This research study is investigating whether alpha beta T-cell depleted hematopoietic stem cell transplant (HSCT) can be an immune system replacement for Crohn disease patients and whether this is safe and effective for patients with early onset, medically refractory Crohn disease.

This is a single center, non-randomized, non-controlled open-label Phase 1b/2a trial to study the safety and efficacy of performing TCRαβ+ T-cell/CD19+ B-cell depleted (TCRαβ-depleted) HSCT to induce immune tolerance in patients with monogenic or early onset, medically refractory Crohn disease to re-establish normal immune-intestinal homeostasis.

Recipient Inclusion Criteria:

1. Meets at least one of the following criteria:

a. Known monogenic ("Mendelian") cause of IBD for which HSCT has been successfully performed i. Causative gene mutation known for which HSCT is demonstrated to be curative (e.g., IL10, IL10RA, IL10RB, XIAP, IPEX, WAS, CD40L, CGD, LRBA, CTLA4, DOCK8 and SCID syndromes).

b. Known monogenic cause of CD for which HSCT has not been previously performed i. Causative gene mutation expressed in lymphohematopoietic cells, for which HSCT has not been previously performed; AND ii. Moderate disease activity (shown through endoscopic, MRI, or PCDAI score); AND iii. Has been treated with at least two available treatment pathways (e.g., TNF inhibitors, anti-IL12 and /or IL-23 antibodies, JAK inhibitors, anti-integrin), but did not have adequate response, experienced significant toxicity, or had adverse effect(s) c. Suspected monogenic cause of CD i. Rare variant in a gene predicted to be functionally deleterious, suspected to drive IBD, and expressed in lymphohematopoietic cells; AND ii. Moderate disease activity or corticosteroid-dependence despite trials of at least two biologic or small molecule therapies of different mechanisms or significant toxicity or adverse effect related to such medical therapy.

d. Medically refractory CD with suspected strong genetic component, but no clearly identified deleterious single gene mutation.

i. Moderate or severe disease activity with either:

1. history of corticosteroid-dependence despite trials of at least two biologic or small molecule therapies of different mechanisms,
2. significant toxicity, or adverse effects related to such medical therapy;

AND at least one of the following criteria from ii or iii below:

ii. Severity unlikely to be tolerable long-term due to the presence of either:

1. Disease not amenable to surgical therapy without risk of short bowel syndrome or permanent ileostomy;
2. Requirement for long-term parenteral nutrition;
3. Intolerable extraintestinal symptoms (e.g., arthritis, dermatitis); iii. Presence of any of the following features associated with high genetic contribution to disease:

1. Parental consanguinity 2. Strong family history of IBD (present in first degree relatives) 3. Diagnosis earlier than 6 years of age 4. Extraintestinal manifestations 5. Family history of CD, IBD or autoimmune disease 2. Age >2 year and < 30 years. 3. The donor and recipient must be identical, as determined by high resolution typing, at least one allele of each of the following genetic loci: HLA-A, HLA-B, HLA-Cw, HLA-DQB1 and HLA-DRB1.

4. Lansky/Karnofsky score ≥50; the Karnofsky Scale will be used in subjects ≥ 16 years of age, and the Lansky Scale will be used for those < 16 years of age.

5. All subjects ≥ 18 years of age must be able to give informed consent, or adults lacking capacity to consent must have a legally authorized representative (LAR) available to provide consent. For subjects <18 years old their legal authorized representative (LAR) (i.e. parent or guardian) must give informed consent. Pediatric subjects will be included in age-appropriate discussion and written assent will be obtained for those > 7 years of age, when appropriate.

6. Female subjects of childbearing potential must agree to use an effective means of birth control to avoid pregnancy throughout the transplant procedure, while on immunosuppression.

Recipient Exclusion Criteria:

1. Ulcerative colitis

2. CD and associated extraintestinal manifestations responsive to medical therapy without corticosteroid-dependence or significant toxicity or adverse effects

3. Known or suspected functionally deleterious mutation in a gene that meets either of the following expression criteria:

   1. Specifically expressed in epithelial or stromal cells, but not expressed in lymphohematopoietic cells (e.g., TTC7A)
   2. Expected to be more functionally deleterious in cell types other than lymphohematopoietic cells than in lymphohematopoietic cell types

4. Active hemophagocytic lymphohistiocytosis (HLH). Patients with a history of hemophagocytic lymphohistiocytosis (HLH) are eligible, if there is no current clinical, histological, or biochemical evidence of HLH activity.

5. Dysfunction of liver, defined as:

   1. ALT/AST > 5 times upper normal value, or direct bilirubin > 3 times upper normal value; or
   2. Cirrhosis with bridging fibrosis (grade F3 or greater) or sclerosing cholangitis

6. Severe cardiovascular disease (e.g. left ventricular ejection fraction < 40%), or clinical or echocardiographic evidence of severe diastolic dysfunction.

7. Severe renal dysfunction defined as serum creatinine >1.5 X upper limit of normal (ULN) or 24-hour creatinine clearance <50 ml/min/m2

8. Human immunodeficiency virus (HIV)-infected patients or patients with evidence of chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.

9. Past exposure to therapeutic radiation.

10. Previous allogeneic HSCT. Patients who have received previous autologous HSCT are eligible.

11. Active malignancy and patients who have history of malignancies, unless disease free for at least 2 years, with the exception of nonmelanoma skin cancer or carcinoma in situ (e.g., bladder, breast).

12. Pregnant or lactating females.

13. Lack of patient/parent/guardian informed consent.

14. Any severe concurrent uncontrolled disease which, in the judgement of the investigator, would place the patient at increased risk during participation in the study, other than primary disease.