Reverse Transcriptase Inhibitors in Aicardi Goutières Syndrome

Children's Hospital of Philadelphia

Overview

The overall objectives are to explore the safety and efficacy of Reverse Transcriptase Inhibitors Tenofovir (TDF)/ Emtricitabine (FTC) administered in AGS affected children 2 to 18 years of age.

The investigators propose that a trial to assess the proof of principle that antiretroviral therapy through a drug combination of Tenofovir (TDF) and Emtricitabine (FTC) can decrease endogenous retroelement accumulation, and alter interferon signaling in Aicardi Goutières Syndrome (AGS) patients is reasonable and warranted at this time, based on existing in vitro and animal data. Additionally, this trial will further the investigators understanding of this disorder, measuring for the first time retroelements in human participants, exploring the retroviral burden in cerebrospinal fluid (CSF), the Interferon (IFN) signaling response, as well as evaluating antigen targets of autoimmunity and cytokines. If successful, this approach will clearly demonstrate the need for a larger trial of antiretrovirals in AGS with more clinically relevant outcomes.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Conditions

Aicardi Goutières Syndrome

Interventions

Tenofovir (TDF) and Emtricitabine (FTC)DRUG

Tenofovir (TDF): a nucleotide reverse transcriptase inhibitor (NtRTI) an acyclic nucleotide analog of adenosine 5'-monophosphate. This is used in children as young as age 2. Emtricitabine (FTC): a nucleoside reverse transcriptase inhibitor (NRTI), a synthetic analog of cytidine which binds at the active site of the reverse transcriptase.

PlaceboOTHER

Placebo for Tenofovir and Placebo for Emtricitabine

Eligibility

Sex: ALLMin age: 2 YearsMax age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Molecular, neuroimaging, and clinical findings consistent with a diagnosis of AGS, with the exception of Double-stranded RNA-specific adenosine deaminase (ADAR1) and IFIH1, which are not postulated to result in nucleic acid accumulation * Evidence of interferon activation such as elevation of CSF neopterin/tetrahydrobiopterin measured on the first evaluation. * Ages 2-18 years (the age of 2 years is used because the drugs are FDA approved in children greater than 2 years) * Weight of at least 10 kg * Willingness to undergo serial lumbar punctures and blow draws for evaluation of laboratory based outcome measures * Willingness to abstain from initiating the use of immune modulating therapies including corticosteroids * Able to receive medications orally, by nasogastric (NG) tube or by Gastric (G)-tube * No concomitant illness which would preclude safe participation as judged by the investigator * Signed informed consent by the subject's legally acceptable representative * Negative testing for HIV * Negative testing for Hepatitis B * Concurrent enrollment in the Myelin Disorders Biorepository Project (MDBP, ClinicalTrials.gov NCT03047369) and willingness to undergo associated procedures Exclusion Criteria: * Age \< 2 years or \>18 years * Hepatic insufficiency with liver function tests greater than 3-times the upper limit of normal * Renal insufficiency with creatinine clearance \<60 * Significant malabsorption * Any clinical or laboratory abnormality or medical condition that, at the discretion of the investigator, may put the subject at an additional risk by participating in this study * HIV infection * Hepatitis B infection * Mutations in ADAR1 or IFIH1

Outcomes

Primary Outcomes

Change in interferon activation as measured by interferon response genes

The investigators propose to measure genes in the IFN stimulatory pathway in AGS patients, as a measure of disease activity and as a possible biomarker of therapeutic activity. Current data suggests that IFN related genes remain elevated in the late teens in AGS affected subjects, making it a more reliable measure of disease activity than IFN alpha. Validation of this preliminary data includes serial measurements in blood across several time points, to assess for variability.