Multiple sclerosis (MS) is a challenging disease to treat, but we have a growing arsenal of evidence-based medications that target different aspects of its pathophysiology.
Baharlooi et al recently wrote a paper titled “Nucleic Acids as Novel Therapeutic Modalities to Address Multiple Sclerosis Onset and Progression.” In the review, the authors explored a number of therapeutic approaches other than conventional disease-modifying treatments (DMTs) in the management of MS.
Baharlooi and colleagues understood the profound challenges of gaining a complete understanding of MS pathophysiology and developing an adequate therapeutic response to it. They wrote, “Since the pathophysiology of MS resembles a jigsaw puzzle, researchers need to put a host of pieces together to create a promising window towards MS treatment.”
Why does the pathophysiology of MS resemble a jigsaw puzzle? “The exact cause [of MS] is unknown, the onset of CNS demyelination, rehabilitation, and relapses has no prior warning and no absolute cure has yet been found,” the study team explained.
Read more about MS etiology
And why the need for researchers to piece together different therapies to create the most promising treatment approach?
“Despite the therapeutic efficacy of DMTs for MS, a meaningful group of affected individuals does not show objective responses to these routine treatments,” Baharlooi et al wrote. “In addition, some patients face difficulties like lymphopenia, lymphadenopathy, dyspnea, and lipoatrophy after using DMTs.”
In short: we don’t understand very much about MS, and the most common DMTs we use have significant side effects in some patients. So what other potential treatment options do we have? We will look specifically into the role of antisense oligonucleotides (ASOs) in the management of MS today.
A Promising Novel Therapy
“ASO therapies are coming of age, with multiple approved drugs and tens of late phase clinical trials ongoing,” wrote Kuijper and colleagues in a study on the opportunities and challenges for ASO therapies.
So, what are they? ASOs are short strings of nucleic acids that bind to their complementary RNA targets and modify gene expression. They have a much higher specificity than chemical compounds.
Kuijper et al reported that ASO therapies are largely being investigated in the context of their usefulness in treating inherited metabolic disorders. However, they have also been tested for their efficacy in treating neurodegenerative diseases. The use of ASO therapies for neurodegenerative diseases started in the early 2000s. Today, it is approved by the FDA for treating Duchenne muscular dystrophy and spinal muscular atrophy.
Why do scientists believe that ASOs have such potential in treating neurodegenerative diseases? One reason is their chemical modification capability; this means ASOs are protected from degradation by endonucleases and exonucleases. In addition, ASOs go a step further and improve their pharmacological characteristics. Clearly, these features would be an advantage in treating neurodegenerative disorders.
Baharlooi and colleagues quoted a landmark study in 2014 that investigated a chemically modified ASO called ATL1102 for use in patients with relapsing-remitting MS. The research team discovered that ATL1102 significantly reduced the active and gadolinium-enhancing T1 lesions compared to the control after 8 weeks.
Read more about MS therapies
One major drawback of ASO therapies highlighted by Kuijper and colleagues is that they are currently very expensive. The reason? ASO therapies are mostly developed for rare diseases. Since the number of treated patients would naturally be lower, the development cost per patient is high. In addition, many ASO therapies require hospital visits (for intrathecal and intravenous infusions, for example), which adds to the cost of administering these drugs.
This has not slowed down research into ASO therapies. Kuijper et al concluded on a note of optimism: “With 10 approved ASO, 3 of which in the last 6 months, and more ASOs being tested in phases II and III clinical trials with favorable results so far, it seems that ASO therapy is now coming of age as a therapeutic modality.”
The Role of Combination Therapy
In their study, Baharlooi and colleagues discussed extensively the promise of nucleic acid-based therapies other than ASOs: deoxyribozymes, short interfering RNAs, aptamers, DNA vaccines, long noncoding RNAs, and circular RNAs. The sheer number of nucleic acid-based therapies for MS should reassure us that clinical research into novel therapies for MS is alive and well.
In the view of Baharlooi et al, this is important because no single therapy is currently effective enough to target all aspects of MS treatment. Nucleic acid therapies are mainly focused on the immunological dysfunctions of MS. Other therapies, including metaphysical procedures such as hypnosis and electromagnetic therapy, are currently used to manage MS symptoms such as pain, fatigue, and reduced mobility.
In other words, different therapies targeting different aspects of MS can work synergistically to provide the best possible outcomes.
“It is plausible to envisage a future when using a combination therapy of nucleic acids to modulate the unbalanced immune response coupled with hypnotherapy to relieve MS symptoms will likely succeed in dealing with the disease,” Baharlooi et al wrote.
As our understanding of MS pathophysiology and our arsenal of MS medications grows, we can expect the treatment landscape of MS to be vastly different in the decade to come, with possibly an improved prognosis for MS patients.
Baharlooi H, Mansourabadi AH, Minbashi Moeini M, Mohamed Khosroshahi L, Azimi M. Nucleic acids as novel therapeutic modalities to address multiple sclerosis onset and progression. Cell Mol Neurobiol. Published online October 25, 2021. doi:10.1007/s10571-021-01158-4
Kuijper EC, Bergsma AJ, Pijnappel WWMP, Aartsma-Rus A. Opportunities and challenges for antisense oligonucleotide therapies. J Inherit Metab Dis. Published online June 3, 2020. doi:10.1002/jimd.12251.