Background

Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder which affects memory
and cognitive function and is the most common cause of dementia in older adults. An estimated 6.5 million Americans have AD. By 2050, the number of people aged 65 and older with AD is projected to reach 12.7 million.

The pathophysiology of AD is complex, thus multiple different strategies are being explored to
manage symptoms, delay progression, and modify clinical outcomes. Amyloid plaques
comprised of aggregated Aβ peptides are a hallmark of AD. There is clinical evidence that
amyloid-lowering treatments may slow cognitive decline when administered early in disease.

There are only 6 approved treatments for AD. Three of these are cholinesterase inhibitors
which provide only temporary symptomatic relief, and one is a combination of cholinesterase
inhibitor donepezil with the remaining approved drug memantine. The most recently approved
drug, bapineuzumab, is controversial and has been approved for only limited stages of disease.

New approaches to treatment are needed. Peptide inhibitors of Aβ or tau aggregation have
been well-studied in vitro due to their potential for high specificity and low toxicity. However,
peptide drugs suffer from a short half-life in vivo and poor brain penetrance. Approaches to
overcome these limitations offer the potential to harness peptide inhibitors for use in disease
management 

Technology Overview

Inventors at Baylor College of Medicine have generated a minigene construct that can be
packaged into a viral vector for extracellular release of variant Aβ. Once released from the cell, the variant Aβ is thought to bind wild type Aβ to reduce aggregation. The construct allows for expression of the pro-peptide, trafficking to the plasma membrane, gamma-secretase cleavage, and extracellular release of the variant Aβ peptide. Multiple Aβ42 variants (Aβ42-F19P/L34D and Aβ42-F20P) were made and tested in a mouse model of Alzheimer’s amyloidosis. These unique genetic constructs are built for AAV packaging to facilitate gene delivery in the nervous system. 

Stage of Development

• Genetic constructs have been built 
• Variant Aβ coding sequences have been optimized to inhibit the aggregation of wild-type Aβ42.
• One variant peptide (F19D/L34P) produces disaggregation of pre-formed fibrils in vitro
• Gamma-secretase cleavage and extracellular release of the pro-peptide encoded by the minigene has been validated in cells 
• Viral vectors containing the F20P and F19D/L34P minigene constructs were tested in a mouse model of Alzheimer’s amyloidosis 
  • When APP/PS1 mice were treated with the AAV prior to accumulation of Aβ plaques, the F20P variant virus reduced Aβ plaque formation and total Aβ 

Further Information

Park KW, Wood CA, Li J, Taylor BC, Oh S, Young NL, Jankowsky JL. Gene therapy using Aβ
variants for amyloid reduction. Mol Ther. 2021 Jul 7;29(7):2294-2307.
DOI: 10.1016/j.ymthe.2021.02.026 

Benefits

• Reduces plaque load and toxic amyloid accumulation in AD mouse model
• Provides lifelong delivery of secreted Aβ variants thus avoiding need for repeated dosing
• The selected Aβ variants display 4 key properties required for therapeutic use:
  • Do not aggregate on their own
  • Diminish toxicity of Aβ oligomers 
  • Inhibit aggregation of wildtype Aβ 
  • Promote disassembly of pre-formed Aβ fibrils 

AAV-based gene therapy has been approved by the FDA for two CNS disorders

Applications

Delay and/or inhibit Aβ aggregation by gene therapy for Alzheimer’s Disease