Non-myeloablative Haploidentical HCT Study for Patients With Sickle Cell Disease, Including Compromised Organ Function

* INCLUSION CRITERIA: Recipient: Participants must fulfill one disease category, either at least one organ damage or no other access to curative therapy. 1. Adult patients with sickle cell disease at high risk for disease-related morbidity or mortality, according to A, B, C, D, or E or complication(s) not ameliorated by SICKLE CELL-SPECIFC THERAPIES (F): A. Stroke defined as a clinically significant neurologic event that is accompanied by an infarct on cerebral MRI OR an abnormal trans-cranial Doppler examination (\>=200 m/s); OR B. Silent cerebral infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2- weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s); OR C. Sickle cell-related renal insufficiency defined by a creatinine level \>=1.5 times the upper limit of normal and kidney biopsy consistent with sickle cell nephropathy OR nephrotic syndrome; OR D. Tricuspid regurgitant jet velocity (TRV) of \>=2.5 m/s at least 3 weeks after a vaso-occlusive crisis and/or right heart catheterization-documented pulmonary hypertension; OR E. Sickle hepatopathy defined as EITHER ferritin \>1000 mcg/L OR direct bilirubin \>0.4 mg/dL at baseline AND a platelet count \<250 K/microliter (without vaso-occlusive crisis); OR F. Any one of the below complications: Complication: Vaso-occlusive crises; Eligible for HCT: \>1 hospital admission per year while on a therapeutic dose of a SCD treatment/medication Complication: Acute chest syndrome (ACS); Eligible for HCT: Any ACS while on SCD treatment/medication Pediatric patients with sickle cell disease at high risk for disease-related morbidity or mortality, defined as A, B, C, D, E, or F A. A neurological event resulting in focal neurologic deficits that lasted \>= 24 hours (classical clinical definition of stroke, not requiring imaging studies of the brain) OR a focal neurological event resulting in abnormalities on T2-weighted or FLAIR images using a MRI scan, indicative of an acute infarct, with no other reasonable medical explanation (definition of a stroke supported with MRI imaging scans of the brain), OR both; OR B. Abnormal transcranial Doppler (TCD) measurement with a timed average maximum mean velocity of at least 200 cm/sec in the terminal portion of the internal carotid or proximal portion of middle cerebral artery or if the imaging TCD method is used \> 185 cm/sec plus evidence of intracranial vasculopathy; OR C. Silent Cerebral Infarct defined as an infarct-like lesion based on an MRI signal abnormality at least 3 mm in one dimension and visible in two planes on FLAIR or T2-weighted images (or similar image with 3D imaging) and documented neurological examination performed by a neurologist demonstrating the participant has a normal neurologic examination or an abnormality on examination that could not be explained by the location of the brain lesion(s); OR D. Three acute severe vaso-occlusive pain episodes requiring hospitalization and recalcitrant to maximum medical therapy; OR E. At least one acute chest syndrome episode resulting in intensive care admission requiring nonmechanical ventilatory support: simple nasal cannula, face mask that requires oxygen content (venti mask, non-rebreather), simple nasal cannula, face mask oxygen (e.g. ventimask, nonrebreather), continuous positive airway pressure, synchronized inspiratory positive airway pressure, bilevel positive airway pressure, high flow nasal cannula or invasive mechanical ventilatory support (delivered by endotracheal tube or tracheostomy); OR F. Right heart catheterization confirmed pulmonary hypertension defined as pulmonary artery pressure \>25 mmHg 2. AND evidence of severe organ damage with at least one of the following who are typically excluded from other HCT protocols: A. Kidney damage: CrCl \<60 mL/min/1.73m\^2 cystatin C-based or iothalamate/iohexol-based or other equivalent GFR testing including patients on hemodialysis or peritoneal dialysis B. Heart damage: Ejection fraction 35-40% C. Liver damage: Bridging fibrosis, cirrhosis, direct bilirubin \>= 2x the upper limit of normal and/or ALT \>= 5x the upper limit of normal D. Lung damage: Adjusted diffusion capacity of carbon monoxide (DLCO) 35-40% OR who have no other option for curative therapy (including allogeneic HCT, gene therapy, or gene editing studies) on a different SCD HCT protocol. 3. Non disease-specific: * Male or female, age \>=18 years (pediatric subjects \>=16 years may be enrolled after 6 successful adult transplants) * Haploidentical relative donor available * Ability to comprehend and willing to sign an informed consent before the initiation of any study procedures * Negative serum or urine b-HCG, when applicable * Agree to use birth control for 12 months after drug product infusion. * Female subjects must agree to use a medically acceptable method of birth control such as an oral contraceptive, intrauterine device, barrier and spermicide, or contraceptive implant/injection from start of screening through 12 months after drug product infusion. * Male subjects must agree to use effective contraception (including condoms) from start of screening through 12 months after drug product infusion. * Stated willingness to comply with all study procedures and availability for the duration of the study Donor: Haploidentical relative donor deemed suitable and willing to donate, per clinical evaluations. Donors age 4 or older and \>=20 kg, eligible to donate hematopoietic stem cells, and who are additionally willing to donate blood for research. Related donors will be evaluated in accordance with existing Standard NIH Policies and Procedures for determination of eligibility and suitability for clinical donation. Note that participation in this study is offered to all related donors, but is not required for a donor to make a stem cell donation, so it is possible that not all related donors will enroll onto this study. EXCLUSION CRITERIA: Recipient: An individual who meets any of the following criteria will be excluded from participation in this study: * Available HLA-matched sibling donor * ECOG performance status of 3 or more. * DLCO \<35% predicted (corrected for hemoglobin). * Baseline oxygen saturation of \<85% or PaO2 \<70 mmHg * Left ventricular ejection fraction: \<35% estimated by ECHO * Evidence of uncontrolled bacterial, viral, or fungal infections (currently taking medication and progression of clinical symptoms) within one month prior to starting the conditioning regimen. HCT candidates with pre-transplant respiratory viral infections will undergo careful clinical assessment with the help of our transplant infectious disease team for lower respiratory tract disease, which may include thorough physical examination, imaging, and/or bronchoalveolar lavage. In case of lower respiratory tract disease or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity, the transplant will be delayed until resolution. * Major anticipated illness or organ failure incompatible with survival from PBSC transplant. * Pregnant or breastfeeding * Donor specific anti-HLA antibodies (DSAs) \>=2000 Mean Fluorescence Intensity (MFI) * Patients seronegative for EBV who have EBV seropositive donors