Stem Cell Therapy for Inherited Metabolic Brain Diseases
(DUOC-01 Trial)
Recruiting in Palo Alto (17 mi)
Overseen byJoanne Kurtzberg, MD
Age: < 65
Sex: Any
Travel: May Be Covered
Time Reimbursement: Varies
Trial Phase: Phase 1
Recruiting
Sponsor: Joanne Kurtzberg, MD
Must not be taking: Immunosuppressives, Chemotherapy
Disqualifiers: Prior transplant, Seizures, HIV, others
Stay on Your Current Meds
No Placebo Group
Trial Summary
What is the purpose of this trial?
The primary objective of the study is to determine the safety and feasibility of intrathecal administration of DUOC-01 as an adjunctive therapy in patients with inborn errors of metabolism who have evidence of early demyelinating disease in the central nervous system (CNS) who are undergoing standard treatment with unrelated umbilical cord blood transplantation (UCBT). The secondary objective of the study is to describe the efficacy of UCBT with intrathecal administration of DUOC-01 in these patients.
Will I have to stop taking my current medications?
The trial information does not specify if you need to stop taking your current medications. However, it mentions that you cannot participate if you are receiving certain treatments like radiotherapy, immunosuppressive medications, or cytotoxic chemotherapy.
What data supports the effectiveness of the treatment DUOC-01 for inherited metabolic brain diseases?
Research on similar stem cell therapies shows promise, such as a study where stem cells were used to reduce harmful substances in the brain of mice with a condition similar to metachromatic leukodystrophy, leading to improved brain function. Additionally, another study demonstrated that stem cell-derived neural cells improved brain function and reduced inflammation in a mouse model of Gaucher disease, suggesting potential benefits for similar brain conditions.12345
How does stem cell therapy differ from other treatments for inherited metabolic brain diseases?
Stem cell therapy for inherited metabolic brain diseases is unique because it uses induced pluripotent stem cells (iPSCs) to model and potentially treat the disease by replacing or repairing damaged cells in the brain. Unlike traditional treatments that may only address symptoms, this approach aims to directly target the underlying cellular defects, offering a more comprehensive and potentially curative solution.16789
Eligibility Criteria
This trial is for children and young adults (1 week to <21 years old) with certain inherited metabolic brain diseases, who can perform daily activities at least 40% of the time. They should have a life expectancy over 6 months, specific enzyme or mutation-confirmed diseases, signs of disease in their nervous system, and good heart, liver, kidney, and lung function. A matching umbilical cord blood unit for transplant must be available.Inclusion Criteria
My disease shows up on brain scans or affects my nervous system.
My kidney, liver, heart, and lung functions are all within normal ranges.
My genetic condition was confirmed by two separate tests.
See 4 more
Exclusion Criteria
Pregnant or breastfeeding.
Inability to obtain patient's, parent's or legal guardian's consent.
You cannot have an MRI scan or lumbar puncture.
See 9 more
Trial Timeline
Screening
Participants are screened for eligibility to participate in the trial
2-4 weeks
Treatment
Participants undergo unrelated umbilical cord blood transplantation (UCBT) followed by intrathecal administration of DUOC-01 between day 26 and 28 post-transplant
4 weeks
Multiple visits for transplantation and intrathecal administration
Follow-up
Participants are monitored for safety and effectiveness, including evaluations for infusional and neuro toxicity, and standard of care follow-up evaluations
1-5 years
Regular follow-up visits for evaluations
Treatment Details
Interventions
- DUOC-01 (Cell Therapy)
Trial OverviewThe study tests the safety and feasibility of DUOC-01 cells given into the spinal fluid as an extra treatment during standard unrelated cord blood transplants in patients with early signs of demyelinating disease due to inherited metabolism errors.
Participant Groups
1Treatment groups
Experimental Treatment
Group I: Intrathecal administration of DUOC-01Experimental Treatment1 Intervention
Administration of DUOC-01, given intrathecally, between day 26 and 28 post unrelated cord blood transplant
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
Duke University Medical CenterDurham, NC
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Who Is Running the Clinical Trial?
