Phase I/II Pilot Study of Mixed Chimerism to Treat Hemoglobinopathies

This proposal is a phase I/II feasibility study to demonstrate that mixed chimerism can be
established with minimal risk in recipients with hemoglobinopathies treated with
Campath-1H-based nonmyeloablative conditioning and graft engineering to reduce the risk of
Graft Versus Host Disease (GVHD), but preserve engraftment of donor cells.

1. Inclusion Criteria

The following criteria are established to identify subjects with hemoglobinopathies,
hematologic or bone marrow failure syndromes who have a high predicted morbidity and
are at risk for early mortality:

- Patients with alpha or beta thalassemia major.

- Patients with Diamond-Blackfan anemia and other bone marrow failure syndromes,
characterized by severe chronic anemia.

- Patients with other complex and transfusion-dependent hemoglobinopathies,
including sickle cell disease.

- Patients with sickle disease who have one or more of the following:

- Overt or silent stroke

- Neurocognitive impairment

- Pain crises 2 or more episodes per year for past year

- One or more episodes of acute chest syndrome

- Osteonecrosis involving 1 or more joints

- Evidence of retinopathy

- Priapism

- Microalbuminuria or evidence of sickle cell nephropathy

- Alloimmunization

Subjects must also meet all of the following general inclusion criteria:

- Subjects must have a related donor which can consist of Histocompatibility
Leukocyte Antigen (HLA)-matched donor up to haploidentical match, mismatched for
1, 2 or 3 HLA-A, B or -DR loci.

- Subjects must have adequate cardiopulmonary function as documented by
echocardiogram or radionuclide scan. (Shortening fraction >26% or ejection
fraction >40% or ≥ 80% of normal value for age).

- Subjects must have adequate pulmonary function documented by Forced expiratory
volume in 1 second (FEV1) of ≥ 50% of predicted for age and/or Diffusing capacity
of the lung for carbon monoxide (DLCO) (corrected for hemoglobin) ≥50% of
predicted for age for patients > 10 years of age.

- Subjects must have adequate hepatic function as demonstrated by a serum albumin ≥
3.0 mg/dL, and serum glutamic pyruvic transaminase (SGPT) or serum glutamic
oxaloacetic transaminase (SGOT) less than or equal to 5 times the upper limit of
normal. Liver biopsy or a liver MRI is necessary if the patient has received
chronic transfusions for over a year and/or has a ferritin level of ≥ 1600.

- Subjects must have adequate renal function as demonstrated by a serum creatinine
less than or equal to 2 mg/dL. If serum creatinine is ≥ 2 mg/dL, then a
creatinine clearance test or nuclear medicine GFR should document GFR of ≥ 50
ml/min/1.73 m2.

- Subjects or legal guardians must give written informed consent.

- Female patients of childbearing potential cannot be pregnant or
lactating/breast-feeding and must be either surgically sterile, postmenopausal
(no menses for the previous 12 months), or must be practicing an effective method
of birth control as determined by the investigator (e.g., oral contraceptives,
double barrier methods, hormonal injectable or implanted contraceptives, tubal
ligation, or partner with vasectomy).

- Less than or equal to 45 years of age.

2. Exclusion Criteria

- Patients with cirrhosis, extensive bridging hepatic fibrosis, or active hepatitis
are excluded from enrollment.

- Uncontrolled infection or severe concomitant diseases, which in the judgment of
the Principal Investigator, indicate that the patient could not tolerate reduced
intensity transplantation.

- Severe impairment of functional performance as evidenced by a Karnofsky score
<70% (patients ≥16 years old) or Lansky (children <16 years old) score <70%

- Renal insufficiency (GFR <50 ml/min/1.73 m2).

- Subjects with a positive human immunodeficiency virus (HIV) antibody test result.

- Subjects who are pregnant, as indicated by a positive serum human chorionic
gonadotrophin (HCG) test.

- Subjects whose only donor is pregnant at the time of intended transplant.

- Subjects of childbearing potential who are not practicing adequate contraception
as defined by the investigator at the site.

- Allogeneic hematopoietic stem cell transplant within the previous 1 year.

- Subjects must not have had previous radiation therapy that would preclude total
body irradiation (TBI) (as determined by a radiation therapist).

- Jehovah's Witness unwilling to be transfused .

- Uncontrolled hypersplenism.

- Severe alloimmunization with inability to guarantee a supply of adequate packed
red blood cell (PRBC) donors.

- Subjects with thalassemia who are Lucarelli Class 3

- Fanconi anemia.

- Insufficient funds for the bone marrow processing costs