AAV2/9-PLA2G4E, Alzheimer’s Disease novel approach

Enfermedad de Alzheimer

Target: cPLA2G4E

Alzheimer's disease (AD) is particularly devastating: there is no cure, no prevention, and no way to slow its progression. Currently, some 18 million people worldwide suffer from this disease and it will reach more than 30 million by 2025.

  • To avoid this, new strategies for symptomatic and disease-modifying treatment of Alzheimer's disease are needed. 
  • Data from our research support the hypothesis that loss of PLA2G4E may play a key role in the onset and/or progression of AD:
    • Novel approach: cPLA2G4E-inducing agents (also known as cPLA2ε) reverse the AD phenotype in APP/PS1 mice.

  • Keywords:
  • Enfermedad de Alzheimer
    • ,
  • Terapia génica
  • Early Discovery
  • Discovery
  • Preclinical
  • Clinical
  • Diagnostics

Target proposal

  • The correlation between neuropathological lesions and cognition is modest and, in fact, some individuals remain cognitively intact despite the presence of significant AD pathology (asymptomatic AD).
  • Besides environmental factors, it might be also intrinsic genetic and/or epigenetic modulators that confer resilience to AD.
  • The analysis of resilient individuals in behavioural tests in the Tg2576 line can offer useful insights.
  • We have found that there is an overexpression of cPLA2G4E in the brain of aged Tg2576 mice that escape from the disease(Resilient Tg2576) compared to that of demented ones (Tg2576) and similar to that of WT mice (A).
  • The expression of PLA2G4E (B) and synapsin (C) decrease in AD patients with memory impairment (Braak stage V-VI) compared to controls and to AD patients with no evidence of cognitive deficits (Braak stage II-IV).
  • These data support the hypothesis that the loss of PLA2G4E might play a key role in AD onset and/or progression.
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Hypothesis

PLA2G4E is an enzyme of the PLA2G family of cytosolic phospholipases (group IV, calcium dependent activity) with a specific subcellular location in the membranes and in the lysosomes. It only shares between 20-40% homology with other PLA2 isoforms and in fact, it has been demonstrated that it has low phospholipase activity. At the brain, is specifically expressed in neurons but its function in synaptic plasticity is unknown. Our hypothesis is that the over expression of cPLA2G4E in the brain of aged AD mice can prevent from dementia.

Proof of concept

Validation of PLA2G4E long term expression vectored through a suitable Adeno-Associated Virus as a disease modifying therapy for AD and/or age-related cognitive impairment.

Preclinical assays

PLA2G4E was overexpressed in the hippocampus of aged-WT mice AAV2/9-PLA2G4E (pilot study) and in a group of APP/PS1 mice. The mentioned virus, that overexpressed the murine form of PLA2G4E under the synapsin promoter, was injected specifically in the CA1 region of the hippocampus by stereotactic surgery.

Proof of Concept

Results

  • AAV2/9-PLA2G4E enhanced memory function in aged-WT mice (D, pilot study) and rescued memory deficits of aged-APP/PS1 mice(E and F).
  • Amyloid pathology is not affected in APP/PS1 mice injected with AAV2/9-PLA2G4E (data not shown).
  • AAV2/9-PLA2G4E increases spine density in the hippocampus of aged APP/PS1 mice (G).

Icono propiedad intelectual Intellectual Property

New Patent application filed (WO2013143940).