Transplantation of Clustered Regularly Interspaced Short Palindromic Repeats Modified Hematopoietic Progenitor Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease
Transplantation of Clustered Regularly Interspaced Short Palindromic Repeats Modified Hematopoietic Progenitor Stem Cells (CRISPR_SCD001) in Patients With Severe Sickle Cell Disease
This is an open label, non-randomized, 2-center, phase 1/2 trial of a single infusion of
 sickle allele modified cluster of differentiation (CD34+) hematopoietic stem progenitor cells
 (HSPCs) in subjects with in subjects ≥12 years old to 35 years old severe Sickle Cell Disease
 (SCD). The study will evaluate the hematopoietic stem cell transplantation (HSCT) using
 CRISPR/Cas9 edited red blood cells (known as CRISPR_SCD001 Drug Product).
This is an open label, non-randomized, 2-center, phase 1/2 trial of a single infusion of
 sickle allele modified CD34+ HSPCs in subjects with severe SCD. The primary endpoint of the
 trial will determine the safety of CRISPR_SCD001 through a 3+3 design with staggered
 enrollment and a pause in enrollment for safety review after each of the first 3 patients has
 had drug product infused. After safety is assessed in the 3rd patient, enrollment of the next
 3 patients will not be staggered. The first six subjects will be adults. If CRISPR_SCD001 is
 determined to be safe in the first six subjects, the trial will continue to enroll 3
 adolescents 12 - 18 years of age to evaluate the safety in younger patients. The younger age
 cohort also will follow staggered enrollment.
Inclusion Criteria:

 1. Male or female 12.00 - 34.99 years of age (at time of consent) who have one or more of
 the following:

 1. History of two or more episodes of acute chest syndrome (ACS) in the 2-year
 period preceding enrollment despite the institution of supportive care measures
 (i.e. asthma therapy and/or hydroxyurea);

 2. History of at least 4 severe vaso-occlusive pain events in the 2-year period
 preceding enrollment despite the institution of supportive care measures (i.e. a
 pain management plan and/or treatment with hydroxyurea); painful episodes related
 to or any sickle-related acute event are acceptable; a severe painful
 vaso-occlusive event is defined as receiving analgesic treatment (opioid or other
 analgesic) for longer than 24 -hours in a hospital or emergency room (ER)
 observation unit visit or at least 2 visits in a day unit or ER over 72 hours
 with both visits requiring intravenous analgesics.

 2. Participants must have adequate physical function as measured by all of the following:

 1. Karnofsky performance score ≥60.

 2. Cardiac function: Left ventricular ejection fraction (LVEF) >40%; or LV
 shortening fraction > 26% by cardiac echocardiogram or by (multiple-gated
 acquisition) MUGA scan.

 3. Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥85% and
 diffusion capacity of lung for carbon monoxide(DLCO) > 40% (corrected for
 hemoglobin).

 4. Renal function: Serum creatinine ≤ 1.5 x upper limit of normal for age and
 estimated or measured creatinine clearance ≥ 70 mL/min/1.73 m2.

 5. Hepatic function:

 i. Serum conjugated (direct) bilirubin < 2x upper limit of normal for age as per local
 laboratory. Participants with hyperbilirubinemia as the result of hyperhemolysis, or a
 severe drop in hemoglobin post blood transfusion, are not excluded.

 ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AS < 5 times upper
 limit of normal as per local laboratory.

 f. Liver MRI using a validated methodology per institutional preference (T2* or R2* or
 by ferriscan [R2 MRI]) for estimation of hepatic iron content is required for
 participants who are currently receiving ≥8 packed red blood cell transfusions per
 year for ≥1 year or have received ≥20 packed red blood cell transfusions (lifetime
 cumulative). Participants who have hepatic iron content ≥ 8 mg Fe/g liver dry weight
 by liver MRI must have a Gastroenterology/hepatology consultation with liver biopsy
 and histological examination including documentation of the absence of cirrhosis,
 bridging fibrosis[1], and active hepatitis.

 3. Written informed consent or assent obtained from subject or subject's legal
 representative and ability for subject to comply with the requirements of the study.

 Exclusion Criteria:

 1. Participants with uncontrolled bacterial, viral or fungal infection in the 6 weeks
 before enrollment (currently taking medication with evidence of progression of
 clinical symptoms or radiologic findings).

 2. Participants with evidence of HIV infection or seropositivity for HIV or active
 hepatitis B or C.

 3. Participants who have received a Hematopoietic Cell Transplant (HCT)

 4. Participants who have received a solid organ transplant.

 5. Participants who have participated in another clinical trial in which the participant
 received an investigational or off-label use of a drug or device within 3 months prior
 to enrollment.

 6. Females who are pregnant or breast feeding.

 7. Females of child bearing potential (to include all female participants > 10 years of
 age, unless postmenopausal for a minimum of 1 year before the time of consent or
 surgically sterilized) who do not agree to practice two (2) effective methods of
 contraception at the same time, or who do not agree to practice true abstinence when
 this is in line with the preferred and usual lifestyle of the subject, from the time
 of signing of informed consent through 12 months post-stem cell infusion.

 8. Males (even if surgically sterilized) who do not agree to practice effective barrier
 contraception, or who do not agree to practice true abstinence from the time of
 signing informed consent through 12 months post-stem cell infusion.

 9. Participants who have had a stroke OR who are receiving red blood cell (RBC)
 transfusions to prevent primary stroke or silent cerebral infarction.

 10. Patients who have a human leukocyte antigen identical (HLA-ID) sibling donor

 11. Presence of a condition or abnormality that in the opinion of the Investigator would
 compromise the safety of the patient or the quality of the data.

 12. Any non-homozygous sickle hemoglobin (HbSS) genotype of SCD