A Multicenter Study of NAP (AL-108) in Schizophrenia
Condition: Schizophrenia
MeSH terms: Schizophrenia
Study type: Interventional
Phase: Phase 2

Summary: 
      The TURNS is a NIMH-funded contract for the evaluation of new compounds for the treatment of
      cognitive impairments in schizophrenia (HHSN 27820044 1003C; P.I.: Steve Marder, M.D.).
      Despite advances in the safety, tolerability, and effectiveness of antipsychotic medications
      for the treatment of schizophrenia, many patients continue to be plagued by impairments in
      social and work functioning. Persons with schizophrenia commonly show deficits in a number of
      areas of cognition that include impairments in attention, memory, and executive functioning
      (the ability and organize one's behavior). Importantly, a large body of literature now shows
      a link between cognition and community functioning in schizophrenia. It is believed that
      treatments that improve cognitive deficits may lead to improvements in work and social
      functioning.

      One approach to improve the community functioning of patients with schizophrenia is to
      develop new agents that treat the cognitive deficits of the illness. A promising agent is
      called AL-108. This drug is administered as a nasal spray. Studies in animals suggest that
      this drug may protect neurons and may improve cognition in schizophrenia. The current study
      is a twelve-week multicenter, double-blind, randomized clinical trial of two doses of AL-108
      (5 and 30 mg/day intranasally) versus placebo in the treatment of persistent cognitive
      dysfunction in schizophrenia. The study medication will be added to patients' current
      atypical antipsychotic medication or to their current injectable first-generation
      antipsychotic medication. The primary outcome measure will consist of the composite score of
      the MATRICS neuropsychological battery. Secondary outcome measures will include scores on
      symptoms, functional outcome, and safety measures. Sixty clinically stable patients with
      schizophrenia, drawn from eight sites, will participate in the study. Twenty-five patients
      will be enrolled at UCLA.
    

Detailed description: 
      Background

      AL-108 is an intranasal drug product containing NAP, an 8 amino-acid peptide
      (Asn-Ala-Pro-Val-Ser-Ile-Pro-Gln; NAPVSIPQ, MW=824.9) fragment of the much larger (approx.
      124KD) Activity-Dependent Neuroprotective Protein (ADNP), which participates in
      neurodevelopment and neuroprotection. In mice, ADNP knockouts are lethal exhibiting CNS
      dysgenesis. ADNP mediates its effects in part through interaction with microtubules. Because
      of its large size, ADNP is assumed to not penetrate the BBB and thus cannot be used
      pharmacologically. NAP was chosen because it represents the epitope most associated with
      microtubule interaction and neuroprotection. NAP is absorbed following IV or intranasal
      administration, and has been shown to cross the BBB.

      Rationale for NAP treatment: tubulin function in brain function

      The cytoskeleton plays a key role in maintaining the highly asymmetrical shape and structural
      polarity of neurons that are essential for neuronal physiology. The cytoskeleton is made up
      of microfilaments, intermediate filaments and microtubules. Microfilaments (4-9 nm diameter)
      are made up of actin monomers and they function mainly to provide mechanical support and
      locomotion to the cell. Intermediate filaments are cytoplasmic fibers of ~10nm diameter. They
      provide supporting framework within the cell. Microtubules (~24nm diameter) consist of
      tubulin and microtubule associate proteins. They function to transport nutrients and chemical
      messengers along the cell. Neurofibrillary tangles are twisted bundles of neurofibrils formed
      when the microtubule-associated protein, tau, dissociates from microtubules and clusters to
      form an insoluble mass. Under normal conditions tau binds to microtubules, stabilizing
      neuronal structure and integrity.

      Hyperphosphorylation of tau is assumed to be the cause for the formation of neurofibrillary
      tangles. Although neurofibrillary tangles are most associated with cognitive dysfunction in
      Alzheimers disease, some increase in neurofibrillary pathology has also been reported in
      schizophrenia, potentially as consequence of antipsychotic medication (1). Thus, mechanisms
      underlying microtubular function may be relevant to schizophrenia as well. In association
      with tubulin polymerization into microtubules, NAP influences tau dynamics by increasing the
      ratio of non-phosphorylated tau to phosphorylated tau, implying a dynamic process of cellular
      maintenance of the microtubular network, which is essential for the survival of the cell.

      In brain, tubulin frameworks are stabilized by recently described STOP proteins (2) (aka
      MAP6). Linkages to allelic variation in STOP genes has been reported in schizophrenia, along
      with altered STOP protein expression in some brain regions (3). STOP knockdown mice show
      disturbances in dopaminergic neurotransmission (4) along with deficits in PPI and
      hypermotility that were partially reversed with clozapine (5). Thus, neuropathological
      features of schizophrenia may be due, in part, to abnormal STOP-related stabilization of
      microtubular structure, and NAP may stabilize STOP-related abnormal neurophysiological
      processes in schizophrenia.
    

Intervention name(s): AL-108; AL-108; Placebo; Placebo
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): AL-108, 5 mg/day- one spray in each nostril once per day; AL-108, 30 mg/day- 3 sprays in each nostril, twice per day; Placebo- 3 sprays in each nostril, twice per day; Placebo- one spray in each nostril, once per day
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Cognition; Schizophrenia