Gene Therapy for Frontotemporal Dementia

(ASPIRE-FTD Trial)

Recruiting at 15 trial locations

Overseen By AviadoBio Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: AviadoBio Ltd

Disqualifiers: Severe dementia, Other dementias, Stroke, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 day

9 Participants Needed

Trial Summary

What is the purpose of this trial?

The goal of this clinical study is to learn about an investigational gene therapy product called AVB-101, which is designed to treat a disease called Frontotemporal Dementia with Progranulin Mutations (FTD-GRN). FTD-GRN is an early-onset form of dementia, a progressive brain disorder that affects behavior, language and movement. These symptoms result from below normal levels of a protein called progranulin (PGRN) in the brain, which leads to the death of nerve cells (neurons), affecting the brain's ability to function. The main questions that the study aims to answer are: 1. Is a one-time treatment with AVB-101 safe for patients with FTD-GRN? 2. Does a one-time treatment with AVB-101 restore PGRN levels to at least normal levels? 3. Could AVB-101 work as a treatment to slow down or stop progression of FTD-GRN? In this study there is no placebo (a dummy pill or treatment used for comparison purposes), so all participants will receive a one-time treatment of AVB-101 delivered directly to the brain, with follow-up assessments for 5 years.

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 have been treated with any investigational medicinal product within 60 days or 5 half-lives before the study, you may not be eligible to participate.

What makes the treatment AVB-101 unique for frontotemporal dementia?

AVB-101 is a gene therapy that uses adeno-associated virus serotype 1 to deliver genetic material, aiming to increase levels of progranulin, a protein often deficient in frontotemporal dementia. This approach is novel because it targets the underlying genetic cause of the disease, potentially providing a more effective treatment than current options, which are limited and do not address the genetic basis of the condition. ^{1 2 3 4 5}

Eligibility Criteria

This trial is for adults aged 30-75 with Frontotemporal Dementia (FTD) due to a specific genetic mutation (GRN). Participants must have certain symptoms, be able to consent, and have a study partner. They need enough thalamic volume in the brain and should commit to the study's procedures and schedule.

Inclusion Criteria

I am between 30 and 75 years old.

FTD as evidenced by CDR + NACC FTLD global score of 0.5, 1.0, or 2.0

A protocol defined minimum thalamic volume on each side on Screening MRI

Exclusion Criteria

Severe dementia, defined as CDR + NACC FTLD global score of 3.0, or other symptoms that preclude the ability to comply with study procedures and/or pose unacceptable safety risk to the subject

Previous treatment with any investigational medicinal product (IMP) within 60 days or 5 half-lives (whichever is longer) prior to study drug treatment

Concomitant disease, any clinically significant laboratory abnormality, or treatment which, in the opinion of the Investigator, may pose an unacceptable safety risk to the participant or interfere with study conduct or the participant's ability to comply with study procedures including neurosurgical administration under anesthesia

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a one-time treatment of AVB-101 delivered directly to the brain

1 day

Initial Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments of adverse events and suicidal ideation

26 weeks

Long-term Follow-up

Participants undergo follow-up assessments to monitor changes in cognitive function, brain structure, and immunogenicity

5 years

Treatment Details

Interventions

• AVB-101

Trial Overview The trial tests AVB-101, a gene therapy delivered once directly into the brain. It aims to see if this treatment is safe for FTD-GRN patients, can restore normal protein levels associated with dementia, and potentially halt or slow disease progression.

Participant Groups

Group I: Cohort 2 (dose 2) Experimental Treatment 2 Interventions

Escalated dose, delivered as a one-time only, intrathalamic administration.

Group II: Cohort 1 (dose 1) Experimental Treatment 2 Interventions

Initial dose, delivered as a one-time only, intrathalamic administration.

AVB-101 is already approved in United States, European Union for the following indications:

Approved in United States as AVB-101 for:

• Frontotemporal Dementia with Progranulin Mutations (FTD-GRN) - Investigational

Approved in European Union as AVB-101 for:

• Frontotemporal Dementia with Progranulin Mutations (FTD-GRN) - Investigational

Who Is Running the Clinical Trial?

AviadoBio Ltd

Lead Sponsor

Trials

1

Recruited

9+

Findings from Research

Researchers created a human embryonic stem cell line with a CHMP2B mutation to model frontotemporal dementia (FTD), focusing on the role of astrocytes alongside neurons in disease progression.

The study found that astrocytes in FTD exhibit early alterations in their endolysosomal system and increased responsiveness to glutamate, which may lead to neuronal hyperactivity and synchronization, suggesting that astrocyte changes could trigger neuronal impairments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Astrocyte dysfunction and neuronal network hyperactivity in a CRISPR engineered pluripotent stem cell model of frontotemporal dementia. Canals, I., Comella-Bolla, A., Cepeda-Prado, E., et al.[2023]

Plasma levels of progranulin (PGRN) are significantly lower in individuals with granulin gene mutations compared to controls, indicating a potential biomarker for frontotemporal dementia (FTD).

Plasma PGRN levels are stable over a week, making them suitable for monitoring treatments aimed at increasing PGRN, but since they only moderately correlate with cerebrospinal fluid (CSF) PGRN levels, CSF sampling will still be necessary in clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers. Meeter, LH., Patzke, H., Loewen, G., et al.[2022]

Mutant CHMP2B, associated with frontotemporal dementia, disrupts endolysosomal trafficking in neurons, leading to impaired function and increased dendritic branching due to its inability to recruit the ATPase VPS4.

Treatment with antisense oligonucleotides targeting TMEM106B can restore endosomal health and improve trafficking in neurons, suggesting a promising therapeutic strategy for frontotemporal dementia linked to endolysosomal dysfunction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown. Clayton, EL., Milioto, C., Muralidharan, B., et al.[2022]

Gene therapy using adeno-associated viral vectors to deliver the progranulin gene into the cerebrospinal fluid has shown promising results in mouse models and nonhuman primates, significantly increasing progranulin levels and normalizing markers of deficiency.

The AAV1 vector demonstrated superior efficacy in increasing progranulin expression compared to other variants, and the treatment was well tolerated with no significant toxicity, supporting its potential as a safe therapeutic option for frontotemporal dementia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adeno-associated virus serotype 1-based gene therapy for FTD caused by GRN mutations. Hinderer, C., Miller, R., Dyer, C., et al.[2021]

Frontotemporal degeneration (FTD) presents unique clinical and molecular features, such as rapid disease progression and distinct pathology, making it a promising target for developing effective therapies compared to other neurodegenerative disorders.

Recent consensus diagnostic criteria and sensitive assessment scales for FTD, along with insights from ongoing drug development in similar diseases, indicate that FTD research is now ready to advance towards clinical trials for specific treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier). Boxer, AL., Gold, M., Huey, E., et al.[2021]

References

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

Astrocyte dysfunction and neuronal network hyperactivity in a CRISPR engineered pluripotent stem cell model of frontotemporal dementia. [2023]

2. Switzerland pubmed.ncbi.nlm.nih.gov

Progranulin Levels in Plasma and Cerebrospinal Fluid in Granulin Mutation Carriers. [2022]

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

Frontotemporal dementia causative CHMP2B impairs neuronal endolysosomal traffic-rescue by TMEM106B knockdown. [2022]

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

Adeno-associated virus serotype 1-based gene therapy for FTD caused by GRN mutations. [2021]

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

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier). [2021]