MEET
PROFESSOR
MARCO BORTOLATO

Professor Marco Bortolato, Faculty of Pharmacology and Toxicology at the University of Utah

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MEET PROFESSOR MARCO BORTOLATO

Tourette Key Opinion Leader

“This research represents a new direction in the treatment of Tourette”, Professor Marco Bortolato, Faculty of Pharmacology and Toxicology at the University of Utah:

If the clinical endpoint is reached, the reduction in tics according to the YGTSS (the Yale Global Tic Severity Scale), then I would certainly hope to see a new wave of research into the role of neurosteroids in a range of stress and compulsion disorders—even beyond Tourette.”

“A highly targeted hormone metabolite like Sepranolone offers the possibility of a treatment that could be efficacious, without any of the side effects commonly caused by anti-psychotics like Haldol. It would be a positive and promising result for patients”
Associate Professor Marco Bortolato

THE SERIOUS SIDE EFFECTS OF TODAY’S TREATMENTS

Today’s most commonly prescribed effective treatments (anti-psychotic neuroleptics like haloperidol (Haldol) and pimozide) are associated with frequent and serious side effects.

As tic symptoms often do not cause impairment, and recede in later life, the majority of people with Tourette require no medication. But for those who do, current treatments involve challenges. Today’s most commonly prescribed effective treatments (anti-psychotic neuroleptics like haloperidol (Haldol) and pimozide) are associated with frequent and serious side effects. Paradoxically, the neurological side effects (like tremor, Parkinson-like symptoms and involuntary dyskinetic movements) can be so severe that they themselves are mistaken for symptoms—meaning higher doses of anti-psychotics being prescribed and so a worsening of side effects. Consequently there is a large unmet medical need for an effective treatment for Tourette not associated with serious side effects. Prof Bortolato’s initial research on tics used Finasteride, an experimental drug that blocks the synthesis of ALLO. “Because Tourette occurs predominantly in males, with a prevalence of roughly 4-to-1 male to female, we began working on Finasteride, which reduces the levels of some male hormones, and the

effects were profound. However, as research progressed in animal models, we started realizing that a good part of the efficacy was accounted for by the reduction of Allopregnanolone. Plus, there was an issue of stress reactivity that we had not originally hypothesized, with some patients reporting an improvement with Finasteride because it seemed to control their tics particularly in stressful contexts. “We knew from animal literature that Finasteride reduced the synthesis of steroids implicated in stress response, like Allopregnanolone, so based on this we started looking at stress sensitivity, finding that one of our Tourette animal models too was exquisitely sensitive to stress.” But it didn’t end there… Bortolato believes that ALLO may also be crucial in the brain’s central mechanism for balancing obsession with compulsion—and our need to act on compulsion.

Marco-Bortolato-2015[1]

COMPULSION IS KEY

“The role of Allopregnanolone and stress may be crucial in the mechanisms by which individuals feel the urge to carry out a tic,” says Bortolato “this sequence is roughly similar to the link between obsessions and compulsions.

Tourette patients can temporarily suppress their tics, but this then increases the stress itself—and ultimately the severity of the tics. Many adult patients report that they compulsively enact their tics in order to relieve themselves of a premonitory urge. It is likely that, when Tourette people suppress their tics, their Allopregnanolone levels in the brain go higher and higher—to the point where they may just not be able to stop from acting on them. We believe ALLO is crucial to that irresistible drive, that compulsion to tic and keep ticing.”

Paradoxically, Bortolato points out, for most people Allopregnanolone has the positive function of helping people find positive ways of relieving stress. “In the case of Tourette, however, this way of relieving stress is maladaptive and pathological, and results in an exacerbation of tics. In fact, several Tourette patients do experience a certain level of relief from their urges when they tic.”

THE AGE OF ALLO

“I believe we are on the crest of a new wave of understanding of just how broad the implications of Allopregnanolone really are,” says Bortolato.  
“Compulsivity impacts on so many different conditions, from ADHD and OCD/B through to eating disorders and addiction. Our preliminary data lead us to believe that these processes are not limited just to Tourette, but point to a much broader biological mechanism that speaks directly to the relationship between obsession and compulsion. If we can prove that mechanism, then this therapy would be relevant to a far, far wider set of problems.”
CEO Peter Nordkild

SEPRANOLONE AS AN ADJUNCT TREATMENT FOR CBIT?

“Sepranolone could, if successful, help patients get far better results from their CBIT, (comprehensive behavioural intervention for tics).”

CBIT is a major therapy for TS primarily based on teaching patients how to recognize their urges to tic and suppress them. At this point CBIT is quite effective for many patients, but many don’t get the results they need. Pharmacological aid could help people who do not experience improvement with CBIT to reduce stress, improve control and get better results. I definitely think that, if effective, Sepranolone could work as an adjunct therapy for CBIT. Any possibility we have to intervene pharmacologically on the key triggers that unleash tics would be extremely important for treatment”.

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