Stem Cell Therapy for Inherited Metabolic Brain Diseases

(DUOC-01 Trial)

Overseen By PTCT Referrals

Age: < 65

Sex: Any

Trial Phase: Phase 1

Sponsor: Joanne Kurtzberg, MD

Must not be taking: Immunosuppressives, Chemotherapy

Disqualifiers: Prior transplant, Seizures, HIV, others

Stay on Your Current Meds You can continue your current medications while participating

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: 4 weeks

40 Participants Needed

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. ^{1 2 3 4 5}

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. ^{1 6 7 8 9}

Research Team

Joanne Kurtzberg, MD

Principal Investigator

Duke University

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.

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.

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

Trial Overview The 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

Group I: Intrathecal administration of DUOC-01 Experimental Treatment 1 Intervention

Administration of DUOC-01, given intrathecally, between day 26 and 28 post unrelated cord blood transplant

Who Is Running the Clinical Trial?

Joanne Kurtzberg, MD

Lead Sponsor

Trials

19

Recruited

710+

The Marcus Foundation

Collaborator

Trials

19

Recruited

2,200+

Findings from Research

Researchers developed an induced pluripotent stem cell (iPSc) model of Gaucher's disease (GD) that retains the disease's genetic mutations and low enzyme activity, allowing for effective study of the neuronopathic form of the disease.

Using this iPSc model, they identified two nojirimycin analogues that can increase acid-β-glucosidase activity, suggesting potential therapeutic options for treating neuronopathic GD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neuronopathic Gaucher's disease: induced pluripotent stem cells for disease modelling and testing chaperone activity of small compounds. Tiscornia, G., Vivas, EL., Matalonga, L., et al.[2021]

Transplanting VLA4+ neural stem and precursor cells (NPCs) into a mouse model of neuronopathic Gaucher disease (nGD) led to significant improvements in sensorimotor function and increased lifespan, demonstrating the potential efficacy of this treatment approach.

The VLA4+NPCs not only engrafted successfully in the brain but also reduced neuroinflammation and neurodegeneration, while enhancing GCase activity and decreasing harmful substrate levels, suggesting a multifaceted mechanism of action that supports neuronal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Peng, Y., Liou, B., Inskeep, V., et al.[2023]

Embryonic stem cell-derived glial precursors engineered to overexpress human arylsulfatase A (hASA) showed a significant increase in enzyme activity, up to 30-fold, and effectively differentiated into brain cells, indicating their potential for gene therapy.

In a mouse model of metachromatic leukodystrophy, transplantation of these engineered cells resulted in a 46.7% reduction of harmful sulfatide deposits in the brain, demonstrating their efficacy in correcting metabolic defects associated with the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy. Klein, D., Schmandt, T., Muth-Köhne, E., et al.[2012]

A new human induced pluripotent stem cell (iPSC) line was created from a Pompe disease patient, which can help researchers study the disease and develop new treatments.

This iPSC line is particularly valuable because it comes from a patient with a specific mutation in the GAA gene, allowing for targeted disease modeling and drug discovery efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A human induced pluripotent stem cell line (TRNDi007-B) from an infantile onset Pompe patient carrying p.R854X mutation in the GAA gene. Cheng, YS., Li, R., Baskfield, A., et al.[2020]

A new induced pluripotent stem cell (iPSC) line was created from an 11-day-old girl with maple syrup urine disease type Ib, which is caused by a mutation in the BCKDHB gene.

This iPSC line shows a normal karyotype and can differentiate into all three germ layer lineages, indicating its potential for research and therapeutic applications in treating MSUD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Wang, B., Liu, C., Zhang, H., et al.[2021]

Patient-derived neural stem cells from individuals with Pompe disease displayed key disease characteristics, such as glycogen accumulation and increased lysosomal staining, making them a valuable model for studying the disease and testing treatments.

Treatment with recombinant human acid alpha-glucosidase (rhGAA) and a combination of hydroxypropyl-β-cyclodextrin and δ-tocopherol effectively reduced disease-related phenotypes in these neural stem cells, suggesting potential therapeutic strategies for addressing CNS involvement in Pompe disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells. Cheng, YS., Yang, S., Hong, J., et al.[2021]

Researchers created a new induced pluripotent stem cell (iPSC) line from a 19-year-old female with Fanconi Bickel Syndrome (FBS), which is caused by mutations in the SLC2A2 gene responsible for GLUT2, a glucose transporter.

This iPSC line can be used as a valuable model to study the mechanisms of FBS and to explore potential new treatments for the disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Elsayed, AK., Aghadi, M., Al-Khawaga, S., et al.[2022]

Mucopolysaccharidosis type IIIA is caused by a deficiency of the sulfamidase enzyme, leading to harmful heparan sulfate buildup and severe neurological issues, highlighting the need for effective treatments.

Genetically modified embryonic stem cells can be engineered to produce high levels of lysosomal enzymes, potentially offering a renewable source of cells for therapy in lysosomal storage disorders, which can be tested in animal models before clinical application.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Directed differentiation and characterization of genetically modified embryonic stem cells for therapy. Lau, AA., Hemsley, KM., Meedeniya, A., et al.[2008]

Two human-induced pluripotent stem cell lines (hiPSCs) were successfully created from the blood cells of a mother and son with Fabry disease, providing a unique model to study this genetic disorder.

These hiPSCs exhibited normal characteristics of stem cells and can differentiate into various cell types, which may help researchers better understand the disease mechanisms and develop potential therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

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. Cui, S., Shin, YJ., Ko, EJ., et al.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Neuronopathic Gaucher's disease: induced pluripotent stem cells for disease modelling and testing chaperone activity of small compounds. [2021]

2. England pubmed.ncbi.nlm.nih.gov

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]

3. England pubmed.ncbi.nlm.nih.gov

Embryonic stem cell-based reduction of central nervous system sulfatide storage in an animal model of metachromatic leukodystrophy. [2012]

4. England pubmed.ncbi.nlm.nih.gov

A human induced pluripotent stem cell line (TRNDi007-B) from an infantile onset Pompe patient carrying p.R854X mutation in the GAA gene. [2020]

5. England pubmed.ncbi.nlm.nih.gov

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]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Modeling CNS Involvement in Pompe Disease Using Neural Stem Cells Generated from Patient-Derived Induced Pluripotent Stem Cells. [2021]

7. England pubmed.ncbi.nlm.nih.gov

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]

8. United States pubmed.ncbi.nlm.nih.gov

Directed differentiation and characterization of genetically modified embryonic stem cells for therapy. [2008]

9. England pubmed.ncbi.nlm.nih.gov

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]