Grant reports (2019 – 2021 not currently available)

2018

Reintroducing FMRP to Reduce Symptoms of Fragile X Syndrome

We are very pleased to announce that a research grant has been awarded to the lab of Dr. Raymond Turner at the University of Calgary in Alberta, through a special partnership between the Fragile X Research Foundation of Canada and FRAXA Research Foundation. Dr. Turner and his postdoctoral fellow Xiaoqin Zhan, PhD are attempting to reintroduce a segment of FMRP to reverse the symptoms of Fragile X in the mouse model for this disorder.

Fragile X Syndrome results from a loss of “Fragile X Mental Retardation Protein” (FMRP), and this leading genetic cause of autism spectrum disorder has no established treatment. FMRP affects the production of thousands of other proteins during the development of brain connections, and these proteins are essential to the normal function at synapses (junctions between nerve cells). When FMRP cannot be produced by the brain cells, it results in synapses that show less “plasticity”, or the ability to modify their connections to each other in response to prior experience. This is key to the process of learning.

The Turner lab is working to find a safe, effective way to transfer FMRP directly back into brain cells. In order to do this, this team will attach a short string of amino acids (called “TAT” or Trans-Activator of Transcription”) to FMRP. TAT will act as a carrier molecule that will facilitate the passage of FMRP from the blood stream into the brain cells.

Injection of this tat-FMRP segment into the tail vein of mice has been shown to start functioning in brain cells less than one hour later. Initial behavioural tests confirm that injection of tat-FMRP into the Fragile X mouse significantly reduces hyperactivity within 1 hr of injection, and at concentrations that showed no toxic effects after 6 days exposure. These exciting results open the door to reintroducing FMRP as a potential treatment strategy to reduce the abnormal behaviours and symptoms of Fragile X Syndrome.

Adeno-Associated Viral Gene Therapy for the Treatment of Fragile X Syndrome

Fragile X Syndrome (FXS) is caused by the absence of fragile X mental retardation protein  (FMRP), which in turn regulates the messages that produce many other proteins related to the structure and function of neurons in the brain. It is for this reason that it has been challenging to develop a single pharmaceutical treatment capable of alleviating all of the resultant complex symptoms. Thus, our aim is to target or override the disease-causing gene itself by introducing a functional version of the FMR1 gene, thereby preventing “downstream” pathology at the source. We will do this in the lab by using Adeno-associated viral (AAV) vectors to deliver a long-lasting transgene (a gene which is artificially introduced into the genome of another organism). The AAV vector is a non-pathological delivery system for therapeutic genetic material, which have been shown to be effective at delivering long-lasting transgene expression in various organs. There are currently multiple human trials of gene therapies utilizing AAVs, several of which are showing promise for positive patient outcomes.

Our goal is to optimize a single administration of AAV-FMRP that translates into sustained therapeutic benefits. We previously identified a therapeutic range of AAV-FMRP transgene expression that led to improvements in the autistic-like behaviours of Fmr1-knockout (Fmr1-KO) FXS mice. Our current work is focused on designing an AAV-FMRP vector to deliver the therapeutic transgene protein in a temporal and tissue-specific pattern that mimics the natural expression of the FMR1 gene. By manipulating the elements of the transgene that control the developmental timing and expression levels of FMRP, we are optimizing the safety and efficiency of the therapy. We are also expanding our research to include a rat knockout model of FXS, as this will validate and inform our research as we work towards the development of treatment for humans.

The Fragile X Research Foundation of Canada Grants and Fellowship Program has been crucial in our success to date; we are very grateful for the support provided.

Electrophysiological biomarkers of altered brain plasticity in children with Fragile X Syndrome

The ultimate goal of this research project is to find better outcome measures to assess whether or not a new treatment for Fragile X is actually working. Scientists refer to these outcome measures as “biomarkers” because they connect the alterations in the structural and functional abnormalities of brain cells with the impairments in cognitive and behavioural responses seen in people with Fragile X. These are also objective measurable quantities, which means that they can appear in blood and urine samples, or are physiologic variables like brainwaves seen on electroencephalograms (EEG’s).

With previous grants from the Fragile X Research Foundation of Canada, this lab has been able to make substantial progress in investigating the electrophysiological biomarkers of basic sensory processing and basic learning in children with Fragile X Syndrome (FXS). Their work has shown the importance of electrophysiology as a sensitive biomarker, displaying modifications in brain processes preceding cognitive and behavioural development in FXS. This could make it a valuable outcome measure for future clinical trials.

Electrophysiological biomarkers allow an efficient, non-invasive and widely applicable assessment of brain functioning. The Lippé lab will continue to collect more data, and measure the protein profiles in the cells obtained from urine samples of the participants. They will then correlate the changes in the cellular protein profiles with the EEG findings so they can create a “cellular portrait” of the major signaling pathways in Fragile X Syndrome.