What is the mechanism of action of this treatment?

The most common treatments for Frontotemporal Dementia (FTD) include gene therapy, such as PBFT02, which aims to deliver a functional copy of the GRN gene to the brain. This approach is crucial because mutations in the progranulin gene (GRN) are a significant cause of FTD, leading to reduced levels of progranulin, a protein essential for neuronal survival and function. By restoring the normal function of the GRN gene, gene therapy can potentially halt or reverse the neurodegenerative processes in FTD patients. This is particularly important as it addresses the root cause of the disease, offering hope for more effective and long-lasting treatments compared to symptomatic therapies like memantine or antiseizure medications, which do not modify the disease's progression.

What side effects are associated with this type of intervention?

Gene therapy, such as PBFT02 which delivers a functional GRN gene to the brain, is still under investigation, and specific side effects are not fully established. However, general side effects of gene therapy can include immune reactions, inflammation, and potential off-target effects. For other common treatments of Frontotemporal Dementia, such as acetylcholinesterase inhibitors (e.g., donepezil) and memantine, side effects may include gastrointestinal issues, headaches, dizziness, and confusion. It is important to discuss potential risks and benefits with a healthcare provider.

What prior FDA approvals exist?

As of now, there are no FDA-approved gene therapies specifically for the treatment of Frontotemporal Dementia (FTD). PBFT02, which aims to deliver a functional copy of the GRN gene to the brain, is currently under investigation. Most treatments for FTD focus on managing symptoms rather than modifying the disease. The field of gene therapy for neurodegenerative diseases is still emerging, with ongoing research and clinical trials exploring its potential.

What other types of research exist?

Promising alternatives to PBFT02 for Frontotemporal Dementia patients include antisense oligonucleotide therapies targeting progranulin (GRN) mutations, such as those that modulate RNA to increase progranulin levels. Additionally, therapies targeting C9orf72-repeat expansions with stereopure oligonucleotides are being explored for their potential in treating neurodegenerative disorders associated with FTD. These approaches are in various stages of research and clinical trials, showing potential for efficacy in managing FTD.

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Gene Therapy

Gene Therapy for Frontotemporal Dementia (upliFT-D Trial)

Phase 1 & 2

Recruiting

Research Sponsored by Passage Bio, Inc.

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Documented to be a pathogenic GRN mutation carrier

Clinical diagnosis of frontotemporal dementia

Must not have

Homozygous GRN mutation carrier

Any contraindication to the ICM administration procedure

Timeline

Screening 3 weeks

Treatment Varies

Follow Up up to 5 years (multiple visits)

Awards & highlights

No Placebo-Only Group

Summary

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.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

Potential side effects may include reactions related to gene therapy such as immune responses against the introduced genes or delivery system components. There could also be complications from procedures required for administration like lumbar puncture and MRI.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I carry a mutation in the GRN gene.

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I have been diagnosed with frontotemporal dementia.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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I carry two copies of a GRN gene mutation.

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

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I am allergic or cannot use corticosteroids due to health reasons.

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I have a genetic mutation linked to Alzheimer's disease.

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My kidney function is severely reduced.

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I have had serious thoughts about suicide in the last 6 months.

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I have cancer other than skin cancer or a genetic cancer syndrome.

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I have tested positive for HIV, HTLV-1/2, Hepatitis B/C, or tuberculosis within the last year.

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I need extra oxygen to breathe properly.

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My immune system is weakened.

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I don't have health issues that would make certain medical procedures risky.

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I have nerve damage in my hands or feet that affects my sense of touch.

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I have a brain condition that explains my symptoms.

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I have not had gene therapy or treatments affecting PGRN levels without a proper washout period.

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I have never treated my vitamin B12 deficiency.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ up to 5 years (multiple visits)

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~up to 5 years (multiple visits)

This trial's timeline: 3 weeks for screening, Varies for treatment, and up to 5 years (multiple visits) for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Assess Humoral Response Against the Vector and Transgene in CSF

Assess Humoral Response Against the Vector and Transgene in Serum

Change in Nerve Conduction Amplitude from Baseline on Nerve Conduction Studies

+2 more

Secondary study objectives

Change from baseline in FTD clinical domains as assessed by the Clinical Dementia Rating National Alzheimer's Coordinating Center frontotemporal lobar degeneration domains (CDR Plus NACC FTLD)

Change from baseline in neurocognitive and other assessments

Change in Activities of Daily Living Scales

+7 more

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

3Treatment groups

Experimental Treatment

Group I: Optional Cohort 3Experimental Treatment1 Intervention

Drug: PBFT02 Dose 3: 2.2 x 10\^11 GC/g\* Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight

Group II: Cohort 2Experimental Treatment1 Intervention

Drug: PBFT02 Dose 2: 1.1 x 10\^11 GC/g\* Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight

Group III: Cohort 1Experimental Treatment1 Intervention

Drug: PBFT02 Dose 1: 3.3 x 10\^10 GC/g\* Single dose of PBFT02, via intra cisterna magna \*GC/g: gene copy per gram of estimated brain weight

0 / 17Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

The most common treatments for Frontotemporal Dementia (FTD) include gene therapy, such as PBFT02, which aims to deliver a functional copy of the GRN gene to the brain. This approach is crucial because mutations in the progranulin gene (GRN) are a significant cause of FTD, leading to reduced levels of progranulin, a protein essential for neuronal survival and function. By restoring the normal function of the GRN gene, gene therapy can potentially halt or reverse the neurodegenerative processes in FTD patients. This is particularly important as it addresses the root cause of the disease, offering hope for more effective and long-lasting treatments compared to symptomatic therapies like memantine or antiseizure medications, which do not modify the disease's progression.

Insights into disease mechanisms and potential therapeutics for C9orf72-related amyotrophic lateral sclerosis/frontotemporal dementia.Use of Curcumin, a Natural Polyphenol for Targeting Molecular Pathways in Treating Age-Related Neurodegenerative Diseases.Methods to Investigate the Molecular Basis of Progranulin Actions on Brain and Behavior In Vivo Using Knockout Mice.