Following the game-changing success of Spinraza, a molecular-based therapy that was crucial in the treatment of SMA (Spinal Muscular Atrophy), which used to be one of the leading genetic killers of babies, the appreciation of research on the molecular-level is driving towards new, effective therapies for ALS, The Malta Independent on Sunday has learnt.

Ruben J. Cauchi, Professor of Neurogenetics within the Department of Physiology & Biochemistry at the Faculty of Medicine & Surgery and a principal investigator at the Centre for Molecular Medicine & Biobanking of the University of Malta, said the direction research is taking with regard to ALS appears promising.

"We are now appreciative of the early molecular changes that drive the disease, including alterations in messenger RNAs, which are the molecules that contain the instructions or 'recipes' for making proteins, the building blocks of our body."

He stressed the importance of the molecular-level research saying that "knowing the molecular cause and targeting the cause, using molecular-based therapies as we have done successfully with Spinraza and Qalsody, is the recipe for success".

He added that mRNA vaccine technology, made famous during the Covid-19 pandemic, has a major role in future therapies and is "actually at the heart" of breakthrough therapies like Spinraza and Qalsody. Furthermore, "given that I'm a frequent participant in international conferences on ALS, I can tell you that there are several treatments or treatment approaches in the pipeline," he said.

Ruben J. Cauchi, Professor of Neurogenetics within the Department of Physiology & Biochemistry at the Faculty of Medicine & Surgery

Cauchi described ALS (amyotrophic lateral sclerosis) as follows: "ALS affects the nerves that control the muscles of the body so signals are not transmitted to the limbs. When that happens, the limb muscles stop being stimulated or functioning, leading to difficulties with walking, talking, eating and, eventually, breathing."

Indeed, he pointed out that "the main cause of death in ALS is respiratory failure". In a nutshell, as the diseases runs its course, the signals going to the muscles involved in breathing, such as the diaphragm, which allow the lungs to expand, do not receive appropriate nerve signals, telling them to "do their job" and end up dysfunctional. "Essentially this leads to low oxygen levels in the blood, and the cells of the body cannot function without adequate levels of oxygen," he said.

Cauchi said that this deterioration may be seen in ALS patients who have a "pipe" attached to their throat, called as a tracheostomy. He explained that this is a hole, formally called a stoma, made in the windpipe, known as the trachea, through a surgical procedure to allow the insertion of a specialised pipe to provide air to the patient and allow them to breathe easier. Though shocking to some, he explained, "the main reason for this procedure is to ease the significant difficulties that patients eventually experience in breathing due to the weakening of the respiratory muscles, and provides benefits, that are well-known to prolong survival".

Going into further detail on the disease, Cauchi said that "ALS causes the death or destruction of motor neurons, which are those nerve cells that control the limb muscles. There are various mechanisms or rather disruptions in the internal operations of motor neurons, that cause their death". As an example, he said "it is worth mentioning the formation of protein aggregates (or clumps) that interfere with various cellular processes". That said, he pointed out that the nerves giving information on the senses, such as touch, are not affected in most patients.

Looking past the medical perspective, Cauchi pointed out that "there are various social challenges the patients suffering from ALS face, including the loss of independence, the eventual difficulty in communication, accessibility issues". He added that "emotional distress on patients and their family members, including financial strains, are unfortunately, common in Malta".

Cauchi stressed the importance of the Motor Neuron Disease Laboratory at the University of Malta. "Due to an aging population, conditions that affect the nervous system - including neurodegenerative diseases such as ALS - are set to become the leading maladies worldwide. Their intensive study is therefore timely." He said: "It was no surprise that we have also discovered that the incidence rate of the disease in Malta is one of the highest in Europe."

Fruit flies are the model organism of choice in the studies being conducted

Indeed, Cauchi said that among the lab's "several breakthrough discoveries" it found that "the genetics of the Maltese puts the population at a greater risk of developing ALS". Furthermore, "we have made great strides in exposing some causes of ALS in Malta, including prominent genes which are different to those in other European populations due to our isolation as well as occupational risks, including strenuous work-related activity", he said.

Honing in on the Motor Neuron Disease Lab's work, Cauchi said that "essentially, my lab is identifying, tracking and investigating Maltese ALS patients to discover the cause of the disease, specifically in Malta. It is with this in mind that we set up a national ALS Registry and Biobank at the University of Malta several years back". Going into specifics, he said that "by making use of animal models, chiefly the fruit fly in our lab's case, we can modify their DNA to copy the genetics of Maltese ALS patients. We have also made, and are making, great advances in exposing the molecular underpinnings of the disease".

When asked for the reason behind the lab's choice of the fruit fly as the chosen insect model, Cauchi explained that "fruit flies are our model organism of choice for three reasons: first, there is a remarkable degree of genetic and, therefore, biological similarity between us humans and flies; secondly, we have at hand an organism that can age rapidly allowing us to model a neurodegenerative disease of middle age like ALS well. Finally, the fruit fly is one of the most studied organisms on earth that has been used in labs worldwide for over a century, paving the way for several Noble prize-worthy discoveries in the process".

Prof. Cauchi explained that one of the major questions the lab is tackling, alongside peers worldwide, is an explanation for the aetiology, the cause/s, of the majority of ALS cases which, thus far, remain unexplained. "It is important to understand that knowing the cause is essentially the first step towards the discovery of targeted treatments, which are the ones that ultimately work, and underscores the need for further research in this regard," he said. A pertinent and recent example of this can be seen in the Relyvrio ALS medication, which was withdrawn from the US and Canadian markets back in April, most likely due to its molecular targets being unclear and so the reason for its lack of success, he added.

With this in mind, Prof. Cauchi looked forward however, and spoke of his time as a researcher looking into SMA (spinal muscular atrophy) at the University of Oxford during "an amazing breakthrough in genetic therapy, known today as Spinraza, due to advances in our understanding of its cause". He explained "[the genetic therapy for] SMA, which some decades ago was one of the leading genetic killers of infants, has slowed disease progression and improved the quality of life of many young, affected patients". He added that "the discovery of this new generation of medicine has given so much hope to MND patients, clinicians and researchers, like us, that investigate these diseases. More so, with a huge number of tools and knowhow available today to manipulate genes and answer questions on whether gene disruption can lead to disease".

Causation is only one of many questions ALS poses however, with Cauchi pointing out that "we do notice that we have patients that progress quite fast and others that are essentially 'slow progressors'. Something needs to be done about it because it can lead to discovery of targets that will allow us to slow the disease". Ultimately, "the problem with answering these important questions is that one needs funds and ALS, as a disease, is competing for funding with other 'common' diseases like cancer, so it is always a struggle. Essentially, the lack of progress on ALS is because it is heavily underfunded".

In conclusion, Prof. Cauchi said "there is no doubt that Malta has an increased public awareness of ALS - this is the result of awareness campaigns by high profile individuals, as well as our breakthrough discoveries over the years, on this disease and its impact on the Maltese population". On the other hand, he said: "While awareness probably rivals that of most European nations, the same cannot be said for funding support. Funds are what drive research and innovation that lead to advances in treatments that slow the disease. We have done so much with such limited resources - can you imagine how much more we can do if more funds are directed to ALS research?"

Research at the Motor Neuron Disease Laboratory at the University of Malta is presently funded by the REACH HIGH II scholars programme (co-funded by ESF+ 2021-2027), Tertiary Education Scholarship Schemes (TESS) and the Ministry for Education, Sport, Youth, Research and Innovation through the Post-Doctoral Fellowship Scheme 2024