Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology New and Emerging Treatments in PD Alpha synuclein aggregation Lysosomal Dysfunction Mitochondrial Dysfunction ID: 935752
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Slide1
Nirosen Vijiaratnam
Janet Owens FellowDepartment of Clinical and Movement NeurosciencesUCL Queen Square Institute of Neurology
New and Emerging Treatments in PD
Slide2Alpha synuclein aggregation
Lysosomal
Dysfunction
Mitochondrial
Dysfunction
Neuroinflammation
Risk Factors
Age
Genetics
Diet
Toxins
Diabetes
Cell to cell propagation
Cell Death/Survival
PD Neurodegeneration
Modified slide courtesy of T
Foltynie
Slide3Symptom relief or Disease modifying?
Slide4Clinical markers
Remote monitoring of PD symptoms
Blood tests/GeneticsCerebrospinal fluid
Imaging
Patient selection & demonstrating disease modification
Slide5Slide6Slide7Slide830 patients
UDCA for 12 months according to weight
Safety, tolerability
Pilot data for efficacy.
Slide9Slide10Precision approaches for lysosomal
parkinsons
Gcase
enzyme activity lower in PD GBA carriers, patients with GD, PDGBA, Controls
Ambroxol
used to treat humans for airway mucus hyper-secretion diseases and found to increase mutant
GCase
activity and protein levels
Slide11AIM-PD trial
N= 20 (10 GBA mutations, 10 sporadic)
Dose- 420mg
tds
for 6 months
2016 until 2018
Primary outcome-
GCase
and
Ambroxol levels in blood/ CSFSecondary outcome- Safety, TolerabilityForward plans are to assess the optimal dose
Slide12Slide13C-
abl is a non-receptor tyrosine kinaseMultiple actions in cell survivalC-abl promotes accumulation of alpha synucleinC-abl inhibitor licensed for treatment Chronic Myeloid leukaemia
Nilotinib- improvements in small open label study at 24 weeks (Pagan et al. 2016)
76 patientsRandomised 1.1.1 Placebo, 150mg, 300mg<0.5% penetration into CSF
No effect on
cABL
Slide14Slide15Slide16Slide17Slide18Slide19Slide20Small cohort size
Differences in baseline severity of patients between groupsNo improvement in secondary outcome measuresMore evidence of pathophysiological process change suggesting disease modifying action
Slide2160
72
84
96
Exenatide PD- Phase 3- UK
Slide courtesy of T
Foltynie
Slide22Slide23Slide24Slide25Dietary supplementation/ plans
Probiotics/Prebiotics/
Synbiotics
Live biotherapeutic productsFaecal microbiota transplantation
Slide26Conclusions
Parkinson’s is complex and its underlying mechanisms and their stages/degrees can vary between individuals despite similarities in presentationsDeciding which agent should be used at the right time and what is the best way to measure these aspects to demonstrate disease modification will likely determine future success
Despite previous disappointing trial results, understanding these underlying aspects and changing approaches will hopefully deliver our goal of disease modification over the next decade