Gene Therapy for Frontotemporal Dementia

(upliFT-D Trial)

Recruiting at11 trial locations

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: Passage Bio, Inc.

Must not be taking: Anticoagulants, Corticosteroids

Disqualifiers: Gene therapy, Brain lesions, HIV, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests PBFT02, a gene therapy that uses a virus to deliver a healthy GRN gene to the brain. It targets patients aged 35-75 with frontotemporal dementia caused by GRN mutations. The virus helps bring the healthy gene to brain cells, which may improve their condition. This approach has been proposed as a treatment for this type of dementia.

Will I have to stop taking my current medications?

The trial requires that any therapies with the potential to alter PGRN levels must be stopped for at least 5 half-lives before joining the study. Additionally, anticoagulants should not be used in the 2 weeks prior to screening, and any dose of riluzole or edaravone must be stable for at least 30 days before the trial starts.

How is the treatment PBFT02 for Frontotemporal Dementia different from other treatments?

PBFT02 is a gene therapy that uses a viral vector to deliver therapeutic genes directly to the brain, aiming for long-term and targeted delivery of proteins that can protect and restore neurons. This approach is unique because it addresses delivery challenges that have limited the success of other treatments for neurodegenerative diseases. ^{1 2 3 4 5}

Research Team

Tiffini Voss, MD, PhD

Principal Investigator

Passage Bio, Inc.

Eligibility Criteria

This trial is for individuals with a clinical diagnosis of frontotemporal dementia who carry a specific pathogenic GRN mutation. They must have a caregiver, live outside of nursing homes (with some exceptions), and be able to give full consent. People with severe kidney issues, respiratory failure requiring oxygen, certain infections or recent vaccinations, untreated hypothyroidism or vitamin B12 deficiency, history of significant suicidal ideation or substance dependence, recent hospitalization due to acute illness, known mutations causing Alzheimer's disease, immunocompromised status or hypersensitivity to the study drug are excluded.

Inclusion Criteria

I carry a mutation in the GRN gene.

I have been diagnosed with frontotemporal dementia.

Living in the community (i.e., not in a nursing home); assisted living may be permitted at the discretion of the investigator

Exclusion Criteria

I carry two copies of a GRN gene mutation.

I have no health issues preventing me from undergoing the ICM procedure.

Women who are breastfeeding

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a single dose of PBFT02 via intra cisterna magna

Single dose

1 visit (in-person)

Main Study

Participants are monitored for safety, tolerability, and pharmacodynamic effects over a 2-year period

2 years

Multiple visits (in-person and virtual)

Safety Extension

Participants continue to be monitored for long-term safety over an additional 3-year period

3 years

Multiple visits (in-person and virtual)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• PBFT02 (Gene Therapy)

Trial Overview The trial is testing PBFT02 gene therapy designed to deliver a functional copy of the GRN gene directly into the brain. It aims to evaluate how safe and effective this treatment is for those affected by frontotemporal dementia due to progranulin gene mutations.

Participant Groups

Group I: Cohort 2, 3, 4 and 5 Experimental Treatment 1 Intervention

Drug: PBFT02 Dose 1 or 2; Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight

Group II: Cohort 1 Experimental Treatment 1 Intervention

Drug: PBFT02 Dose 1; Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight

Who Is Running the Clinical Trial?

Passage Bio, Inc.

Lead Sponsor

Trials

6

Recruited

112,000+

Findings from Research

The study tested the safety and feasibility of administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen and substantia nigra in 6 patients with moderately advanced Parkinson's disease, and found that the procedure was well-tolerated with no serious adverse events over a two-year period.

This research provides initial evidence that bilateral stereotactic delivery of CERE-120 is a safe approach for potentially improving treatment outcomes in Parkinson's disease, addressing issues related to axonal transport of neurotrophic factors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. Bartus, RT., Baumann, TL., Siffert, J., et al.[2021]

Gene therapy for Parkinson's disease is being explored as a promising alternative to traditional treatments, focusing on strategies like enhancing dopamine delivery, reducing subthalamic nucleus activity, and protecting neuronal function.

Early safety data from phase 1 trials of four different gene therapy agents are encouraging, and one phase 2 trial indicates some symptomatic improvement, although more research is needed to confirm overall efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An update on gene therapy in Parkinson's disease. Witt, J., Marks, WJ.[2021]

AAV2 viral vectors have been developed to deliver neurotrophic factors like NGF and NRTN, showing promising results in animal studies with sustained protein expression and no safety issues, paving the way for clinical applications in Alzheimer's and Parkinson's diseases.

These vectors have successfully advanced into multi-center, double-blind clinical trials, indicating their potential to address long-standing delivery challenges associated with neurotrophic factors in treating neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. Herzog, CD., Bishop, KM., Brown, L., et al.[2018]

The phase I trial involving 10 patients with Parkinson's disease confirmed that the putaminal convection-enhanced delivery (CED) of the AAV2-hAADC gene therapy was accurately targeted, as shown by MRI imaging that revealed T2 hyperintensity around the cannula tracts shortly after treatment.

The correlation between MRI findings and PET uptake suggests that T2-weighted MRI can effectively visualize the distribution of the hAADC gene therapy, which is crucial for optimizing future trials and ensuring effective treatment delivery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Qualitative imaging of adeno-associated virus serotype 2-human aromatic L-amino acid decarboxylase gene therapy in a phase I study for the treatment of Parkinson disease. Valles, F., Fiandaca, MS., Eberling, JL., et al.[2012]

Gene therapy for Parkinson's disease involves delivering genes that can produce dopamine or protect neurons, using recombinant adeno-associated viral (rAAV) vectors that are effective and safe for long-term use in the brain.

These rAAV vectors have minimal inflammatory responses and can be monitored using imaging techniques, highlighting their potential for safe clinical applications as researchers work on improving transgene expression regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene therapy for Parkinson's disease using recombinant adeno-associated viral vectors. Muramatsu, S., Tsukada, H., Nakano, I., et al.[2019]

References

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

Safety/feasibility of targeting the substantia nigra with AAV2-neurturin in Parkinson patients. [2021]

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

An update on gene therapy in Parkinson's disease. [2021]

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

Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. [2018]

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

Qualitative imaging of adeno-associated virus serotype 2-human aromatic L-amino acid decarboxylase gene therapy in a phase I study for the treatment of Parkinson disease. [2012]

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

Gene therapy for Parkinson's disease using recombinant adeno-associated viral vectors. [2019]