Engineered B Cell Therapy for Mucopolysaccharidosis I

Recruiting at1 trial location

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Immusoft Corporation

Must not be taking: Immune suppressants, Oxygen therapy

Disqualifiers: Cancer, Autoimmune disorders, HSCT, others

No Placebo Group

Trial Summary

What is the purpose of this trial?

This trial tests ISP-001, which uses modified immune cells to help adults with Mucopolysaccharidosis Type I Hurler-Scheie and Scheie by making a missing enzyme. The goal is to see if this approach is safe and tolerable.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. However, if you require systemic immune suppression or continuous supplemental oxygen, you may not be eligible to participate.

What data supports the effectiveness of the treatment ISP-001 for Mucopolysaccharidosis I?

Research on enzyme replacement therapy (ERT) for Mucopolysaccharidosis I shows that treatments like alpha-L-iduronidase can be effective in managing symptoms, especially in less severe cases. Clinical trials have demonstrated that ERT can help reduce the accumulation of harmful substances in the body, which is a key issue in this condition. ^{1 2 3 4 5}

How is the treatment ISP-001 different from other treatments for Mucopolysaccharidosis I?

ISP-001 is unique because it involves engineered B cells, which may offer a novel way to address the enzyme deficiency in Mucopolysaccharidosis I, potentially overcoming limitations of existing treatments that struggle to address central nervous system involvement. ^{1 6 7 8 9}

Research Team

Immusoft Clinical Development

Principal Investigator

Immusoft of CA, Inc.

Eligibility Criteria

Adults over 18 with Mucopolysaccharidosis type I Hurler-Scheie or Scheie can join this trial. They must live close to the study site, have good kidney function and heart health, and be able to attend all follow-ups. Those with certain medical conditions, oxygen needs, immune suppression, past stem cell transplants or B cell cancers cannot participate.

Inclusion Criteria

I can stay within a 45-minute drive from the study site for at least 5 days after treatment.

I can travel to the study site for follow-up visits.

I am 18 years old or older.

Exclusion Criteria

I have a history of B cell cancer, EBV disease, or autoimmune disorders.

Any medical condition likely to interfere with assessment of safety or efficacy of the study treatment.

I need medication to suppress my immune system.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a dose of 5 x 10e7 cells/kg of autologous plasmablasts engineered to express α-L-iduronidase (IDUA) on Day 0

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessment of adverse events and various biomarkers

24 weeks

Multiple visits (in-person and virtual) over 24 weeks

Long-term follow-up

Participants are monitored for long-term safety and biomarker levels, including glycosaminoglycan (GAG) and antibody levels

1 year

Treatment Details

Interventions

• ISP-001 (Virus Therapy)

Trial Overview The trial is testing a new treatment using patients' own modified B cells (ISP-001) for adults with Mucopolysaccharidosis Type I Hurler-Scheie and Scheie. It's a first-of-its-kind study focusing on safety and how well it works in humans.

Participant Groups

Group I: Autologous Plasmablasts (B cells) Experimental Treatment 1 Intervention

Dose Level: 5 x 10e7 cells/kg on Day 0

Who Is Running the Clinical Trial?

Immusoft Corporation

Lead Sponsor

Trials

1

Recruited

2+

Immusoft of CA, Inc.

Lead Sponsor

Trials

1

Recruited

2+

Findings from Research

Alpha-L-iduronidase enzyme replacement therapy has been developed as an effective treatment for patients with mucopolysaccharidosis I, particularly those with attenuated forms of the disease, as shown in recent Phase I/II and Phase III clinical trials.

While the therapy has proven effective for patients with less severe symptoms, further advancements are needed to address the more severe neurological and skeletal issues seen in Hurler syndrome patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alpha-L-iduronidase and enzyme replacement therapy for mucopolysaccharidosis I. Brooks, DA.[2022]

Laronidase enzyme replacement therapy led to significant and sustained reductions in urinary glycosaminoglycan levels in patients with attenuated mucopolysaccharidosis type I over a mean follow-up of 6.1 years, indicating effective treatment.

The therapy stabilized disease progression in most patients, with younger patients (under 10 years at treatment initiation) showing better maintenance of health measures and fewer complications compared to older patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Long-Term Treatment with Laronidase in Patients with Mucopolysaccharidosis Type I. Laraway, S., Mercer, J., Jameson, E., et al.[2022]

Galsulfase enzyme replacement therapy (ERT) initiated in adulthood for patients with mucopolysaccharidosis (MPS) VI was well tolerated and led to a significant reduction in urinary glycosaminoglycans (uGAG) levels by an average of 66% over a median follow-up of 7.2 years.

