Ariel Ionescu, the scientist who co-founded Rinnerva Therapeutics and has spent years developing a truly innovative therapy for amyotrophic lateral sclerosis (ALS), sat down with Nicolae Tomescu. In this exclusive interview for SLA România – first published on NEUROOTS.co – Dr. Ionescu gives the straight answers to the questions that matter most to the ALS community.
“Now the real work truly begins. We have to advance this breakthrough through the full safety and efficacy studies demanded by regulators. It’s an entirely new journey, but the team is deeply confident and driven to push it forward as fast as we possibly can.”
– Dr. Ariel Ionescu
NEUROOTS:
1. You are the first author of this groundbreaking study published in Nature Neuroscience. How did this journey begin for you personally? Was there a particular moment or experience that made you dedicate years of your life to ALS research?
Dr. Ariel Ionescu:
“I have been studying ALS for the past 14 years. As a sports enthusiast, I have been interested in the physiology of sport for a long time, and so I began my training by studying medical sciences for my bachelor’s degree, hoping to persue a carreer as a sports doctor. During this time, Prof. Eran Perlson, who was a new researcher at the faculty of medicine of Tel-Aviv University, presented his research about motor neurons and the neuromuscular system and his unique approach for studying this system to us students. The neuromuscular system, also known as the ‘motor unit’ is the main anatomical and physiological compartment affected in ALS. I immediately decided to join Prof. Perlson’s lab, combining my passions for sports, movement, and science. To make a long story short, I fell in love with molecular neurobiology research, with the lab life, and with the ALS challenge. I even crisply remember talking to myself on my way home on one of the first days in the lab – “I will solve this disease – they are just not stubborn enough like me!”. Obviously, I was naïve, and shortly after that I realized that this is not going to be a ‘walk in the park’ – there is so much knowledge, so many open questions, and it is very easy to take the worng turn and get to a dead-end. Israel has a very strong ALS patient organization IsrA.L.S, that supports patients, raise the awareness for the disease and promote basic research. As researchers we were lucky to meet many patients and their families over the years – this gives us endless ambitions to work day and night to continue our research, identify the molecular basis of the disease, which could then help in developing precise medicines.”
NEUROOTS:
2. Many patients and families in Romania want to understand in simple terms: what exactly is happening in their bodies, and how does microRNA-126 stop the “fire” that destroys motor neurons? Why does the muscle normally “talk” to the nerve through these microRNAs, and why does this conversation break down in ALS? Is it fair to say the muscle “forgets” to tell the nerve “stop producing more TDP-43”?
Dr. Ariel Ionescu:
“To understand ALS, one needs to understand motor neurons. These are the longest cells in our body. Motor neurons have an extremely long ‘arm’ called an axon, which can be more than a meter long – going from the spinal cord to the tip you our toe. Thousands of these axons together form the known sciatic nerve that innervates our lower limbs. To add more complexity – this axon splits and forms hundreds to thousands of junctions with skeletal muscle fibers. We call these junctions or synapses – neuromuscular junctions (NMJs). This is the place where a command to more our finger, or leg, which comes from the brain translated into action – movement. In ALS, this junction is the first site to fail and degenerate – which leads to weakness that develops into a paralysis. Few years ago we identified that a protein called TDP-43 aberrantly accumulates and forms aggregates in these junctions – impairing their proper function by blocking the energy production driven by mitochondria (the power plants of our body). Us and other researchers have identified that this pathology happens early in the disease in over 97% of patieths. When there’s no energy, the junction, cannot repair itself, cannot signal or synthesize the proteins it needs – and degenerates. When many junctions of the same neuron degenerate, the axon itself degenerates and initiates the death of motor neurons in the spinal cord. Important to note, that neurons, unlike most cells in our body, cannot renew themselves – they live in our body before we are born and until we pass away, or until they start dying ALS. The death of the motor neuron is irreversible. As for the question about miR-126-5p – I began by saying that motor neurons are the longest cells in our body. We showed that in order to function properly and respond rapidly to changes, the axons depend on continuous communication from surrounding cells that regulate their activity. We revealed that the skeletal muscle at neuromuscular junction transmits a regulatory molecule called microRNA-126-5p which continuosly prevents the excess production of the protein TDP-43 at the junction – in other words: it controls the fire. We detected that this microRNA is missing, or found at extremely lower levels in ALS model mice and in serum samples of patients (which many times mirror the muscle condition). This depletion of microRNA-126 is correlated with the accumulation of TDP-43 and the degeneration of neuromuscular junctions. We believe, but still have to prove this hypothesis, that microRNA levels continuously fluctuate in the neuromuscular junctions to allow their remodeling during normal lifecycle of muscles (for example after physical training when the muscles need to recover and renew). What most probably happens in ALS is that loss of control over microRNA-126 which at some point stops fluctuating and remains continuously low – unleashing the toxic expression and accumulation of TDP-43.”
NEUROOTS:
3. If a Romanian patient with ALS is reading this right now, what would you like to say to them directly – from the scientist who saw the damaged nerves start to regenerate in the lab?
