Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome

• Status: Not yet recruiting
• Trial end date: 2023-01-01
• Target enrollment: 0
• Participant gender: All

Summary

Aicardi-Goutières syndrome (AGS) is a disease of children, particularly affecting the brain and the skin. There is a close link between AGS and increased amounts of a chemical called interferon. Normally humans only produce interferon when they are infected with a virus. In AGS, there is no viral infection. Instead, the cells in the cells of affected patients are confused into thinking that their own genetic material is coming from a virus. As a result they produce interferon all the time, which acts as a poison that damages the cells. The Investigators wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs), used to fight the HIV-1 virus that causes AIDS. The investigators will monitor the effect of treatment on interferon levels, and look at other markers which might give us clues to how the drugs are working. The trial is funded by the Medical Research Council, and involves experts based in Edinburgh, Birmingham, Manchester and Great Ormond Street Hospital.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Edinburgh
• Collaborators: Medical Research Council; NHS Lothian
• Treatments: Abacavir; Dideoxynucleosides; Lamivudine; Zidovudine

Criteria

Inclusion Criteria:

• Patients with mutations in any of TREX1, the three components of the RNase H2 complex (RNASEH2A, RNASEH2B, RNASEH2C: considered as one genotype) or SAMHD1.

• Greater than age 3 months and less than 16 years of age at the time of recruitment

• Resident in the United Kingdom (UK)

• Informed Consent obtained from parent or personal legal representative

Exclusion Criteria:

• Patients with AGS due to mutations in ADAR1 and IFIH1 will not be considered, given that the induction of interferon relating to these genotypes does not involve a reverse transcription step.

• Pre-existing disease, not due to AGS, which would preclude the use of zidovudine, lamivudine and abacavir

• Patients with abnormally low neutrophil counts (<0.75 x 109/l) and / or abnormally low haemoglobin levels (<7.5 g/dl)(particularly relevant to zidovudine), significant renal (creatinine clearance < 50 ml/min; particularly relevant to lamivudine) or significant hepatic impairment (particularly relevant to abacavir; avoid if Child Pugh > 5)

• Participation in another Clinical Trial of an Investigational Medicinal Product (CTIMP) trial

• Pregnancy

• Potential hypersensitivity to abacavir, assessed according to HLA-B*5701 status

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1 of the Summary of Product Characteristics (SPC)

• Where, in the opinion of the Investigator the participant cannot fulfil the requirements of the trial protocol