Stem Cell Gene Therapy for Cystinosis

Cystinosis is a rare inherited recessive disease belonging to the family of Lysosomal Storage Disorders and is characterized by lysosomal accumulation of cystine in all the cells of the body leading to multi-organ failure. Cystinosis has a devastating impact on the affected individuals, primarily children, and young adults, even with cysteamine treatment. The prevalence of cystinosis is 1 in 100,000 to 1 in 200,000. The gene involved in cystinosis is the gene CTNS that encodes for the transmembrane lysosomal cystine transporter - cystinosin. The current standard of care does not prevent the progression of the disease and significantly impacts the quality of life of patients with cystinosis.

For this study, up to 6 subjects meeting eligibility criteria will be transplanted following a 3-cohort staggered treatment design with 2 subjects per cohort. The first 2 cohorts will consist of 4 adults (18 years or older), potentially followed by a cohort consisting of 2 adolescents or adults (> 14 years old). Following the informed consent process, enrolled subjects will be screened to confirm full eligibility for participation. Eligible subjects will undergo hematopoietic stem cell (HSC) mobilization and collection (leukapheresis). A portion of cells will be kept as "back-up" for rescue purpose if necessary, and a portion will be ex vivo gene-modified with a lentiviral vector, pCCL-CTNS or pCDY.EFS.CTNS.T260I, to express CTNS gene (product name: CTNS-RD-04). Clinical manufacturing for patients in Cohort 3 will introduce a transduction enhancer LentiBOOST (product name for these patients will be CTNS-RD-04-LB, where the suffix "-LB" stands for LentiBOOST). The subjects will receive marrow cytoreduction with busulfan prior to infusion of CTNS-RD-04. Subjects will discontinue cysteamine treatment during the assessment period. The assessment follow-up period will include an initial 2 years of active end-point evaluations, where the subjects will be evaluated at 3-, 6-, 9-, 12-, 18- and 24-months post-transplantation. A Long-Term Follow-Up study (LTFU) for a total 15-year follow-up period will be offered to all subjects.

The objectives of this Phase 1/2 clinical study are to assess the safety/tolerability of CTNS-RD-04, and its efficacy through a number of clinical, molecular and biochemical assessments.

Inclusion criteria

The following criteria must be met by all subjects considered for study participation.

• Cohorts 1 and 2: Male or female subject is ≥ 18 years of age.
• Cohort 3: Male or female subject is ≥ 14 years of age.
• Subject is diagnosed with cystinosis, i.e., early onset of Fanconi syndrome, and history of elevated white blood cell cystine level and/or history of or presence of cystine crystals in the eye.
• Subject has a Karnofsky Performance Status or age-dependent Lansky Performance of ≥ 60.
• If subject has had a kidney transplant, he or she must be at least one-year post kidney transplant status.
• Subject has adequate hematologic function:

• Absolute neutrophil count (ANC) ≥ 1.5 x 1000/mm^3
• Platelet count ≥ 100 x 1000/mm^3
• Hemoglobin ≥ 9.0 gm/dL
• Subject has an adequate hepatic function:

• Bilirubin ≤ 2.0 mg/ dL
• ALT ≤ 3 x institution's upper limit of normal (ULN) U/L
• Subject has an adequate renal function:

a. Serum creatinine <2x ULN mg/dL

• Subject has adequate coagulation:

• PT/aPTT ≤ 1.2 x ULN seconds
• INR ≤ 2
• Subject has adequate thyroid function (with or without thyroid replacement therapy):

• TSH 0.27-4.2 mIU/mL
• Total T4 ≤ 2 x ULN mcg/dL
• If female: female of childbearing potential (i.e., not surgically sterile [tubal ligation, hysterectomy, or bilateral oophorectomy] or not at least 2 years naturally postmenopausal) agrees to remain sexually abstinent or utilize the same acceptable form of highly effective contraception from screening through two years post-transplant.

