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.
Male or female, 30 to 75 years of age
Carriers of a pathogenic GRN mutation
FTD as evidenced by CDR + NACC FTLD global score of 0.5, 1.0, or 2.0
Presence of 1 or more of the criteria for diagnosis of possible bvFTD or PPA
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
Any concurrent disease that may cause cognitive impairment unrelated to mutations in the GRN gene, such as other causes of dementia, neurosyphilis, hydrocephalus, stroke, small vessel ischemic disease, uncontrolled hypothyroidism, or vitamin B12 deficiency
Clinically significant abnormality on MRI at Screening considered to be a contraindication to Intrathalamic infusion
Surgically significant pattern of brain atrophy on MRI at Screening that interferes with planned neurosurgical trajectory
Sequential
Intrathalamic AAV.PGRN administration
Procedure/SurgeryOne-time MRI-guided stereotaxic infusion of AAV.PGRN into the brain
Intrathalamic AVB-101
GeneticAVB-101 is made from an adeno-associated virus, serotype 9 (AAV9). AAVs are small viruses that are naturally occurring and do not cause illness or infection on their own. AVB-101 has been modified to contain a copy of the correct (non-mutated) GRN gene, plus some other genetic material to enable the GRN gene to function inside neurons (cells within the brain). AVB-101 has also been modified so that it cannot divide and make new copies of itself (known as 'replication'), which means that it cannot cause disease or a large immune response in your body.
Number and incidence of AEs and SAEs
Type and incidence of adverse events
Change from baseline in the Mini-Mental State Examination (MMSE)
Mini-Mental State Examination (MMSE) is a global assessment of cognitive status. Score range 0-30; higher scores reflect better cognitive function. Change in MMSE score from baseline visit to post-treatment visit will be assessed.
Incidence of treatment emergent suicidal ideation or behavior
The Columbia-Suicide Severity Rating Scale (C-SSRS) is an assessment tool that evaluates suicidal ideation and behavior. C-SSRS will be measured at each visit to assess for absence/presence of suicidal ideation and/or behavior.
Incidence of treatment-emergent clinically significant abnormalities in clinical examination findings
Change from baseline in PGRN protein levels in CSF and blood
Change over time in level of PGRN
Change from baseline in NfL levels in CSF and blood
Change over time in level of NfL
Change from baseline in CDR + NACC FTLD-SB score
The Clinical Dementia Staging Instrument (CDR) plus National Alzheimer's Coordinating Center Frontotemporal Degeneration domains (NACC FTLD) was developed as a way to improve characterization of cognitive and global function in patients with FTLD. The CDR+NACC FTLD score will capture patients' disease status. CDR+NACC FTLD Sum of Boxes (SB) score refers to the sum of the scores of each domain (sum of boxes) that ranges from 0 to 24.
Time to achieve clearance of vector genomes
Measured in plasma and semen (males only)
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