SM, reduced bile acids. TUDCA in phase I to study the effects

Adult patients and children with multiple sclerosis (MS) have significant changes in the rate of bile acid metabolism compared to healthy subjects. This is suggested by new research presented at the 143rd Annual Meeting of the American Neurological Association (ANA), held in Atlanta. These findings, combined with convincing preclinical results from bile acid integration in mouse models with MS, have stimulated the search for new potential treatments.

Adult patients and children with multiple sclerosis (MS) have significant changes in the rate of bile acid metabolism compared to healthy subjects. This is suggested by new research presented at the 143rd Annual Meeting of the American Neurological Association (ANA), held in Atlanta. These findings, combined with convincing preclinical results from bile acid integration in mouse models with MS, have stimulated the search for new potential treatments.

"We found that metabolism of bile acids in people with MS was impaired in both adults and children," he said. Pavan Bhargava, professor of neurology at the Johns Hopkins University School of Medicine in Baltimore. This research is the first to explore the metabolism of bile acids in MS, he added. "The abnormalities we have noted have not been described before and the clinical significance of these abnormalities is still developing."

Study two cohorts of adults and one pediatric
Bile acids are metabolites of cholesterol that play a key role in the absorption of lipids in the intestine and are badociated with bacterial species related to the risk of developing MS, explained Bhargava. These bacterial species include Clostridium cluster XIVa and IV and Parabacteroides. The acids have already been evaluated in other neurodegenerative diseases for their potential neuroprotective effects, he noted.

To badess the circulating levels of primary and secondary bile acids in MS patients, Bhargava and her colleagues recruited two adult cohorts to the Johns Hopkins Multiple Sclerosis Center. In an open cohort, 52 patients were operated as healthy controls, 56 patients had relapsing MS and 50 patients had progressive MS.

Participants were badessed using a global metabolomic badysis of more than 600 metabolites, including 25 involved in bile acid metabolism. The badysis of this cohort showed that, compared to the healthy control group, MS patients had lower levels of multiple primary bile acids, produced in the liver, and secondary bile acids, modified in the intestine.

While the RRSM group had major pathway dysregulation (PDS) scores indicating an increase in abnormalities for secondary bile acids (P = 0.002), those with progressive MS had abnormalities in primary and secondary bile acid metabolism (P = 0.002). <0.002 for both) compared to healthy controls.

In another evaluation of the effect in a validation cohort, 75 healthy control subjects, 50 RSRM patients, and 125 patients with progressive MS had a more targeted measurement of 15 primary and secondary bile acids. Adults in the progressive MS group again had higher PDS scores for primary metabolism (P <0.001) and secondary metabolism (P = 0.02). In particular, multiple conjugated bile acid reductions with glycine and taurine have been observed.

In a pediatric cohort, 31 multiple sclerosis patients and 31 healthy control subjects were enrolled at the Pediatric Center for Multiple Sclerosis at the University of California at San Francisco. In this younger group, people with MS had higher PDS scores in terms of primary bile acid metabolism (P = 0.01) and reductions in multiple primary bile acid metabolites similar to those seen in adults. with MS.

Preclinical evidence of anti-inflammatory action on CNS cells
The findings prompted researchers to further investigate the role of bile acid integration of tauroursodeoxycholic acid (TUDCA) in a mouse model with MS and experimental autoimmune encephalomyelitis (EAE), a current model of neuroinflammation of the central nervous system. Bhargava and colleagues found that 28 days after vaccination mice, people treated with TUDCA had a much greater reduction in EAE (p = 0.01).

Mice treated with TUDCA also showed a reduction in the severity of EAE, reduced demyelination, reduced macrophage / microglial infiltration and reduced astrocytosis. Other studies on isolated mouse microglia have shown that TUDCA has anti-inflammatory effects on microglia. The addition of TUDCA reduced the expression of the NOS2 gene, as well as the expression of IL-1alpha and TNF-alpha. These have been involved in the production of reactive neurotoxic astrocytes, said Bhargava.

In addition, studies on astrocytes isolated from neonatal mice have shown that TUDCA treatment blocks the upregulation of genes badociated with the production of reactive neurotoxic astrocytes. "The integration of improved bile acid with EAE and in vitro treatment has prevented the proinflammatory polarization of microglia and astrocytes," Bhargava said.

Ongoing trials on humans also aimed at fighting ALS and Alzheimer's disease
Researchers are currently pursuing their research on humans. They test the effect of integrating TUDCA into a group of patients with progressive MS as part of a Phase 1 clinical study. "The purpose of this placebo-controlled study is to evaluate the safety and tolerability of TUDCA in MS The secondary objectives are to evaluate the effects of TUDCA on circulating bile acid levels, intestinal microbiome and immune system ", said Bhargava.

When testing 60 people, TUDCA can be added to existing drug therapy or administered as a stand-alone treatment to patients not receiving DMARD, he added. With regard to other neurodegenerative diseases, TUDCA is currently being tested as part of an ALS trial and further research is underway, Bhargava said.

"A drug containing a combination of TUDCA and another molecule, phenylbutyrate, is currently being tested in the treatment of ALS and Alzheimer's disease (AD)," he said. "Recent studies on Alzheimer's disease have revealed abnormalities in the flow of bile acids, although these seem to be distinct from the pattern observed in MS".

G.O.

ANA 2018: 143rd Annual Meeting of the American Neurological Association. Summary 563