Phase I/II Pilot Study of Mixed Chimerism to Treat Inherited Metabolic Disorders

The goal of this research study is to establish chimerism and avoid graft-versus-host-disease (GVHD) in patients with inherited metabolic disorders.

Study Overview

• Status: Terminated
• Conditions: Niemann-Pick Disease; Alpha-mannosidosis; Tay Sachs Disease; Sandhoff Disease; Metachromatic Leukodystrophy (MLD); Hurler-Scheie Syndrome; Hurler Syndrome (MPS I); Hunter Syndrome (MPS II); Sanfilippo Syndrome (MPS III); Krabbe Disease (Globoid Leukodystrophy); Adrenoleukodystrophy (ALD and AMN); Pelizaeus Merzbacher (PMD)
• Intervention / Treatment: Biological: hematopoietic stem cell infusion

Detailed Description

The objective for the study is to establish chimerism following reduced intensity conditioning with no grade III/IV GVHD. The primary endpoint we will follow is production of the missing enzyme at ≥ 10% of the normal level at day 180 post-transplant in > 90% of patients.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2; Phase 1

Expanded Access

No longer available outside the clinical trial. See expanded access record.

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27705
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion criteria:

1. Patients must have a confirmed diagnosis of inherited metabolic disorder / inborn error of metabolism. Diagnosis should be confirmed by appropriate test(s) (enzyme and/or mutation analysis) before study entry. Patients must not be eligible for myeloablative chemotherapy as a preparative regimen for transplant due to age, co-morbidities or organ dysfunction.

   Inborn errors of metabolism / Inherited Metabolic Disorders (IMD) eligible for this study include the following:

   • Hurler Syndrome (MPS I)
   • Hurler-Scheie Syndrome with early neurologic involvement and/or sensitization to ERT
   • Hunter Syndrome (MPS II)
   • Sanfilippo Syndrome (MPS III)
   • Krabbe Disease (Globoid Leukodystrophy)
   • Metachromatic Leukodystrophy (MLD)
   • Adrenoleukodystrophy (ALD and AMN)
   • Sandhoff Disease
   • Tay Sachs Disease
   • Pelizaeus Merzbacher (PMD)
   • Niemann-Pick Disease
   • Alpha-mannosidosis

2. Patients must have adequate function of other organ systems as measured by:

   • Creatinine less than or equal to 2.0 mg/dl and creatinine clearance ≥60 cc/min/1.73m2. Newborns must have a creatinine clearance ≥ 25 cc/min. For babies less than or equal to 3 months of age, the raw value on glomerular filtration rate (GFR) must be ≥ 1 cc/kg/min.
   • Hepatic transaminases (ALT/AST) 2.5 x normal, bilirubin <2.0mg/dl
   • Normal cardiac function by echocardiogram or radionuclide scan (ejection fraction or shortening fraction >80% of normal value for age)
   • Pulmonary function tests (PFTs) demonstrating forced expiratory volume at one second (FEV1) of ≥50% of predicted for age. If child is too young or unable to perform PFTs, crying vital capacity result of >50% of normal value for age or resting pulse oximeter >92% on room air or clearance by pulmonologist will be required.
3. Patient must have a related donor (identical or mismatched for 1, 2 or 3 Human Leukocyte Antigen (HLA)-A, -B or -DR loci).
4. Patient, and parent, or legal guardian must have given written informed consent according to FDA guidelines.
5. Patients must have a minimum life expectancy of at least 6 months.
6. Female patients of childbearing potential cannot be pregnant or lactating/breast-feeding and must be either surgically sterile, postmenopausal (no menses for the previous 12 months), or must be practicing an effective method of birth control as determined by the investigator (e.g., oral contraceptives, double barrier methods, hormonal injectable or implanted contraceptives, tubal ligation, or partner with vasectomy).
7. There is no upper or lower age limit for this study.

