 10^9/l

- Creatinine ≥ 1.5 mg/dl

- Hypertension with systolic blood pressure (BP) ≥ 140 mmHg or diastolic BP ≥ 90 mmHg

- History of active tuberculosis, fungal disease or other chronic infection

- History of chronic disease that would adversely affect performance other than
hemophilic arthropathy

- Detectable antibodies reactive with AAV8

- Subjects who are unwilling to provide the required semen samples

- Poor performance status (WHO performance status score >1) or

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

- Presence of lung nodule(s) suspicious of malignancy on screening chest tomography

- Presence of liver abnormalities suspicious of malignancy on screening liver ultrasound