Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model.
Summary by Amisha Parmar
Background:
Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disease affecting adults, characterized by progressive death of motor neurons (nerve cells present in the central nervous system). Motor neurons talk to muscle cells to control their function and when these cells are damaged in some way, motor neuron disease can arise. This is characterized by a loss of control over muscle movement. This can be voluntary movement like walking and/or involuntary like chewing and breathing. More than 90% of ALS patients do not carry a known defective gene (genes are the inherited information that determines a person’s traits, e.g. their features or characteristics) which can cause the disease, this kind of condition is called sporadic (cause unknown).
What did the authors do and how did they do it?
In our body, there are molecules that bind to substances, e.g. medicines or hormones, and lead to specific changes. These molecules are called receptors. In some ALS patients, a specific type of receptor has been observed to act abnormally due to changes in its structure. This defect arises from the reduction in a protein called ADAR2 (adenosine deaminase acting on RNA 2). The authors of this paper have created a genetically modified mouse model, which does not have ADAR2 protein (called AR2 mice), to study how the absence of ADAR2 affects these receptors. They observed that AR2 mice had progressive symptoms of ALS, due to incorrect functioning of receptors in the absence of the ADAR2 protein.
In this study, the authors prepared therapeutically active agents called RNA aptamers to block the incorrect functioning of those receptors. Nucleotides are building blocks of DNA (a blueprint of life), and RNA is a copy of this specific information, like an instruction manual, to enable the cell to make a new protein. RNA aptamers are small chains of nucleotides that can bind specific targets with high specificity. In this study, it was hypothesized that the administration of the dose of such aptamers as low as possible would achieve therapeutic effects with minimal or no adverse effects.
The authors selected two RNA aptamers (FN1040, FN58) as medicines. AR2 mice were treated via the brain with these two RNA aptamers for 2-weeks to see their safety and therapeutic effects. Mice were divided into four groups: control (no treatment), FN1040-treated, FN58-treated, and perampanel-treated orally. Perampanel is an established drug that blocks faulty receptors and was used in this study as a standard to compare the therapeutic effects of RNA aptamers. After completion of this experiment, mice were culled, and the structure of motor neurons was assessed using microscopy. Further, the authors did a new experiment to check the long-term safety and effects of FN1040 and FN58 aptamers, where mice were treated with RNA aptamers for 12 weeks. The authors started the treatment of AR2 mice at 20 weeks of age when the motor neuron death and mobility dysfunction were clearly underway. The authors used a rotarod test to measure motor function, similar to using a treadmill in humans to assess balance and co-ordination. Also, the health and survival of motor neurons were checked using microscopy after the end of an experiment
What are the results?
Interestingly, in 2-weeks experiment, the authors observed an increase in the number and size of motor neurons in FN1040 or FN58 treated groups.
Further, in a 12-weeks experiment, the authors found that all the AR2 mice treated with FN1040 behaved normally during the treatment time. In the rotarod test, the performance of mice was steadily improved just after a few weeks of delivery of FN1040 or FN58. FN1040 had no side effect on either body weight or growth during this 12-week testing period, whereas AR2 mice treated with FN58 failed to gain body weight. Thus, FN1040 was a safer aptamer compared with FN58, although both aptamers were almost equally effective in improving motor (mobility) function. The authors also counted and examined the size of motor neurons in the spinal cord, where they found significantly higher and larger motor neurons in both FN1040- and FN58-treated groups, as compared to the untreated group.
The current study has demonstrated that RNA aptamers block defective receptors in sporadic ALS and are able to rescue motor neuron death. FN1040 is stable, well-tolerated, and more effective as compared to FN58.
Why is the study important?
Even though ALS was identified more than 150 yr ago, to date, no therapy has been developed to effectively slow or prevent the progression of ALS. Currently, there are two ALS drugs (riluzole and edaravone) on the market, none, however, have been effective in improving the quality of life and/or prolonging patients’ lives. As such, there is an unmet, urgent need in developing new and effective drugs for ALS treatment. This study was designed to identify an effective treatment for ALS by targeting the abnormal AMPA receptor functioning.
What do the finding mean going forward for people with the disease?
This study suggests that FN1040 can be therapeutically used to block receptors and is a promising approach in the treatment of ALS, with no side effects. Many other medicines are effective but have associated side effects. RNA aptamers can be an effective treatment approach for preventing ALS in people.
Original paper: Testing of the therapeutic efficacy and safety of AMPA receptor RNA aptamers in an ALS mouse model.
DOI: http://doi.org/10.26508/lsa.202101193
Author list: Megumi Akamatsu, Takenari Yamashita, Sayaka Teramoto, Zhen Huang, Janet Lynch, Tatsushi Toda, Li Niu, Shin Kwak
Citation: Life Sci Alliance. 2022 Jan 12;5(4):e202101193. doi: 10.26508/lsa.202101193. Print 2022 Apr.