**7. Human endogenous retroviruses: from aetiological to therapeutic implications in neurological diseases**

Given the now well-established knowledge regarding the implication of HERVs in different pathological conditions, new avenues for the development of targeted therapies directed against HERV products have been opened. In this direction, a humanized monoclonal antibody (mAb) directed against HERV-W ENV, called GNbAC1 or temelimab, has been developed. The drug targets a linear nonglycosylated epitope of the surface unit domain of the HERV-W Env, blocking its interaction with the TLR-4 receptor and thus, the release of pro-inflammatory mediators and the inhibition of the myelin repair process. Different *in vitro* and preclinical studies offered promising results that culminated in clinical trials in which temelimab has been proposed as novel drug for MS treatment first to test pharmacokinetics, safety and efficacy providing encouraging results about its neuroprotective and regenerative effects in parallel with antiretroviral effects, which does not impair the immune system [137, 138]. Starting from the observations that also in type 1 diabetes (T1D) patients, HERV-W Env has been detected in blood and pancreatic acinar cells and after different reports concerning the activity of temelimab in *in vivo* and *in vitro* models of T1D [139], this drug was offered to patients as a part of a clinical trial to test the safety and its effect on the autoimmune process. Also in the case, the drug was well tolerated and reduced the events of hypoglycaemia and the levels of anti-insulin autoantibodies after the first period of treatment [139, 140]. More recently, the same research group

*Human Endogenous Retroviruses in Autism Spectrum Disorders: Recent Advances… DOI: http://dx.doi.org/10.5772/intechopen.108671*

proposed an anti-HERV-K Env mAb for the treatment of ALS. In addition to the antibody-based immunotherapy targeting HERV ENV, also the use of antiretroviral drugs has been evaluated in different setting, ranging from the *in vitro* studies to clinical trials, opening new prospects for exploring novel treatments of diseases such as MS [141]. The underlying rationale is that patients with HIV treated with antiretroviral drugs have a lower risk of developing MS than non-infected, healthy population thus suggesting that the antiretroviral treatment may reduce the risk of evolving MS also acting on HERV expression [141, 142]. Also in the treatment of patients with ALS the use of antiretroviral drugs has been proposed. As such, a recent clinical trial including a combination of antiretroviral drug has been conducted showing a decrease in HERV-K expression as well as of disease markers when administered to patients. Remarkably, a high percentage of patients were classified as 'responsive' to treatment reinforcing even more the role of HERV-K in the clinical course of the disease [143, 144].

Taken together, these findings provide the background for hypothesizing other therapeutic approaches targeting HERVs in different clinical setting towards a personalized medicine.

#### **8. Conclusions and new future perspectives**

The physiological roles of HERVs in pregnancy and embryogenesis, their intrinsic responsiveness to external stimuli and the interaction with the immune

#### **Figure 3.**

*The potential involvement of human endogenous retroviruses (HERVs) in the interaction among genetic susceptibility, environmental risk factors and immune activation in complex neurodevelopmental disorders (created by BioRender).*

system support the hypothesis that their deregulation affects the neurodevelopmental process (**Figure 3**). Nevertheless, it is still debated if HERVs are cofactors or epiphenomenon in neurodevelopmental disorders, and more efforts are needed to investigate the potentially detrimental effect of HERV products in the aetiopathogenic processes. In this complex landscape, the use of animal models could offer countless advantages to deeply investigate the embryonic phase that is certainly crucial for the onset of ASD, and brain district, mostly inaccessible in human studies. Since the brain remains the district of choice for the study of neurodevelopmental alterations, preclinical models of ASD allow to explore and characterize this anatomical district in depth, helping clinical research to make further progress towards the identification of new biomarkers, potentially useful for diagnosis and pharmacological intervention. Moreover, HERVs seem to be a reliable biomarker for ASD, readily detectable in peripheral blood, representing a potential efficient diagnostic tool to complement the current clinical behavioural diagnosis. Furthermore, a biomarker detectable before the onset of symptoms could facilitate early screening and timely initiation of treatment by improving the long-term prognosis of the mental health of affected individuals. Further studies are needed and could represent a new approach to unravel the aethiopathogenesis of ASD, bearing in mind that the retroelements cannot be appropriately understood only through a virologic or genetic approach, since their complex roles in physiology as well in diseases. Both preclinical models and human studies indicate that the abnormal expression of ERVs could represent a molecular signature of neurodevelopmental disorders.
