Parkinson's Disease: Disease Modifying Therapies Remain Elusive

The disappointing news of the failure of yet another PD disease modifying (or neuroprotective) clinical trial—FS-ZONE (pioglitazone)—probably highlighs the year in Parkinson’s research, says Zoltan Mari, MD. The Holy Grail in PD research remains finding interventions that can alter the progression of the disease or offer prevention or prophylaxis. Not one compound or intervention thus far proved to do that and among the many trials this was the latest failure.

Along the same lines, the launch of the STEADY-PD III clinical trial—to test isradipine for the same disease-modifying efficacy—has gathered attention and hope. The first subjects are about to be enrolled. Also, the so called “prion theory” for the etiopathogenesis of PD (Virginia Lee, John Trojanowski, and others) has been gaining a momentum.

A big breakthrough discovery is the identification of ribosomal protein s15 phosphorylation as the mediating mechanism of LRRK2-related neurodegeneration in Drosophila and human neuron PD models.¹ Researchers found phosphodeficient s15 carrying a threonine 136 to alanine substitution rescues dopamine neuron degeneration and age-related locomotor deficits in G2019S LRRK2 transgenic Drosophila and substantially reduces G2019S LRRK2-mediated neurite loss and cell death in human dopamine and cortical neurons. Remarkably, the authors noted, “pathogenic LRRK2 stimulates both cap-dependent and cap-independent mRNA translation and induces a bulk increase in protein synthesis in Drosophila, which can be prevented by phosphodeficient T136A s15.” These results revealed a novel mechanism of PD pathogenesis linked to elevated LRRK2 kinase activity and aberrant protein synthesis in vivo.

Regarding therapeutic development, there is buzz right now about a number of new therapies hitting the US market after years of no novelty.

• Droxidopa. Approved in February, it is used in neurogenic orthostatic hypotension, a common problem in PD.

• Levodopa-carbidopa intestinal gel (LCIG). Referred to as Duodopa elsewhere, it became available on the Canadian market in April and is expected to hit the US market later this year or early next year.

• Rytary. A truly extended release levodopa/carbidopa tablet formulation is greatly awaited, which could be superior to all current other levodopa pills (Sinemet IR, Sinemet ER, Sinemet CR, Parcopa, Stalevo) in terms of its pharmacokinetics (longer lasting, in this case). FDA expects a decision by January 9, 2015.

“Looking ahead to 2015, we are excited for the new drugs to enter practice and await how this will shape our clinical care,” says Dr. Mari. “Everybody is also excited about the aforementioned STEADY-PD trial, and I think we are also excited about the developments in the Michael J. Fox Foundation-led prodromal Parkinson Progression Markers Initiative (PPMI). I expect further breakthroughs between basic scientific discoveries (such as the LRRK2 example) being translated to clinical research.”

Zoltan Mari, MD, Associate Professor of Neurology at Johns Hopkins University, Interim Director of the Parkinson’s & Movement Disorder Center, Director, of the National Parkinson Foundation Center of Excellence, and Director of the Deep Brain Stimulation Center.

1. Martin I, Kim JW, Lee BD, Kang HC, Xu JC, Jia H, Stankowski J, Kim MS, Zhong J, Kumar M, Andrabi SA, Xiong Y, Dickson DW, Wszolek ZK, Pandey A, Dawson TM, Dawson VL. Ribosomal protein s15 phosphorylation mediates LRRK2 neurodegeneration in Parkinson’s disease. Cell. 2014 Apr 10;157(2):472-85.