Joanne Kurtzberg, MDLead Sponsor
The Marcus FoundationCollaborator
References
Neuronopathic Gaucher's disease: induced pluripotent stem cells for disease modelling and testing chaperone activity of small compounds. [2021]Gaucher's disease (GD) is caused by mutations in the GBA1 gene, which encodes acid-β-glucosidase, an enzyme involved in the degradation of complex sphingolipids. While the non-neuronopathic aspects of the disease can be treated with enzyme replacement therapy (ERT), the early-onset neuronopathic form currently lacks therapeutic options and is lethal. We have developed an induced pluripotent stem cell (iPSc) model of neuronopathic GD. Dermal fibroblasts of a patient with a P.[LEU444PRO];[GLY202ARG] genotype were transfected with a loxP-flanked polycistronic reprogramming cassette consisting of Oct4, Sox2, Klf4 and c-Myc and iPSc lines derived. A non-integrative lentiviral vector expressing Cre recombinase was used to eliminate the reprogramming cassette from the reprogrammed cells. Our GD iPSc express pluripotent markers, differentiate into the three germ layers, form teratomas, have a normal karyotype and show the same mutations and low acid-β-glucosidase activity as the original fibroblasts they were derived from. We have differentiated them efficiently into neurons and also into macrophages without observing deleterious effects of the mutations on the differentiation process. Using our system as a platform to test chemical compounds capable of increasing acid-β-glucosidase activity, we confirm that two nojirimycin analogues can rescue protein levels and enzyme activity in the cells affected by the disease.
Intravenous infusion of iPSC-derived neural precursor cells increases acid β-glucosidase function in the brain and lessens the neuronopathic phenotype in a mouse model of Gaucher disease. [2023]Gaucher disease (GD) is caused by GBA1 mutations leading to functional deficiency of acid-β-glucosidase (GCase). No effective treatment is available for neuronopathic GD (nGD). A subclass of neural stem and precursor cells (NPCs) expresses VLA4 (integrin α4β1, very late antigen-4) that facilitates NPC entry into the brain following intravenous (IV) infusion. Here, the therapeutic potential of IV VLA4+NPCs was assessed for nGD using wild-type mouse green fluorescent protein (GFP)-positive multipotent induced pluripotent stem cell (iPSC)-derived VLA4+NPCs. VLA4+NPCs successfully engrafted in the nGD (4L;C*) mouse brain. GFP-positive cells differentiated into neurons, astrocytes and oligodendrocytes in the brainstem, midbrain and thalamus of the transplanted mice and significantly improved sensorimotor function and prolonged life span compared to vehicle-treated 4L;C* mice. VLA4+NPC transplantation significantly decreased levels of CD68 and glial fibrillary acidic protein, as well as TNFα mRNA levels in the brain, indicating reduced neuroinflammation. Furthermore, decreased Fluoro-Jade C and NeuroSilver staining suggested inhibition of neurodegeneration. VLA4+NPC-engrafted 4L;C* midbrains showed 35% increased GCase activity, reduced substrate [glucosylceramide (GC, -34%) and glucosylsphingosine (GS, -11%)] levels and improved mitochondrial oxygen consumption rates in comparison to vehicle-4L;C* mice. VLA4+NPC engraftment in 4L;C* brain also led to enhanced expression of neurotrophic factors that have roles in neuronal survival and the promotion of neurogenesis. This study provides evidence that iPSC-derived NPC transplantation has efficacy in an nGD mouse model and provides proof of concept for autologous NPC therapy in nGD.
Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy. [2012]Pluripotency, virtually unlimited self-renewal and amenability to genetic modification make embryonic stem (ES) cells an attractive donor source for cell-mediated gene therapy. In this proof of concept study, we explore whether glial precursors derived from murine ES cells (ESGPs) and engineered to overexpress human arylsulfatase A (hASA) can cross-correct the metabolic defect in an animal model of metachromatic leukodystrophy (MLD). Transfected ES cells showed an up to 30-fold increase in ASA activity. Following in vitro differentiation, high expression of ASA was found in all stages of neural and glial differentiation. hASA-overexpressing ESGPs maintained their ability to differentiate into astrocytes and oligodendrocytes in vitro and in vivo. After transplantation into the brain of neonatal ASA-deficient mice, hASA-overexpressing ESGPs were found to incorporate into a variety of host brain regions. Four weeks after engraftment, immunofluorescence analyses with an antibody to sulfatide revealed a 46.7+/-4.0% reduction of immunoreactive sulfatide deposits in the vicinity of the hASA-positive engrafted cells, thereby significantly extending the rate of sulfatide reduction achieved by the endogenous ASA activity of non-hASA-transfected control cells (21.1+/-5.8%). These findings provide first in vivo evidence that ES cells may serve as a potential donor source for cell-mediated enzyme delivery in storage disorders such as MLD.
A human induced pluripotent stem cell line (TRNDi007-B) from an infantile onset Pompe patient carrying p.R854X mutation in the GAA gene. [2020]Pompe disease is an autosomal inherent genetic disease caused by mutations in the GAA gene that encodes acid alpha-glucosidase. The disease affects patients in heart, skeletal muscles, liver, and central nervous system. A human induced pluripotent stem cell (iPSC) line was generated from the skin dermal fibroblasts of a Pompe patient with homozygosity for a c.2560C > T (p.R854X) mutation in exon 18 of the GAA gene. This human iPSC line provides a useful resource for disease modeling and drug discovery.