While the 6-minute walk test showed a slight decrease in distance, improvements were noted in stair climbing performance, suggesting that ERT may help stabilize certain physical functions in MPS VI patients over the long term.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Enzyme replacement therapy initiated in adulthood: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program. Lampe, C., Harmatz, PR., Parini, R., et al.[2020]

Hematopoietic cell transplantation (HCT) has been successfully used to treat over 500 patients with mucopolysaccharidosis type IH (MPS IH; Hurler syndrome) for nearly 30 years, demonstrating its efficacy as a long-term treatment option.

The introduction of enzyme replacement therapy (ERT) with recombinant alpha-L-iduronidase (IDUA) has expanded treatment options for less severe forms of MPS I, and combining ERT with HCT has been explored in over 50 MPS IH patients, indicating a potential shift towards multimodal therapies in the future.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

alpha-L-iduronidase therapy for mucopolysaccharidosis type I. Tolar, J., Orchard, PJ.[2021]

Encapsulated genetically engineered human amniotic epithelial (IHAE) cells can effectively secrete the enzyme GUSB, which is crucial for treating Mucopolysaccharidosis type VII (MPSVII), a lysosomal storage disease, demonstrating therapeutic potential in both in vitro and in vivo experiments.

This method of encapsulation not only prevents harmful immune responses and tumor formation but also allows for controlled expression of GUSB, addressing the challenge of delivering therapies across the blood-brain barrier, which is critical for treating neurological symptoms associated with MPSVII.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Encapsulation cell therapy for mucopolysaccharidosis type VII using genetically engineered immortalized human amniotic epithelial cells. Nakama, H., Ohsugi, K., Otsuki, T., et al.[2019]

Encapsulating recombinant cells that produce the enzyme IDUA within alginate microcapsules shows promise for treating Mucopolysaccharidosis type I (MPS I), as it initially increases IDUA activity and reduces harmful glycosaminoglycan (GAG) storage in affected mice.

However, the long-term effectiveness is limited due to inflammation and fibrosis around the capsules, which leads to a decrease in IDUA activity and the development of antibodies against the enzyme, indicating a need for improvements in the encapsulation method to enhance stability and reduce immune responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intraperitoneal implant of recombinant encapsulated cells overexpressing alpha-L-iduronidase partially corrects visceral pathology in mucopolysaccharidosis type I mice. Baldo, G., Mayer, FQ., Martinelli, B., et al.[2018]

Valanafusp alpha, an IgG-IDUA fusion protein designed to cross the blood-brain barrier, shows a four-fold increase in plasma clearance in children with MPSI compared to adults, indicating a need for adjusted dosing in pediatric patients.

The pharmacokinetic profile of valanafusp alpha is similar to that of the standard enzyme replacement therapy, laronidase, suggesting that it may be an effective alternative for treating CNS involvement in MPSI without significant effects on plasma glucose levels.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody-Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I. Pardridge, WM., Boado, RJ., Giugliani, R., et al.[2019]

Reprogramming erythroid cells to produce the lysosomal enzyme alpha-L-iduronidase (IDUA) showed promising results, with stable and elevated IDUA levels maintained for at least 9 months in MPS I chimeras after HSC transplantation.

This method not only corrected metabolic issues in MPS I mice, such as normalizing urinary glycosaminoglycan levels, but also significantly improved neurological function and tissue pathology, indicating a potential safe and effective strategy for systemic delivery of therapeutic proteins.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome. Wang, D., Zhang, W., Kalfa, TA., et al.[2021]

References

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

Alpha-L-iduronidase and enzyme replacement therapy for mucopolysaccharidosis I. [2022]

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

Outcomes of Long-Term Treatment with Laronidase in Patients with Mucopolysaccharidosis Type I. [2022]

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

Enzyme replacement therapy initiated in adulthood: Findings from the mucopolysaccharidosis VI Clinical Surveillance Program. [2020]

4. France pubmed.ncbi.nlm.nih.gov

Mucopolysaccharidosis type I (Hurler syndrome) and anesthesia: the impact of bone marrow transplantation, enzyme replacement therapy, and fiberoptic intubation on airway management. [2012]

5. New Zealand pubmed.ncbi.nlm.nih.gov

alpha-L-iduronidase therapy for mucopolysaccharidosis type I. [2021]

6. Japan pubmed.ncbi.nlm.nih.gov

Encapsulation cell therapy for mucopolysaccharidosis type VII using genetically engineered immortalized human amniotic epithelial cells. [2019]

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

Intraperitoneal implant of recombinant encapsulated cells overexpressing alpha-L-iduronidase partially corrects visceral pathology in mucopolysaccharidosis type I mice. [2018]

8. New Zealand pubmed.ncbi.nlm.nih.gov

Plasma Pharmacokinetics of Valanafusp Alpha, a Human Insulin Receptor Antibody-Iduronidase Fusion Protein, in Patients with Mucopolysaccharidosis Type I. [2019]

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

Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome. [2021]