Gene Therapy for Frontotemporal Dementia

(upliFT-D Trial)

Recruiting at 13 trial locations

Overseen By Patient/Family Inquiries

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Passage Bio, Inc.

Must not be taking: Anticoagulants, Corticosteroids

Disqualifiers: Gene therapy, Brain lesions, HIV, others

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: Single dose

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy treatment called PBFT02 for individuals with frontotemporal dementia, a brain disorder affecting personality and behavior. The goal is to determine if delivering a working copy of the GRN gene to the brain can help manage the condition. Researchers focus on patients with a known mutation in the GRN or C9ORF72 genes who live outside of nursing homes. Participants should have a caregiver who checks on them regularly. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group.

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.

Is there any evidence suggesting that PBFT02 is likely to be safe for humans?

Research has shown that PBFT02, a gene therapy for frontotemporal dementia, has been safe in studies so far. Most patients tolerated the treatment well. Some developed antibodies afterward, but this normal reaction did not cause serious problems. PBFT02 also improved important markers indicating disease progression. These results suggest that, while more research is needed, PBFT02 could be a safe option for people with this type of dementia. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for frontotemporal dementia, which mainly focus on managing symptoms through medications like antidepressants or antipsychotics, PBFT02 offers a groundbreaking approach by using gene therapy. This treatment targets the root cause by delivering a functional gene directly into the brain via the intra cisterna magna, potentially correcting the genetic defects responsible for the disease. Researchers are excited because this method could lead to more effective and long-lasting results, addressing the underlying issues rather than just alleviating symptoms.

What evidence suggests that PBFT02 might be an effective treatment for frontotemporal dementia?

Research has shown that PBFT02, a gene therapy for frontotemporal dementia, may help increase levels of progranulin, a protein important for brain health. In one study, patients who received PBFT02 had higher progranulin levels in their spinal fluid within 30 days. Another study found that 89% of patients maintained or exceeded normal progranulin levels six months after treatment. Additionally, the therapy showed positive effects in models for genetic mutations linked to frontotemporal dementia. These findings suggest that PBFT02 could be effective for patients with certain genetic mutations related to this condition. Participants in this trial will receive a single dose of PBFT02, with some receiving Dose 1 and others receiving either Dose 1 or 2, to further evaluate its effectiveness. ^{1 3 6 7 8}

Who Is on the Research Team?

Tiffini Voss, MD, PhD

Principal Investigator

Passage Bio, Inc.

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• PBFT02

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.

How Is the Trial Designed?

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

PBFT02 is already approved in United States for the following indications:

Approved in United States as PBFT02 for:

• Frontotemporal Dementia with Progranulin Mutations (FTD-GRN)

Who Is Running the Clinical Trial?

Passage Bio, Inc.

Lead Sponsor

Trials

6

Recruited

112,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

Citations

1. passagebio.com passagebio.com/investors-and-news/press-releases-and-statements/news-details/2025/Passage-Bio-Reports-Updated-Interim-Data-from-upliFT-D-Study-and-Provides-Program-Update/default.aspx

Passage Bio Reports Updated Interim Data from upliFT-D ... Dose 1 PBFT02 treatment resulted in a robust and durable increase in CSF PGRN expression through 18 months post-treatment. Dose 1 PBFT02 ...

2. clinicaltrials.gov clinicaltrials.gov/study/NCT04747431

A Study of PBFT02 in Participants With FTD and Mutations ... PBFT02 is a gene therapy for frontotemporal dementia intended to deliver a functional copy of the GRN gene to the brain. This study will assess the safety, ...

3. theaftd.org theaftd.org/posts/1ftd-in-the-news/blog-passage-bio-trial-data/

Passage Bio Announces Hopeful Initial Data from Phase 1 ... In Passage Bio's clinical trial, PBFT02 resulted in a significant increase in progranulin in participants' cerebrospinal fluid after 30 days, ...

4. nature.com nature.com/articles/s41591-024-02973-0

Progranulin AAV gene therapy for frontotemporal dementia Among the nine patients with CSF progranulin data at month 6, eight (89%) had progranulin level within or above the normal range, whereas, among ...

5. insideprecisionmedicine.com insideprecisionmedicine.com/topics/precision-medicine/passage-bios-dementia-gene-therapy-trial-expands-patient-pool/

Passage Bio's Dementia Gene Therapy Trial Expands ... ... PBFT02 improves outcomes in FTD models for GRN haploinsufficiency as well as mutations in C9orf72. The data also included safety and robust ...

6. theaftd.org theaftd.org/posts/1ftd-in-the-news/b25-passage-bio-clinical-trial/

Passage Bio Provides Updated Interim Data from UpliFT-D ... Biotechnology firm Passage Bio recently provided updated interim data from its phase 1/2 clinical trial for its gene replacement therapy targeting FTD-GRN.

7. alz.confex.com alz.confex.com/alz/2025/meetingapp.cgi/Paper/103638

Interim Safety and Biomarker Data From upliFT-D Trial of ... Conclusions: Interim safety and biomarker data from the upliFT-D trial provides early evidence that PBFT02 has potential as a one-time therapy for FTD-GRN, thus ...

8. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11108785/

Progranulin AAV gene therapy for frontotemporal dementia One-time administration of PR006 into the cisterna magna was generally safe and well tolerated. All patients developed treatment-emergent anti- ...