Rett Syndrome: a new therapeutic project to give one hope

We are excited to announce that our funded scientist, Dr. Antonello Mallamaci has secured additional funding from Jerome Lejeune Foundation to focus on FOXG1.  We are grateful to the generous foundations across the world for their continued support of scientific research into FOXG1.

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"Significant funding for a SISSA research concerning innovative molecular technologies. The Development Laboratory of the Cerebral cortex of the Trieste Institute will benefit from a grant from the duration of two years September 29, 2017. An unprecedented research path for a rare variant of Rett Syndrome could
become the therapy for many other neurological diseases. This is what the project of the SISSA Cerebral Cortex Development Laboratory in Trieste is hoping for. It has just won a grant from the Jerome Lejeune Foundation, a French institution committed, among other things, to supporting Rett's syndrome research. Progressive disease that affects the nervous system especially of girls, the disease is associated with the mutation of different genes. In particular, a variant linked to the alteration of the FOXG1 gene was discovered in Italy. It is no coincidence that our country is very busy in the search for a cure regarding this specific variant, which manifests itself earlier, it also affects males and is even more rare than the classical form. 

If a disease with such a low incidence hardly attracts the attention of pharmaceutical companies, the need to give an answer to those affected is not missed by the French Jerome Lejeune Foundation. The body that finances
the research dedicated to mental disorders of genetic origin, has selected the project "RNAa therapy of Rett-syndrome-associated FOXG1 haploinsufficiency" as the winner of a two-year grant. The research project was proposed by the SISSA Cerebral Cortex Development laboratory, led by Antonello Mallamaci. The results of the funded research will provide key information for the targeted treatment of the Rett Syndrome variant associated with the haploinsufficiency of the FOXG1 gene, ie the lack of a single copy of the gene, where normally there are two. However, the protocol that will be developed will also be useful for the treatment of a wide spectrum of other rare neurological diseases. In fact, the goal of the project is to develop a new therapeutic design capable of
"repairing" haploinsufficiency neuropathogenesis for specific genes. It is a condition that unites a significant number of pathologies, which are rare in themselves, but very serious and above all without any treatment. The heterogeneity of the mechanisms underlying this spectrum of diseases and their low individual prevalence makes treatment development difficult. For this it would be necessary to develop a general approach that can be applied in an "industrial" manner to all cases. Unfortunately, not even the most modern genomic engineering tools, such as the popular artificial restriction enzymes CRISPR, TALEN or ZF, or the programmable transcription factors that are based on the same platforms, are able to give a suitable answer for this type of pathology.


"To deal with this problem, it is possible to gently stimulate the allele of the gene saved from the mutation. This can be done via a small RNA molecule, which is able to stimulate the transcription and for this reason called aRNA",
suggests Mallamaci. To this end a small specific RNA has already been synthesized and validated, able to promote the transcription of Foxg1, in vitro or in the brain of the live animal. Since the gene regulation of FOXG1 is based on a fine regulation mechanism, it will be essential to optimize the in vivo administration of RNA, in order to obtain a precise modulation of the magnitude of the expression gene. "A further step that awaits us is the verification of the ability of the molecule to restore normal morphological and functional properties in the neurons of mice that possess a single copy of FOXG1", added the professor of SISSA.

Furthermore, based on a technology developed in SISSA by the group of prof. Gustincich, Mallamaci's laboratory is also developing a further gene stimulation system, based on a small RNA capable of promoting its translation. So another method of increasing Foxg1 expression could be based on stimulating its translation. "We think that the combination of different techniques can guarantee efficacy along with low interference with other genes that are potentially sensitive to stimulation," explained the head of the Cerebral Cortex Development Laboratory. "Naturally, the implementation and adaptation of this strategy in patients will have to be carefully studied", added Mallamaci. "We will need further analysis to determine if the therapy is going to alter behavioral or cognitive functions". From the proposed approach we expect a robust feasibility test, molecular tools for the implementation of a protocol suitable for patients and a general paradigm that can be used as an adequate response to numerous
neuropathogenetic aploinsufficiencies."

 

CURE-funded grant yields Dravet syndrome discovery

Research

A recent CURE-funded grant has taken a step forward in the search for therapeutic mechanisms to combat Dravet syndrome, a type of epilepsy that is currently difficult to treat and has no known cure.[1] A CURE-funded team has discovered that RNA-stimulators have the capability of fully restoring functionality to the Scn1a gene (in rodents), which may in turn prevent or reverse the symptoms of Dravet syndrome.

CURE researcher Dr. Antonello Mallamaci of the Scuola Internazionale Superiore di Studi Avanzati is leading the team that seeks to restore functionality to Scn1a, by creating “Scn1a-stimulating RNA devices” to stimulate Scn1a activity.

The team sees great potential in being able to use these devices to compensate for the reduction in Scn1agene functionality. Next steps include plans to test these RNA-stimulators in the Dravet syndrome mouse that has similar symptoms to humans with Dravet syndrome and in human tissue from individuals with Dravet syndrome. There are also plans to create a specialized “tool” called a viral vector that can deliver these RNA-stimulators directly into affected brain areas, pushing this research ever closer to achieving a viable human therapy.

Dravet syndrome is a rare epilepsy that begins in infancy, is lifelong and often leads to developmental disability.[2] It is most often caused by a mutation or deletion in the Scn1a gene, a gene that codes for an important sodium channel whose function is essential in normal transmission of electrical signals within the brain.[3],[4] The loss of functionality of this gene can lead to brain activity and hyperexcitability that characterizes seizures and epilepsy.[5]

Through the critical work of researchers like Dr. Mallamaci, new therapeutic approaches for epilepsy are within our reach. This exciting research has been made possible by funding from CURE as we strive ever closer to our goal of producing treatments and cures for epilepsy to achieve “no seizures, no side effects.”

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[1] Wirrel EC. Treatment of Dravet syndrome. Can J Neurol Sci 2016: 43 Suppl 3:S13-18.

[2] Dravet C. The core Dravet syndrome phenotype. Epilepsica 2011; 52(2):3-9.

[3] Marini C, Scheffer IE, Nabbout R, et al. The genetics of Dravet syndrome. Epilepsia 2011; Suppl 2:24-9

[4] Meisler MH, Kearney JA. Sodium channel mutations in epilepsy and other neurological disorders. J Clin Invest 2005; 115(8): 2010-2017.

[5] Chopra R, Isom LL. Untangling the Dravet syndrome seizure network: The changing face of a rare genetic epilepsy. Epilepsy Curr 2014; 14(2):86-89.