Inhibition of Reverse Transcription in Aicardi-Goutières Syndrome (AGS-RTI)
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|ClinicalTrials.gov Identifier: NCT04731103|
Recruitment Status : Recruiting
First Posted : January 29, 2021
Last Update Posted : August 30, 2022
|Condition or disease||Intervention/treatment||Phase|
|Aicardi-Goutières Syndrome||Drug: Abacavir (ABC) Drug: Lamivudine (3TC) Drug: Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)||Phase 2|
Aicardi-Goutières syndrome (AGS) is a severe childhood disease of the brain associated with very high levels of a chemical called type I interferon. Normally humans only produce interferon when they are infected with a virus. In AGS, there is no obvious viral infection. Instead, due to changes (mutations) in the genetic code in these individuals, it is believed that the cells in the body are fooled into thinking that the person's own DNA is viral - that is to say, there is a confusion in telling 'self' from 'non-self'.
In fact, a large amount of our own DNA is made up of ancient virus (called 'endogenous retrovirus' and sometimes also referred to as 'junk DNA'), that have been included into our own genetic material over millions of years. These endogenous retroviruses can still act like a virus coming from outside of the body, so that they need to be controlled. The Investigators have wondered if the genetic changes causing AGS mean that these normal control mechanisms don't work. If that is true, the endogenous retroviruses could start to make copies of themselves which might be recognised by our immune system as 'non-self' ('foreign' i.e. viral), leading to the continuous production of interferon which then damages the cells in our body.
Since humans cannot repair the genetic code in every cell, the investigators wish to treat AGS patients with drugs called reverse transcriptase inhibitors (RTIs). RTIs are used to fight the HIV-1 virus that causes AIDS. In the case of AGS, it is not treating HIV-1, but the investigators wonder if the same drugs might be able to control endogenous retroviruses that are driving interferon production. Indeed, in a recently completed study the investigators gathered early information to suggest that treatment of patients with AGS with RTIs for one year did lead to a reduction in interferon, with levels increasing again when we stopped the drugs.
The current study will involve three treatment arms, and an assessment of interferon status and other markers which we think will give us information about AGS, and about how RTIs may work in the treatment of AGS.
This study is of potential importance for patients with AGS and their families since there are no licenced drugs for this disorder at the present time. Scientifically, the project will be of considerable interest if the results support the possibility that 'junk DNA' can be associated with human disease. RTIs are very safe drugs, that have been used in millions of people with HIV-1 around the world. If the results turn out to be convincing, the investigators believe that it might be worth thinking about using RTIs to treat other diseases that have also been linked to increased levels of type I interferon, for example the relatively common immune condition called systemic lupus erythematosus.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||24 participants|
|Intervention Model:||Crossover Assignment|
|Intervention Model Description:||Open label, non-placebo controlled. We propose a trial design involving an initial no-drug period of six weeks followed by three treatment arms each of six weeks, with a washout period of four weeks between treatment arms (considering documented drug half-lives).|
|Masking:||None (Open Label)|
|Official Title:||Inhibition of Reverse Transcription in Type I Interferon Mediated Neuropathology|
|Actual Study Start Date :||August 24, 2022|
|Estimated Primary Completion Date :||February 2024|
|Estimated Study Completion Date :||July 2024|
Active Comparator: Abacavir (ABC)
Participants receive Abacavir (ABC) for 6 weeks and 4 weeks of washout.
Drug: Abacavir (ABC)
Tablets or oral solution
Active Comparator: Lamivudine (3TC)
Participants receive Lamivudine (3TC) for 6 weeks and 4 weeks of washout.
Drug: Lamivudine (3TC)
Tablet or oral solution
Active Comparator: Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)
Participants receive Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT) for 6 weeks and 4 weeks of washout.
Drug: Abacavir (ABC)+Lamivudine (3TC)+Zidovudine (AZT)
Tablet or oral solution
- Determine if the use of the reverse transcriptase inhibitors abacavir (ABC), lamivudine (3TC) and zidovudine (AZT) reduces Interferon (IFN) signalling in patients with mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C or SAMHD1 [ Time Frame: At 6 weeks ]The primary outcome is a change in the Interferon(IFN) score over baseline at 6 weeks end of treatment.
- A change in interferon alpha protein levels [ Time Frame: 6 weeks ]Change in interferon alpha protein levels (fg/ml) over 6 weeks per treatment arm.
- A change in cerebral blood flow [ Time Frame: 6 weeks ]Change in cerebral blood flow (ml/min/100g of tissue) over 6 weeks per treatment arm.
- Correlate changes in markers of brain cellular health [ Time Frame: 6 weeks ]Change in levels of NfL and GFAP (pg/ml) over 6 weeks per treatment arm.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04731103
|Contact: Yanick Crow, MBBS; MRCP||07595398159||Yanick.Crow@ed.ac.uk|
|Contact: Claire Battison, BA(Hons)||email@example.com|
|Edinburgh, United Kingdom|
|Contact: Yanick Crow Yanick.Crow@ed.ac.uk|
|Principal Investigator:||Yanick Crow||University of Edinburgh|