An induced pluripotent stem cell line (SDQLCHi033-A) derived from a patient with maple syrup urine disease type Ib carrying a homozygous mutation in BCKDHB gene. [2021]Maple syrup urine disease (MSUD) type Ib is a subclass of MSUD (248600) which is an inborn error of metabolism caused by defects in the branched-chain α-ketoacid dehydrogenase complex. An induced pluripotent stem cell (iPSC) line was generated from an 11-day-old girl diagnosed with maple syrup urine disease type Ib and carrying a novel homozygous mutation of c.1097C>A (p.P366Q) in BCKDHB gene. This cell line demonstrates a normal karyotype and maintains a pluripotent state, displaying the capability to differentiate into the three germ layer lineages and the absence of exogenous pluripotency vector expression.
Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells. [2021]Pompe disease is a lysosomal storage disorder caused by autosomal recessive mutations in the acid alpha-glucosidase (GAA) gene. Acid alpha-glucosidase deficiency leads to abnormal glycogen accumulation in patient cells. Given the increasing evidence of central nervous system (CNS) involvement in classic infantile Pompe disease, we used neural stem cells, differentiated from patient induced pluripotent stem cells, to model the neuronal phenotype of Pompe disease. These Pompe neural stem cells exhibited disease-related phenotypes including glycogen accumulation, increased lysosomal staining, and secondary lipid buildup. These morphological phenotypes in patient neural stem cells provided a tool for drug efficacy evaluation. Two potential therapeutic agents, hydroxypropyl-β-cyclodextrin and δ-tocopherol, were tested along with recombinant human acid alpha-glucosidase (rhGAA) in this cell-based Pompe model. Treatment with rhGAA reduced LysoTracker staining in Pompe neural stem cells, indicating reduced lysosome size. Additionally, treatment of diseased neural stem cells with the combination of hydroxypropyl-β-cyclodextrin and δ-tocopherol significantly reduced the disease phenotypes. These results demonstrated patient-derived Pompe neural stem cells could be used as a model to study disease pathogenesis, to evaluate drug efficacy, and to screen compounds for drug discovery in the context of correcting CNS defects.
Derivation of a human induced pluripotent stem cell line (QBRIi007-A) from a patient carrying a homozygous intronic mutation (c.613-7T>G) in the SLC2A2 gene. [2022]Fanconi Bickel Syndrome (FBS) is an autosomal recessive disease resulting from mutations in the SLC2A2 gene, encoding the GLUT2. FBS patients develop diabetes mellitus. Using non-integrating Sendai virus, we generated an induced pluripotent stem cell (iPSC) line, QBRIi007-A, carrying the c.613-7 T>G homozygous mutation in intron 5 of the SLC2A2 gene from a 19-year-old female with FBS and diabetes. The iPSC line was characterized for pluripotency, differentiation potential, genomic integrity, and genetic identity. This iPSC line provides a useful cell model to understand the role of GLUT2 in the disease development and to discover new drug candidates.
Directed differentiation and characterization of genetically modified embryonic stem cells for therapy. [2008]Lysosomal storage disorders are rare, inherited diseases caused by a deficiency of a specific, lysosomal enzyme. In the case of mucopolysaccharidosis type IIIA, a lack of active sulfamidase enzyme results in heparan sulfate accumulation, severe and progressive neurological deficits, and usually premature death. Embryonic stem cells can be genetically modified to overexpress lysosomal enzymes, providing a renewable reservoir of cells that can be readily expanded in culture. Screening clonal lines of embryonic stem cells for desirable properties such as high levels and maintenance of enzyme activity throughout terminal differentiation to neural phenotypes theoretically provides a reproducible population of cells that can be fully characterized in vitro before implantation within the central nervous system in animal models of lysosomal storage disorders.
Human-induced pluripotent stem cell lines (CMCi006-A and CMCi007-A) from a female and male patient with Fabry disease carrying the same frameshift deletion mutation. [2021]Human-induced pluripotent stem cell lines (hiPSCs) derived from the peripheral blood mononuclear cells (PBMCs) of a woman (CMCi007-A) and her son (CMCi006-A) diagnosed with Fabry disease (FD) caused by the frameshift deletion mutation c.969delC in the alpha-galactosidase A (GLA) gene were generated. These hiPSCs showed typical human embryonic stem cell-like morphology and expressed pluripotency-associated markers, and directly differentiated into all three germ-layers. Karyotyping showed normal 46, XY (CMCi006-A) and 46, XX (CMCi007-A). In summary, we generated novel patient-specific hiPSC lines from both a female and male containing the same mutation, which may provide additional insight into the pathophysiology of FD.