Pisa Therapy, Targeting alpha-synuclein & A Change of Purpose
by Jon Palfreman, PhD on 31 May 2013
Pisa Therapy Pisa syndrome is a rare complication of PD, where the trunk tilts to one side, causing postural instability. Shih et al present a case study of a 62-year-old-woman with right-sided lean, who fell frequently. The team treated her with DBS surgery to her left pedunculopontine nucleus (PPN). A striking video documents the patient’s slow but steady improvement. After 14 months of stimulation, the lean is largely gone. The team speculates “Stimulation of the PPN…may not only affect gait but also extensor muscle tone, thus leading to changes in posture.”
Shih LC, Vanderhorst VG, Lozano AM, Hamani C, Moro E. Improvement of pisa syndrome with contralateral pedunculopontine stimulation. Mov Disord. 2013 Apr; 28(4):555-6.
Targeting alpha-synuclein A multidisciplinary team of German researchers (Wagner et al.) tested 20,000 compounds searching for agents that blocked alpha-synuclein molecules from assembling into toxic aggregates. One substance, named Anle138b after the chemist Andrei Leonov who synthesized it, has proved remarkably effective in mouse models of PD. It readily crossed the blood brain barrier, caused no adverse affects at high doses, and significantly reduced oligomer accumulation. As a result, the researchers claim, Anle138b-treated Parkinsonian mice experienced less nerve cell degeneration and survived for much longer than untreated controls. According to the article in Acta Neuropathologica, Anle138b also appears to work for Creutzfeldt-Jakob disease and may possibly turn out to inhibit the formation of tau aggregates in AD.
A Change of Purpose Developing safe and effective drugs for neurodegenerative conditions like PD is an expensive (over $1 billion/drug), time consuming (15+ years) and commercially risky business. Frustrated with this situation, Cure Parkinson’s Trust, a British non-profit, came up with a clever alternative strategy: to examine already approved FDA drugs (considered safe and effective for other conditions), screen them for anti-Parkinson’s activity, and test the medicines in patients with PD. In the Journal of Clinical Investigation, Iciar Aviles-Olmos et al. report on an open label trial that “repurposes” the type 2 diabetes drug, Exenatide. Preclinical studies have shown Exenatide, an injectable formulation of a glucagen-like-peptide-1(GLP-1) receptor agonist, may have neuroprotective and neurorestorative properties against PD. The authors report that in a 12-month follow up (with a two month washout), the treatment group reduced (i.e. improved) its UPDRS motor score score by 2.7 points while the control group’s score increased (i.e. got worse) by 2.2 points.
Is a spread of 4.9 points between groups meaningful? In an accompanying commentary, Patrik Brundin, Roger Barker, and Mark Stacey, argue that the difference might be clinically relevant, especially given the treatment was only active for 12 months. The trial’s main weakness was that it was open label (the researchers couldn’t afford the substantial cost of an injectable placebo control medicine), so patients knew who was getting the injected Exenatide and who was receiving the non-injected placebo. But Brundin, Barker, and Stacey argue that this flaw was offset by two strengths: the fact that clinical exams were videotaped and rated blind by neurologists; and the finding that the treatment group continued to exhibit improvement compared to the control group after the 2 month washout period after the injections were discontinued. They suggest that if there had been a substantial placebo effect it would most likely have waned during the 2-month washout period, when the patients knew that they no longer were getting active treatment.
The Cure Parkinson's Trust is now exploring ways to further test the efficacy of Exenatide and other drugs that might be suitable for repurposing to PD, through their "Linked Clinical Trials" program.
Should Exenatide ultimately prove successful, one must hope that the pharmaceutical companies behave reasonably. Some readers may recall what happened when the drug company Questor repurposed ACTHAR gel for infantile spasm. In that case, the company hiked the price for a 5-milliliter vial from $50 to $28,000. Such profiteering would undercut the value of this promising strategy in Parkinson’s.