Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease in which the myelin sheaths that insulate the nerves in the brain and spinal cord are damaged severely; there is no known cause and no known cure. Although there are several therapies available, they are primarily for relapsing-remitting MS; Jorge Correale notes in the abstract of his article “Progressive Multiple Sclerosis: From Pathogenic Mechanisms to Treatment” that “current therapeutic options for progressive multiple sclerosis remain comparatively disappointing and challenging.” As recently as 2016, “Intracellular Signaling Pathway Regulation of Myelination and Remyelination in the CNS” offered an analysis that “[c]urrently approved therapies work by modulating the immune system…but are only partially effective since they are not able to restore lost myelin” (Gaesser). This suggests that treatment and therapy options must be expanded, exploring other modes and approaches. Happily, recent developments in research have pointed to the thyroid hormone sobetirome as a potential key, as it enhances oligodendrocytes which promote myelin generation (Hartley). A study released July of 2020 states: “Sobetirome has been shown to promote significant myelin repair in the brain and spinal cord of mouse demyelinating models and it is rapidly moving into clinical trials in humans” (Saponaro). Several studies have been done that look at the efficacy of sobetirome’s derivative Sob-AM2 and its ability to both penetrate the blood-brain barrier and distribute itself in the CNS; all of the results appear to be consistent and in support of pursuing this line of study. Given the large number of studies resulting in data that supports the hypothesis, more funding should be given to the study and research of the thyroid hormone sobetirome as a form of therapy for remyelination in subjects with MS.
To fully understand and appreciate the latest research on sobetirome in relation to MS, it is helpful to understand the roles and connectedness of myelin, oligodendrocytes, thyroid hormones, and sobetirome (and its derivative form Sob-AM2 which will be discussed later). Myelin is an insulating, neuroprotective sheath of extended cell membrane that wraps itself around the axons of nerve cells, facilitating the transmission of “action potentials,” or commands (Gaessner). It also provides protection of the nerve cells. Oligodendrocytes (OL) are myelinating cells that form the myelin sheath (Kuhn). OL generate from oligodendrocyte progenitor cells (OPC), which are the “migratory and proliferative adult progenitor cells that can differentiate” (Kuhn). OPC reside in the central nervous system (CNS), ready to differentiate. When OL die, they can be “replenished from the adult OPC pool and lost myelin can be regenerated during remyelination”; however, this process is often compromised in subjects with MS, and over time, the myelin sheath cannot be fully or sufficiently repaired (Kuhn). Also, the regenerated myelin is thinner than the original, so its vulnerability increases with each injury (Kuhn).
To summarize briefly, myelin is the insulating, protective covering around the nerves that is damaged (to varying degrees) in subjects with MS and/or other neurodegenerative diseases; myelin comes from oligodendrocytes which form the neuroprotective myelin sheath by tightly wrapping its cell membrane around the axons; oligodendrocyte progenitor cells (located in the CNS) are the parent cells that differentiate into oligodendrocytes. Oligodendrocyte processes (which include remyelination and myelin repair) are enhanced by thyroid hormones—namely, sobetirome, a selective T3 agonist.
A recent study published in JCI insight investigated ways to exploit thyroid hormone (TH) action in the CNS—which is necessary in developmental myelination (Hartley 1). (The results of the study are both promising and indicative of necessary further research.) Sobetirome is a thyromimetic that enhances OPC differentiation and promotes myelin repair. This is important because the need is for therapeutic agents that can stimulate exactly that; it’s a neglected field of research related to MS and other neurodegenerative diseases. Testing sobetirome in short-term disease settings demonstrated that “sobetirome mimics T3 to promote OPC differentiation and myelin repair”; in a chronic demyelination model, “thyromimetic action promoted brain and spinal cord myelin repair and correlated with significant improvement in neurological clinical signs that arise from CNS demyelination” (Hartley 1). The results thus far in the research are especially promising. Sobetirome is unique among thyromimetics because it is able to penetrate the blood-brain barrier (BBB) and distribute itself efficiently in the CNS. However, in progressive MS cases especially, MRI studies show “decreased blood-brain barrier permeability” (Correale). This increases the difficulty of getting sobetirome to the brain.
According to the 2016 study “Sobetirome Prodrug Esters with Enhanced Blood-brain Barrier Permeability”: “Sobetirome is the only clinical-stage thyromimetic that is known to cross the blood-brain-barrier (BBB) and we endeavored to increase the BBB permeability of sobetirome using a prodrug strategy” (Placzek). Sob-AM2 (a derivative of sobetirome and an optimized prodrug) is the result of that endeavor (Hartley 9). Sob-AM2 is sobetirome but with a chemical tag, the purpose of which “is to eliminate a negative charge the prevents sobetirome from efficiently penetrating the [BBB]” (“Multiple Sclerosis Foundation”). It is essentially a stronger, more adapted version of sobetirome to better treat demyelination by penetrating the less-permeable BBB, working through the CNS, and enhancing OL.
An article from MS Society published in 2019 reported the results of a study with sobetirome and Sob-AM2, calling for support and more funding. It emphasizes the need to move to clinical trials, as well as two primary goals that Sob-AM2 accomplishes: myelin repair with minimal side effects and efficient delivery. For the former, “[t]he study demonstrated that the compound…promotes remyelination without the severe side effects of thyroid hormone therapy”; for the latter, “[r]esearchers developed a new derivative of sobetirome…that penetrates the blood brain barrier, enabling a tenfold increase in infiltration to the [CNS]” (“Multiple Sclerosis Foundation”). The more research conducted, the farther along, it seems, that researchers are developing a way to use Sob-AM2 to treat demyelination while also avoiding the harmful side effects that are present in traditional TH therapy.
The National Multiple Sclerosis Society also released an article in 2019, citing Dr. Meredith D. Hartley’s study (referred to above). It celebrates her findings of Sob-AM2’s efficacy in promoting myelin repair “with less potential for toxicity” (“Researchers Funded by National MS Society”).
Again, the results of these numerous studies are promising—but it is only the beginning of this research. It cannot be understated, the degree of pain, life disruption, and disability that individuals with MS experience. With such immense support for the findings of Sob-AM2 as a remyelination therapy, it is essential that more funding, research, and study is necessary.