Reverse Transcriptase Inhibitors in AGS
Condition: Aicardi-Goutières Syndrome (AGS)
MeSH terms: Nervous System Malformations; Autoimmune Diseases of the Nervous System; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      The purpose of this study is to determine if treatment with reverse transcriptase inhibitors
      returns the interferon signature observed in patients with AGS to normal levels.
    

Detailed description: 
      AGS is a genetically heterogeneous disease resulting from mutations in any one of the genes
      encoding the 3-prime repair exonuclease TREX1 (AGS1), the three non-allelic components of the
      RNASEH2 endonuclease complex (AGS2, 3 and 4), the Sam domain and HD domain containing protein
      (SAMHD1; AGS5) which functions as a deoxynucleoside triphosphate triphosphohydrolase, the
      double stranded RNA editing enzyme ADAR1, or the cytosolic dsRNA sensor IFIH1. It is
      hypothesized that AGS1-6 are involved in limiting the accumulation of intracellular nucleic
      acid species, a failure of which process results in triggering of an innate immune response
      that is more normally induced by viral nucleic acids. That is, in the absence of AGS-related
      protein activity, endogenous nucleic acids accumulate and are sensed as viral or 'non-self',
      leading to the induction of an interferon (IFN) alpha mediated immune response and the
      production of antibodies against self nucleic acids. AGS is associated with increased levels
      of interferon alpha in the cerebrospinal fluid (CSF) and serum. Available data suggest that
      AGS might be treated with (particular) reverse transcriptase inhibitors (which compounds can
      potentially disrupt both exogenous retroviral and endogenous retroelement cycling). No
      systematic approach to treatment in AGS has been explored. The investigators hypothesis is
      that reverse transcriptase inhibitors will also inhibit the reverse transcription of
      endogenous retroelements which are deemed to be responsible for initiating the tissue damage
      seen in AGS. Consequently, for the purpose of the investigators pilot study, it would be
      ideal to assess the effects of therapy by monitoring a reactive biomarker.

      This is a single centre, open, single arm, phase II study in children with AGS. This study
      design is justified because no data are available about antiretroviral drug efficacy in
      children with AGS. Moreover, this study is the first step before a phase III study of drug
      efficacy.

      The investigators propose a pilot clinical trial of selected reverse transcriptase inhibitors
      in AGS patients, with the specific endpoint of assessing the effect of treatment on the
      disease-associated interferon signature. The investigators propose to evaluate the safety of
      combination therapy comprising the three nucleoside analog reverse-transcriptase inhibitors
      (NRTIs) zidovudine (AZT), lamivudine (3TC), abacavir (ABC) in patients with AGS over a 52
      week period of treatment. The inclusion period is 12 months. Patients can not participate in
      a biomedical trial of another drug during the 18 month follow-up (12 months of treatment
      period plus 6 months post treatment period).

      A total of six visits (including a final visit) are scheduled for this trial over a period of
      18 months (M1, M3, M6, M9, M12, M18) for all patients.

      Drugs will be dispensed for medication at home, at usual doses recommended in HIV infection.
      Subjects will be dosed according to French guidelines. Dosing will be reviewed at each study
      visit against current weight, and modified as necessary in accordance with French dosing
      guidelines.
    

Intervention name(s): Reverse transcriptase inhibitors: Zidovudine, Lamivudine, Abacavir
Intervention type(s): Drug
Intervention description(s): Oral Solution (syrup) or Tablets
Intervention MeSH terms: Lamivudine; Zidovudine; Abacavir; Reverse Transcriptase Inhibitors
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Aicardi-Goutières syndrome; Reverse transcriptase inhibitors; open single study; interferon signature