Neurotrophic Factors for Alzheimer's Disease: Unique Challenges and Promise

(Joao Siffert, Ceregene, Inc.)

Growth factor treatments are being tested for multiple neurodegenerative diseases.

  • Rationale:
    • Promote cell survival and stimulate neuronal function (as shown in animal models of neural dysfunction irrespective of cause)
    • Stimulate anti-apoptotic mechanisms
    • Stimulate functional cell signaling

Problems with delivery of neurotrophic factors have previously prevented use as therapeutics.

  • Neurotrophic factors:
    • do not cross the BBB (no systemic administration)
    • do not easily diffuse (must be injected throughout target area)
    • must be restricted to only the targeted area (to prevent side effects)
    • require a continuous supply to the target

To get around these problems, Ceregene is using an adeno-associated virus type-2 carrying the human NGF gene (AAV2-NGF) to deliver persistent and targeted growth factor to cholinergic neurons.

  • Currently being tested in a phase II clinical trial for Alzheimer’s disease (CERE-110).
  • With the viral NGF delivery:
    • Expression: Shows an orderly dose relationship that is restricted to the target area (basal forebrain cholinergic neurons) and is persistent (at least 2 years).
    • Efficacy: Confirmed in two gold standard rat models of NGF bioactivity (FFX lesion, aged rats) and in a non-human primate.
    • Safety: No long-term toxicity in rats or primates; also wide therapeutic index with no side effects produced (unable to determine maximum tolerated dose).
    • See Ref – Bishop 2008
  • In the phase I clinical trial, patients with mild to moderate AD were given 2-3 injections per hemisphere; no significant adverse events were observed up to the 2 year follow-up.
    • No clinically significant changes in clinical exams or laboratory values.
    • The virus was not detected in serum or urine, and there were no changes in antibody titer to AAV2 or NGF.
    • Majority of adverse events were mild to moderate in severity, with only one related to the virus (several related to the surgical prodcedure).
    • Increase in FDG-PET scan activity over time in the virus-treated patients.
  • Current phase II clinical trial – multicenter, randomized, double-blind, sham surgery-controlled, safety and efficacy study with 50 subjects (mild to moderate AD)
Neurotrophic Factor Mimetics: Target Validation to Lead Optimization >