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 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

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

• 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); ACS is defined as a new radiodensity on chest imaging accompanied by fever and/or respiratory symptoms, treated in the hospital with supplemental oxygen at a minimum.
• 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 via parenteral (PN) route) 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 parenteral analgesics.
• 2 or more episodes of splenic sequestration, defined as an acute decrease in hemoglobin by at least 2 g/dL accompanied by splenomegaly in the 2 years before enrollment.
• Recurrent priapism (episodes lasting at least 4 hours at least twice in the last 12 months or 3 times in the last 24 months before enrollment) recalcitrant to medical treatment
• Any episode of hepatic sequestration defined as right upper quadrant pain, hepatomegaly, and rapidly decreasing hemoglobin level with hepatic dysfunction within the 2 years before enrollment.
• Leg ulcer recalcitrant to treatment within 2 years prior to enrollment.
• Participants must have adequate physical function as measured by all of the following:

• Karnofsky performance score ≥60.
• Cardiac function: Left ventricular ejection fraction (LVEF) >40%; or LV shortening fraction > 26% by cardiac echocardiogram or by (multiple-gated acquisition) MUGA scan.
• Pulmonary function: Pulse oximetry with a baseline O2 saturation of ≥85% and diffusion capacity of lung for carbon monoxide(DLCO) > 40% (corrected for hemoglobin).
• 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.
• 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.

Participants who have liver iron concentration (LIC) on liver MRI of ≥12 mg Fe/g liver dry weight should also have MR elastography (MRE) or Ultrasound elastography obtained. If severe fibrosis is present, no liver biopsy will be performed and participant is excluded. Children with LIC >12 and negative elastography imaging are eligible if a clinically indicated liver biopsy shows no significant fibrosis.

• Baseline prothrombin time or partial thromboplastin time <1.5 ULN except if receiving a prophylactic anticoagulant which causes an elevated prothrombin or partial thromboplastin time.
• 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

• 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).
• Participants with evidence of HIV infection or seropositivity for HIV or active hepatitis B or C.
• Participants who have received a Hematopoietic Cell Transplant (HCT)
• Participants who have received a solid organ transplant.
• 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.
• Females who are pregnant or breast feeding.
• 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.
• 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.
• Participants who have had a stroke OR who are receiving red blood cell (RBC) transfusions to prevent primary stroke or silent cerebral infarction.
• Patients who have a suitable human leukocyte antigen identical (HLA-ID) sibling donor willing and able to donate bone marrow.
• 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.
• Any non-homozygous sickle hemoglobin (HbSS) genotype of SCD
• Either or both of the following findings on screening bone marrow aspirate/biopsy:

• diagnosis of myelodysplastic syndrome (MDS) based on morphology and/or cytogenetics (based on WHO definitions) OR
• any evidence of a pathogenic clonal variant in any candidate gene detected by a standard, licensed next-generation sequencing clinical assay for gene mutations associated with hematological malignancies.
• The participant has an identified pathogenic mutation associated with myeloid malignancy as identified by RHP or a variant of unknown significance (VUS) judged to be pathogenic for myeloid malignancy as determined by one or more members of the adjudication panel.