Dr. Ariel Ionescu:
“My message to the ALS patients in Romania is that, although Israel has become a hub for ALS research, there are enormous worldwide efforts and global collaboration to accelerate research and therapies. In general there’s feeling of a breathrough in recent years and there are many new hopefully effective and mechanims-driven therapies being developed that should reach clinical testing in the near future. This following part of my answer will probably also answer the next question – As for microRNA-126, when we added this molecule artificially to ALS model mice, we saw something that many other studies didn’t until now, almost complete preservation of the motor activity, and yet there is still much to improve in the way we treated, which suggests the effects could be even greater if we would be able to deliver this molecule effectively to all motor neurons and neuromuscular junctions in the body. Yes. This means that this potential treatment is not yet ready to be given to human patients. I had the privilege to be involved in the pre-clinical testing of a molecule that is currently starting the last phase of clinical trials (Pridopidine), and one more molecule aside microRNA-126, which we are also promoting towards clinical trials. Many studies including the above have shown positive signs in model animals and in neuronal cell-cultures. Yet, unfortunately the human body is complex and different from mice in many ways. There have been multiple promising treatments in the past who turned out to be ineffective in clinical trials, sometimes due to choice of the wrong patient sub-populations for testing, safety/toxicity and serious adverse effects, or due to many other reasons. As clinical trials are extremely expensive many companies get one shot to make the right descisions and navigate the way to successful trials. Both microRNA-126 and the second treatment we are developing are based on observations from human patients, are derived from mechanistic understanding of the disease, and were supported also in model mice and in human patient-derived cell cultures. We hope this places us in a good starting position on the path towards clinical trials in humans.”
NEUROOTS:
4. Can you explain (as simply as possible) why adding extra microRNA-126 was able to rescue and even regenerate the destroyed neuromuscular junctions? Was this the first time anyone has observed such regeneration in ALS models?
Dr. Ariel Ionescu:
“In our recent article we discovered that TDP-43 accumulated also in neuromuscular junctions of patients with mutations in the SOD1 gene, and SOD1 model animals. This is unique because until now, patients with mutations in SOD1 were considered a different subset of ALS not presenting with TDP-43 pathology. So actually, now we can say in more confidence that ±99% of patients present with TDP-43 pathology. Since microRNA-126-5p targets the TDP-43 gene produces and prevents the formation of excess TDP-43, almost all ALS patients could potentially benefit from this treatment when it will become available.“
5. Do you believe this microRNA-126-based approach could work for the vast majority of patients – including those with sporadic (non-genetic) forms of the disease?
Dr. Ariel Ionescu:
“Additionally, when we tested for microRNA-126-5p in the blood on a small cohort of sporadic ALS patients, we identified its levels are almost 3-times lower in ALS compared with healthy subjects, suggesting that changes in microRNA-126-5p happen not only in SOD1 mutants, but rather in a broader group of patients, suggesting a common mechanism for sporadic patients.”
NEUROOTS:
6. How soon do you think we might see the first human clinical trial using this microRNA-126 approach? Are we talking 2–3 years, 5 years, or longer?
Dr. Ariel Ionescu:
“The true and painful answer to this question is that the development of microRNA-126-5p as a safe and effective treatment for ALS patients will take a minimum of 5 years to the first in human studies. I hope I am wrong, but experience had taught me to be modest with these kind of estimations, as there are many variables and unexpected turns that can change along this period. Most importantly, the pre-clinical development is a very costly process that requires enough and continuous resources, and a team of multidisciplinary experts to support a series of mandatory experiments, sterile manufacturing of RNA molecules and their biological packaging to promise they get to the correct places in the body and act only there, regulatory support teams, and many more. We are currently raising more funds and strategic partnets to continue effective development of this treatment and bring it to patients as soon as possible.”
Mulțumim, dr. Ariel Ionescu, pentru timpul prețios pe care l-ai dăruit comunității SLA România prin acest interviu! Thank you, Dr.!
The entire Romanian ALS community wants to thank you for this extraordinary interview. Your words, your energy, and especially the hope you have brought into our homes mean more than we can ever express. You didn’t just share information – you gave us light at a time when many of us felt surrounded by darkness.
We are incredibly grateful for your time, your openness, and your relentless fight – not only for yourself, but for all of us. You have reminded us that we are not alone and that, together, we are part of something historic.
Thank you dr. Ariel Ionescu. Thank you from every family, every caregiver, every person living with ALS in Romania and beyond. We are with you, every step of this new road.
This is not the end of the story – it’s only the beginning.
The science is moving faster than ever, and hope is no longer just a feeling; it is becoming a plan, a timeline, a real possibility.
To everyone reading this, wherever you are on this journey: hold on.
We will keep sharing every update, every milestone, every small and big victory.
With hope and gratitude,
NEUROOTS 💙 The Romanian ALS Community
1 Comment
Margaret Kiser
How does one get into the trial? Regards, Peg Kiser