Stem Cell Gene Therapy for Sickle Cell Disease
Stem Cell Gene Therapy for Sickle Cell Disease
This Phase I clinical trial will assess the safety and initial evidence for efficacy of an
 autologous transplant of lentiviral vector modified peripheral blood for adults with severe
 sickle cell disease.
Sickle cell disease (SCD) affects ~90,000 people in the U.S. who suffer significant
 neurological, lung, and kidney damage, as well as severe chronic pain episodes that adversely
 impact on quality of life. While current medical therapies for SCD can reduce short-term
 morbidity, the inevitable progressive deterioration in organ function results in a
 significant decrease in quality of health with early mortality. Allogeneic hematopoietic stem
 cell transplant (HSCT) can benefit patients with SCD, by providing a source for life-long
 production of normal red blood cells. However, allogeneic HSCT is limited by the availability
 of well-matched donors and immunological complications, especially for the more than 80% of
 patients who lack an HLA-identical sibling donor. Autologous HSCT using a patient's own
 peripheral blood stem cells that have been corrected by transfer of a modified human
 beta-globin gene that inhibits polymerization of the HbS (stem cell gene therapy) may provide
 a better therapeutic alternative, as it would avoid the immunologic complications and donor
 limitations of allogeneic HSCT.

 Up to 6 subjects with SCD meeting eligibility criteria for disease severity and adequacy of
 organ function will be enrolled.

 Following informed consent, enrolled subjects will be screened to confirm full eligibility
 for participation. A chronic red blood cell transfusions regimen will be given prior to stem
 cell collection and transplant. Subjects will undergo peripheral blood stem cell collection
 using plerixafor mobilization and apheresis. A portion of their stem cells will be
 cryopreserved as "back-up," with the remaining portion used to prepare the gene-modified
 Final Cellular Product: autologous peripheral blood CD34+ cells transduced ex vivo by the
 Lenti/G-βAS3-FB lentiviral vector to express an anti-sickling (βAS3) gene. The subject will
 receive marrow cytoreduction with busulfan prior to infusion of the gene-modified cells. The
 follow-up period will include an initial 2 years of active follow-up, where the subjects will
 be seen at intervals of no more than 3 months, followed by offer for enrollment into a
 long-term follow-up study during years 3-15.

 The primary objectives of the Phase I study are to assess safety and feasibility, with
 secondary objectives to assess efficacy (engraftment, βAS3-globin gene expression, and
 effects on red blood cells function and clinical hematologic and disease parameters).
PARTICIPANT INCLUSION CRITERIA

 -  Age ≥18 by time of enrollment

 -  Diagnosis of SCD documented by genetic analysis (S/S, S/β-thalassemia-zero)

 -  Must not have medically eligible and available HLA-identical sibling donor or 10/10
 allele-matched unrelated donor (within a year prior to harvest) (or refuses to have an
 allogeneic HSCT)

 -  Inadequate clinical response to hydroxyurea (HU), defined as any one of the following
 outcomes, while on HU for at least 3 months:

 -  2 or more acute sickle pain crises requiring hospitalization

 -  no rise in Hb >1.5 gm/dl from pre-HU baseline or requires transfusion to maintain
 Hb > 6.0 gm/dL

 -  Has an episode of acute chest syndrome defined as development of a new pulmonary
 alveolar consolidation involving at least one complete lung segment associated
 with acute symptoms including: fever >38.5, chest pain, tachypnea, intercostal
 retractions, nasal flaring, use of accessory muscles of respiration, wheezing,
 rales, or cough not attributable to asthma or bronchiolitis) in the preceding two
 year period prior to enrollment. The acute chest syndrome event occurred despite
 adequate supportive care measures.

 -  Or medical decision for other therapy (e.g. chronic transfusion program), or
 subject refusal to take HU.

 -  The patient must be off HU for at least 30 days (+/- 5 days) before PBSC collection.

 -  Must have one or more of the following clinical complications demonstrating disease
 severity:

 -  Clinically-significant neurologic event: stroke or any central nervous system
 deficit lasting >24 hours.

 -  Abnormal head CT or brain MRI demonstrating previous stroke

 -  Administration of regular RBC transfusions for equal or longer than 1 year to
 prevent vaso- occlusive crises or other sickle cell disease complications or to
 maintain Hb >6.

 -  Pulmonary arterial hypertension with tricuspid regurgitant jet velocity > 2.5
 m/sec within 1 year prior to enrollment

 -  At least one episode of acute chest syndrome that required hospitalization,
 within the 2 years prior to enrollment

 -  At least 2 acute sickle pain crises requiring hospitalization within the 2 years
 prior to enrollment

 -  Severe osteonecrosis

 -  History of acute dactylitis during childhood

 -  Recurrent priapism (2 or more episodes)

 -  Karnofsky performance score ≥60%

 PARTICIPANT EXCLUSION CRITERIA

 -  Patient has a medically eligible and available HLA-identical sibling donor or 10/10
 allele-matched unrelated donor (unless they refuse to have an allogeneic HSCT).

 -  Cardiac evaluation: left ventricular ejection fraction (LVEF) < 40% or LV shortening
 fraction < 26% by cardiac echocardiogram or by MUGA scan or clinically significant ECG
 abnormalities.

 -  Poorly controlled hypertension as determined by BP with systolic >135 or diastolic >95
 mmHg despite treatment.

 -  Pulmonary evaluation: baseline oxygen saturation of <85% or DLCO< 40% (corrected for
 Hb)

 -  Renal evaluation: serum creatinine >1.5x upper limit of normal for age or GFR<60
 mL/min/1.73 m2 within 90 days prior to PBSC collection.

 -  Hepatic evaluation: serum conjugated (direct) bilirubin > 2x upper limit of normal for
 age as per local laboratory or ALT and AST > 5 times upper limit of normal as per
 local laboratory within 90 days prior to PBSC collection.

 -  Hematologic evaluation: Leukopenia (WBC< 3x103/uL) or neutropenia (ANC < 1.0x103/uL)
 or thrombocytopenia (platelet count < 100x103/uL) within 90 days prior to PBSC
 collection.

 -  PT/INR or PTT >1.5x upper limit of normal or other clinically significant bleeding
 disorder to

 -  Liver Iron >10mg/g by T2* MRI (within 1 year prior to PBSC collection).

 -  Seropositivity for HIV (Human Immunodeficiency Virus), HCV (Hepatitis C Virus), HTLV-1
 (Human T-Lymphotropic Virus), or active Hepatitis B Virus, or active infection by CMV
 or parvovirus B19, based on positive blood PCR.

 -  Pregnancy

 -  Patient must not have any known cancer or other malignant disease or active infection
 by CT or MRI of head, chest or ultrasound of abdomen

 -  Abnormal karyotype by cytogenetic or other appropriate tests.