Therapeutics

AVB-101

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Overview

Name: AVB-101
Therapy Type: DNA/RNA-based
Target Type: Other (timeline)
Condition(s): Frontotemporal Dementia
U.S. FDA Status: Frontotemporal Dementia (Phase 1/2)
Company: AviadoBio

Background

AVB-101 is a gene therapy designed to deliver a copy of the human progranulin gene to the brain. It is being tested in people with frontotemporal dementia due to pathogenic progranulin mutations. These patients have abnormally low expression of progranulin in the brain, and the goal of this gene therapy is to restore progranulin concentration and function.

AVB-101 is derived from a non-replicating adeno-associated virus, serotype 9 (AAV-9), modified to contain a copy of the non-mutated human PGRN gene under control of a neuron-specific promoter. Thus, the tropism of the virus and gene construction are designed to restrict expression to neurons. The treatment is given as a one-time infusion into the thalamus, using MRI-guided stereotactic surgery. Thalamic delivery is intended to maximize distribution to multiple areas of the cortex via the brain’s extensive thalamo-cortical neural network.

No preclinical work is published on AVB-101. At conferences, the company has shown data indicating that thalamic delivery in progranulin knockout mice re-established protein expression and reversed phenotypes of lysosome dysfunction and neuroinflammation. The company reported that MRI-guided thalamic infusion in sheep and monkeys produced broad brain expression of human progranulin. Thalamic infusion was claimed to give wider distribution and higher expression at lower viral doses compared to delivery by injection into the CSF of the cisterna magna. In monkeys, progranulin concentrations reached physiological levels in the frontal and temporal lobes that are most affected in FTD. The treatment caused no overt toxicity in the animals. The monkeys developed low-grade microgliosis in the thalamus and midbrain, which was more pronounced at higher doses and increased over six months. No progranulin expression and little viral material was found outside the brain (2022 slides; 2022 poster; 2023 poster).

Findings

In August 2023, AviadoBio began a Phase1/2 trial to assess the safety and ability of AVB-101 to restore progranulin levels in people with frontotemporal dementia with progranulin mutations. The open-label study plans to enroll nine participants in two dose cohorts. Patients with mild or moderate dementia will receive a single, bilateral, MRI-guided thalamic infusion of AVB-101, and be followed up for five years. The primary outcomes are adverse events, change from baseline in MMSE, and time for clearance of virus material from the body, as well as clinical, lab, or MRI abnormalities. Secondary outcomes span progranulin and neurofilament light chain levels in CSF and blood, antibodies to AAV9 and progranulin, and brain volume by MRI, plus cognitive, clinical, and other measures. The trial is running at multiple sites in Europe and the U.S. until October 2030.

AVB-101 has Orphan Drug and Fast Track status from the U.S. FDA.

For details on AVB-101 trials, see clinicaltrials.gov.

Last Updated: 02 Jul 2024

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References

External Citations

  1. clinicaltrials.gov
  2. 2022 slides
  3. 2022 poster
  4. 2023 poster

Further Reading

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