The acceptable forms of contraception for this study include hormonal contraceptives (oral, implant, transdermal patch, or injection) associated with inhibition of ovulation at a stable dose for at least 3 months prior to screening, barrier (condom with spermicide, diaphragm with spermicide), intrauterine device, or a partner who has been vasectomized for at least 6 months and has documented medical assessment of surgical success of a vasectomy.

Note: males with cystinosis are sterile.

• If male: males must agree to remain sexually abstinent or utilize an acceptable form of highly effective contraception from screening through two years post-transplant.
• Subject is willing and able to comply with the study restrictions and requirements.
• Subject is willing to provide written informed consent/permission/assent prior to participation in the study.
• Subject must be willing to refrain from donating sperm after receiving the conditioning regimen. For subjects planning on (or for whom there is a possibility of) fathering children in the future, sperm banking prior to administration of conditioning regimen will be recommended.
• Subject must be willing to refrain from donating blood, organs, tissues, or cells for transplantation from 30 days prior to screening through any time after CTNS-RD-04 treatment.
• Subject must be willing and must be able (in the judgment of the investigator) to discontinue his or her cysteamine therapy (oral and/or eye drop).

Exclusion criteria

• Subject has an active, uncontrolled, acute bacterial, viral, or fungal infection during screening or within 30 days prior to starting the conditioning regimen.
• Subject has positive serology at screening for any of the following:

• Human Immunodeficiency Virus (HIV) 1-2
• Human T-cell Lymphotropic Virus (HTLV) - I/II
• Hepatitis B core and Hepatitis B PCR positive
• Hepatitis C Virus (HCV)
• Rapid Plasma Reagin (RPR)
• Chagas' Disease (T. curzi)
• QuantiferonTB
• Nucleic Acid Test (NAT) for HIV
• West Nile Virus (WNV)
• Subject has a known clinically significant immunodeficiency disorder.
• Subject is a female of childbearing potential that is nursing, planning a pregnancy or has a positive serum pregnancy test.
• Subject has received a prior marrow or stem cell transplantation or is planning to receive one within 90 days of study initiation.
• Subject has had an active bleeding disorder within 90 days prior to screening OR requires anticoagulation therapy prior to treatment with ex vivo gene therapy.
• Subject has an active malignancy or history of malignancy including lymphoma (except primary, cutaneous basal cell or squamous cell cancer appropriately treated prior to transplantation).
• Subject has an end-stage renal disease (defined as GFR <15 mL/min) and is already on a transplantation list or who may be planning to register for a kidney transplant within 90 days of study initiation.
• Subject has impaired pulmonary function (based on FEV1 of <=50% of predicted or DLCO of <=40 % of predicted and gender-specific normal threshold value).
• Subject has impaired cardiac function within 90 days prior to screening including any of the following:

• Myocardial infarction
• Clinically significant abnormal electrocardiogram (ECG)
• Ejection fraction of < 40%
• Uncontrolled arrhythmia
• Other clinically significant heart disease (e.g., congestive heart failure, uncontrolled hypertension, history of labile hypertension).
• Subject has a severe or uncontrolled medical disorder (e.g., pancreatitis, severe liver disease, unstable diabetes mellitus) that would, in the investigators' opinion, impair their ability to receive study treatment and follow the study procedures.
• Subject has a history of allergic reactions attributed to compounds of similar chemical or biologic composition to Busulfan or allergy or contraindication to use of other agents used in the study, including iohexol, acid-citrate-dextrose Formula A (ACDA), G-CSF or plerixafor.
• Subject has a known history of drug or alcohol addiction.
• Subject has undergone major surgery within 90 days (or longer if not fully recovered) prior to screening.
• Subject is receiving cytotoxic or immunosuppressive agents, other than for kidney transplant, within 60 days prior to screening or requires treatment with such agents prior to treatment with ex vivo gene therapy.
• Subject has previously received gene therapy at any time.
• Subject is currently receiving or anticipates receiving another investigational agent, device, or procedure from 30 days prior to screening through study completion.
• Subject has any condition, in the opinion of the investigator, that compromises compliance with study requirements.