Exclusion Criteria

1. Patients with uncontrolled seizures, apnea, evidence of recurrent or uncontrolled aspiration, or need for chronic mechanical ventilation.
2. Patients with allogeneic stem cell transplant with cytoreductive therapy in the past 6 months.
3. Subjects must not have had previous radiation therapy that would preclude total body irradiation (TBI) (as determined by radiation therapist)
4. Uncontrolled infection or severe concomitant diseases, which in the judgment of the Principal Investigator, could not tolerate reduced intensity transplantation.
5. Subjects with a positive human immunodeficiency virus (HIV) antibody test result
6. Subjects who are pregnant, as indicated by a positive serum human chorionic gonadotropin (HCG) test
7. Subjects whose only donor is pregnant at the time of intended transplant
8. Subjects of childbearing potential who are not practicing adequate contraception as defined by the investigator at the site
9. Jehovah's witnesses being unwilling to be transfused
10. Patients that have any comorbid condition which, in the view of the Principal Investigators, renders the patient at too high a risk from treatment complications and regimen related morbidity/mortality.
11. Lack of related donors

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Inherited Metabolic Disorder Patients; Recipients are treated with hematopoietic stem cell infusion from living donors	Biological: hematopoietic stem cell infusion; Enriched hematopoetic stem cell infusion

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Production of missing enzyme at levels greater than or equal to 10% of normal	Day 180 post transplant to three years

Secondary Outcome Measures

Outcome Measure	Time Frame
Enriched Hematopoetic Stem Cell Engraftment	One month to three years

Collaborators and Investigators

• Sponsor: Talaris Therapeutics Inc.
• Collaborators: Duke University

Study record dates

Study Major Dates

• Study Start (Actual): April 1, 2011
• Primary Completion (Actual): April 1, 2016
• Study Completion (Actual): April 1, 2016

Study Registration Dates

• First Submitted: June 10, 2011
• First Submitted That Met QC Criteria: June 10, 2011
• First Posted (Estimate): June 13, 2011

Study Record Updates

• Last Update Posted (Actual): April 12, 2023
• Last Update Submitted That Met QC Criteria: April 10, 2023
• Last Verified: April 1, 2023

More Information

Terms related to this study

• Keywords: hematopoietic stem cell Tx, chimerism, leukodystrophy
• Additional Relevant MeSH Terms: Mental Disorders; Pathologic Processes; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Lymphatic Diseases; Demyelinating Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Endocrine System Diseases; Disease; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Connective Tissue Diseases; Carbohydrate Metabolism, Inborn Errors; Metabolism, Inborn Errors; Lysosomal Storage Diseases; Mucinoses; Mental Retardation, X-Linked; Intellectual Disability; Heredodegenerative Disorders, Nervous System; Lipid Metabolism Disorders; Dementia; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Sphingolipidoses; Lysosomal Storage Diseases, Nervous System; Lipidoses; Lipid Metabolism, Inborn Errors; Frontotemporal Lobar Degeneration; Leukoencephalopathies; Histiocytosis, Non-Langerhans-Cell; Histiocytosis; Adrenal Gland Diseases; Hereditary Central Nervous System Demyelinating Diseases; Peroxisomal Disorders; Adrenal Insufficiency; Sulfatidosis; Mucopolysaccharidoses; Frontotemporal Dementia; Gangliosidoses, GM2; Gangliosidoses; Syndrome; Mucopolysaccharidosis II; Mucopolysaccharidosis I; Pick Disease of the Brain; Metabolic Diseases; Niemann-Pick Diseases; Niemann-Pick Disease, Type A; Niemann-Pick Disease, Type C; Mucopolysaccharidosis III; Adrenoleukodystrophy; Leukodystrophy, Metachromatic; Leukodystrophy, Globoid Cell; Mannosidase Deficiency Diseases; alpha-Mannosidosis; Tay-Sachs Disease; Sandhoff Disease
• Other Study ID Numbers: ICT-14070-010611

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No