Is there a treatment?

Treatment

Symptomatic treatment and management of patients
    
Treatment of AGS is currently only symptomatic and includes the use of drugs to control epilepsy, the prevention of complications and postural abnormalities, respiratory physiotherapy to treat lung infections, and dietary monitoring to ensure adequate caloric intake. 
The use of botulinum toxin and  myorelaxant drugs to treat spasticity should be evaluated on a case by case basis in the context of the individual's overall rehabilitation and care programme.
Patients must be regularly screened for the symptoms of the disease which are treatable, such as glaucoma or endocrine problems (e.g. diabetes or hypothyroidism). 
As regards the chilblain lesions, neither vasodilators nor immunosuppressants have been reported to show any real therapeutic efficacy in AGS and the treatment of these symptoms is limited to protecting the vulnerable parts from the cold and preventing infections that could complicate the situation.
Blau, in 2003, suggested that oral treatment with folinic acid might produce a general improvement of the clinical conditions in AGS patients presenting reduced folates in the CSF, but there are, as yet, no data in the literature confirming this hypothesis. 
In addition, a neurosurgical treatment to address the vascular complications (occlusive arterial and aneurysmal problems) has been proposed for patients with mutations in SAMHD1.

New therapeutic perspectives

Given the involvement and activation of the immune system in the pathogenesis of AGS, treatment with immunomodulatory therapies (prednisone + azathioprine, intravenous methylprednisolone + intravenous immunoglobulin (IVIG), methylprednisolone or IVIG alone) has been hypothesised and in some cases proposed. To date, however, these treatments have been used in an empirical manner and in a limited number of patients, and have not been clearly shown to modify the evolution of the disease, even in the rare cases treated in the early stages. It is, in fact, difficult to evaluate the efficacy of these treatments, considering the small number of patients involved and the differences between them, both in genotype and in disease stage at the time of treatment. 
The progress in the understanding of the molecular mechanisms underlying the pathogenesis of AGS has led various authors to envisage new therapeutic strategies: 
1) Biotech drugs
Given the suggested primary role of interferon in the pathogenesis of AGS, a treatment has been proposed based on blocking of IFN activity through the use of monoclonal antibodies selective for different subtypes of IFN and for the type I IFN receptor (alpha and beta subunits). To date, this therapy has been used only on an experimental basis in SLE, and no data are available for AGS. 
2) Immunomodulatory drugs
On the basis of the role of immune system dysregulation in the pathogenesis of AGS, it has been suggested that treatment could be based on the use of substances capable of destroying B cells (such as the monoclonal antibody rituximab) or of inhibiting autoreactive T cells (such as mycophenolate mofetil). 
However, these substances, often approved for paediatric use, can cause serious side effects and they have yet to be applied in therapeutic trials in the field of AGS.
3) Reverse transcriptase inhibitors
In view of the role of reverse transcriptase in the accumulation of DNA originating from endogenous RNA fragments (retroelements), normally metabolised by the proteins encoded by the genes that are mutated in AGS, it has been suggested that there might be a role in treatment of the syndrome for antiretroviral drugs (reverse transcriptase inhibitors, i.e. substances capable of interrupting the replication cycle both of retroviruses and of endogenous retroelements). The pharmacodynamics, safety and toxicity of these therapies are already well known, given that they are commonly prescribed to adults and children infected with HIV-1. At present, the only available data refer to an experimental trial in an animal model: Beck-Engeser showed that neurologically normal mice with the lethal TREX1-null phenotype could be kept alive using a combination of antiretroviral  agents. Crow et al. have thus suggested that the next step could be to conduct a trial using drugs of this kind (even though their effectiveness could be limited by their difficulty crossing the blood-brain barrier) in order to test their applicability and safety in patients with AGS, and to assess whether this therapeutic approach is capable of "lowering" the "interferon signature" in those subjects in whom it can be considered, as we have seen, a biomarker of the disease, present even many years after the diagnosis.
It is indeed important to underline that the identification of an appropriate therapeutic strategy demands, in addition to a homogeneous sample of subjects, the use of easily quantifiable parameters of outcome (response to treatment), such as the interferon signature. 
These new drugs, if applied in the early stage of the disease, could lead to an attenuation of the inflammatory process and thus a lessening of the tissue damage; instead, if applied in patients who are in an advanced stage of the disease and already show marked neurological impairment, they could result in some improvement of the clinical manifestations associated with the immune system dysregulation (e.g. chilblains). At present, there is no proof of the effectiveness of these possible therapeutic approaches, since the first pilot clinical trial is ongoing and has not yet provided results.