Aicardi-Goutières Syndrome (AGS) Clinical Trial
Official title:
A Pilot Clinical Trial of Reverse Transcriptase Inhibitors in Children With Aicardi-Goutières Syndrome (AGS)
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.
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.
;
| Status | Clinical Trial | Phase | |
|---|---|---|---|
| Recruiting |
NCT05613868 -
TPN-101 in Aicardi-Goutières Syndrome (AGS)
|
Phase 2 | |
| No longer available |
NCT01724580 -
Compassionate Use Protocol for the Treatment of Autoinflammatory Syndromes
|