Autism new drug: unravel, unpack, unsilence.

It has long been presumed that there is a common cause at the genetic, cognitive, and neural levels for autism’s characteristic triad of symptoms. Autism has a strong genetic basis, although the genetics of autism are complex; this arises due to interactions among multiple genes, the environment, and epigenetic factors which do not change DNA sequencing but are heritable and influence gene expression. Many genes have been associated with autism through sequencing the genomes of affected individuals and their parents. Nevertheless, many candidate genes have been located, with only small effects attributable to any particular gene. Most loci individually explain less than 1% of cases of autism. Several lines of evidence point to synaptic dysfunction as a cause of autism. Some rare mutations may lead to autism by disrupting some synaptic pathways, such as those involved with cell adhesion. Mostly instead, involve proteins that regulated synapse structure, cell signaling and/or neuronal maturation.

In an article published in the journal Nature Neuroscience, investigators report how low doses of romidepsin – a drug approved in the United States for the treatment of lymphoma – restores gene expression and social deficits are reversed in a murine model of autism. The new study is thought to be the first to demonstrate that it may be possible to alleviate this primary ASD symptom by targeting a large number of genes associated with the disorder. In their study, three days of treatment with low-dose romidepsin reversed social deficits in mice with the deficient SHANK3 gene, which is a known risk factor for ASD. The inversion of social deficits lasted for 3 weeks. The loss of SHANK3 interrupts the NMDA receptor, which helps to regulate emotions and cognition. The interruption caused problems in communication between brain cells and led to social deficits related to ASD. Researchers have shown that romidepsin is able to reverse social deficits by restoring gene function through an epigenetic mechanism.

Epigenetic mechanisms are genetic processes capable of activating and deactivating genes and altering their expression without modifying their underlying DNA code. There are several ways in which epigenetic mechanisms can alter gene expression without changing their DNA. For example, they can silence genes by attaching chemical labels to their DNA. However, the main epigenetic mechanism at work in ASD is the one that remodels the chromatin structure. One of the important findings of the new study is that it may be possible to address a large number of ASD-related genes with just one drug. Romidepsin is a modifier of histones, which are proteins that help organize DNA in the nucleus. The drug dissolves densely packed chromatin: the result is to restore gene expression by making genes more accessible to their regulators. With the help of genome screening, the researchers found that romidepsin restores gene expression in most of the 200 and more genes, which have been “silenced” in the autistic mouse model used in the study.

It is not an immaterial result: if the cause of autism is a genetic defect, only a genetic remedy can correct it. Could rhomidepsin be the starting milestone to pave the way?

  • edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Qi L et al. Nature Neurosci. 2018 Mar 12.

Zhu W et al. Am J Med Genet A. 2018 Feb 9.

Engineer CT et al. Autism Res. 2018 Jan;11(1):59-68. 

Koberstein JN et al. Sci Signal. 2018 Jan 16; 11(513).

Informazioni su Dott. Gianfrancesco Cormaci 2479 Articoli
- Laurea in Medicina e Chirurgia nel 1998 (MD Degree in 1998) - Specialista in Biochimica Clinica nel 2002 (Clinical Biochemistry specialty in 2002) - Dottorato in Neurobiologia nel 2006 (Neurobiology PhD in 2006) - Ha soggiornato negli Stati Uniti, Baltimora (MD) come ricercatore alle dipendenze del National Institute on Drug Abuse (NIDA/NIH) e poi alla Johns Hopkins University, dal 2004 al 2008. - Dal 2009 si occupa di Medicina personalizzata. - Detentore di un brevetto sulla preparazione di prodotti gluten-free a partire da regolare farina di frumento immunologicamente neutralizzata (owner of a patent concerning the production of bakery gluten-free products, starting from regular wheat flour). - Responsabile del reparto Ricerca e Sviluppo per la società CoFood s.r.l. (leader of the R&D for the partnership CoFood s.r.l.) - Autore di un libro riguardante la salute e l'alimentazione, con approfondimenti su come questa condizioni tutti i sistemi corporei. - Autore di articoli su informazione medica, salute e benessere sui siti web salutesicilia.com e medicomunicare.it