Documentos de Académico
Documentos de Profesional
Documentos de Cultura
NEUROCIENCIA
Y MEDICINA TRADUCCIONAL
Dr. R.B. Maccioni Professor of Neurology, F. Medicine, U Chile & Director INTERNATIONAL CENTER FOR BIOMEDICINE (ICC)
Ruta de Presentacin
Alcanzar una saludable longevidad: desafo de la medicina siglo XXI Innovacin: logros del ICC en la comprensin y tratamiento del Alzheimer El aporte y el impacto de las Neurociencias Bsqueda de soluciones mdicas Biomarcadores: solucin hacia la deteccin temprana y diagnstico diferencial. El tratamiento: la tecnologa Brain Up y la estimulacin cognitiva Ensayos clnicos
Compromiso ICC
Triple hlice de la innovacin
Universidad
Industria
Gobierno
Investigaciones en ICC
Enfermedad de Alzheimer
Diagnstico
Frmacos Anti Alzheimer
Biomarcadores
Neuroimagenes
Neuropsicologa
PATENTES
- Molecular markers in the CSF for early diagnosis of Alzheimers disease. Patente U.S.A. (2007) Author: Dr. Ricardo B. Maccioni. Beneficiary: ICC. The solution proposed in this patent document is development of a Diagnosis procedure from CSF samples to determine al algorithm of hyperphosphorylated tau and Ab(1-42) for early diagnosis of Azheimers disease and MCI. Under use throughout the world to detect Alzheimer. - An innovative blood platelets biomarker for early diagnosis of Alzheimers disease Patent PCT/U.S.A.10/55623 and in the U.S.A. Authors: Drs. R.B. Maccioni and G.Faras. Beneficiary: Neuroinnovation. Patent being handled by by Gottielb, Rackmann and Reisman, Attorneys at Law, New York. Status: Published. Product: Diagnosis kit for early detection of AD. - Benzimidazoles as radiotracers for neuroimaging in the diagnosis of neurodegenerative disorders. Authors: Drs. Ricardo B. Maccioni and Leonel Rojo. Beneficiary: Neuroinnovation. PCT Number: PCT/IB2009/006405 and in the U.S.A. EAPI Project CORFO. Status: Published. Potencial Product: PET technology for neuroimaging of Alzheimerss brains - A family of quinolines and their potential usefullness for the treatement of Alzheimers disease. Beneficiary: ICC & Universidad de Chile. Number: Patent 8.198.300 EAPI CORFO Project. Status: APROVED with TITLE CERTIFICATE. Potental Technological Prototype: A compound as a tool to contribute to treatmente of patients with mild Alzheimers Disease. Under technology transfer process. - A novel nutraceutic formulae with neuroprotection and cognitive activities. Authors: Drs. R.B. Maccioni, L.Quiones V. Sandoval, R Sandoval and and I. Saavedra. Beneficiary: ICC- BrainUp Chile. Presented PCT/CL2010/000043 Oct. 2010 at INAPI. Patent in Chile Reg. 01956 /2009. Status: Published in Chile and at the Internacional Office of Patents and in USA, presented Australia, UK, Brazil and Canada . Technological prototype under technology transfer process. - Registration of Intellectual Property and the TradeMark (in Chile) for the software ACTIVAMENTE for psicostimulation and cognitive activity. Corresponds to a software de 6,000 exercises and 50 complex tasks for cognitive intervention. Two versions: 1) Therapeutic version for patents with Alzhemers disease to be used with the therapist. 2) Autonomous subject. Authors: Ps. Alejandra Sekler and Dr. R.B. Maccioni. Beneficiaries: Neuroinnovation Ltd. and Adexus S.A. Product: Software ACTIVAMENTE being
Productividad cientfica y patentes (1999 2009)* Chile Irlanda N. Zelandia Finlandia Pub/ao/millon hab. 117 670 1.097 2.300 Patente/ ao/millon hab. 0.8 67.0 195.0 253.0
PROBLEMA A RESOLVER
Segn OMS 35.6 millones en el mundo sufren de la enfermedad de Alzheimer (EA) con un impacto en la economa de US$ 600 billones(1) . Para 2030 la poblacin con EA ser 65.6 millones(1). Cada ao 970.000 personas entre 30 - 50 aos desarrollan EA prematuro Otras 85 millones sufren de diferentes formas de deterioro cognitivo y una pobre calidad de vida. La incidencia de EA para mayores de 60 aos es alrededor del 12%. En Chile hay 280.000 casos de EA. Los tratamientos son paliativos, con frmacos que tienen serios efectos adversos. No existen productos para su prevencin. Ineficacia de los medicamentos ha forzado a invertir altas sumas de dinero en I&D con
Total worldwide societal cost of Alzheimers disease (2005) US$ 315,4 billion
Latin America Total cost US$ 13.8 billions Total cost per demented US$ 6905
Wimo A, 2007
Epidemiologa
La enfermedad de Alzheimers causa el 60-80% of las demencias en mayores de 65 aos. 12% de las personas >65 tienen AD. 50% de las personas >85 tienen AD. 39.5 millones en el mundo tienen AD. AD genera un costo anual a la economa mundial sobre los USD 620 billones
SMI-32 immunohistochemistry in layer IIIc of a CDR 0.5 case (A) and a CDR 3 case (B).
.
La hiptesis del amiloide llev a un camino equivocado que fren el avance en la solucin teraputica del Alzheimer
NORMAL
EXTRACELLULAR SOLUBLE APP (sAPP) BETA SECRETASE
ALPHA SECRETASE
sAPP
BETA-AMYLOID
BETAAMYLOID
NEURONAL MEMBRANE
AD
GAMMA SECRETASE
sAPP
CARBOXY TERMINUS INTRACELLULAR BETA-AMYLOID
PROBLEMA A RESOLVER
A: Protena Tau se une a los microtbulos. Sitios de fosforilacin e hiperfosforilacin, causa de la AD. B: Diagrama de flujo desde los cambios en tau a la formacin de los ovillos neurofibrilares y la demencia
External Factors
AGES
Microglia
and astrocytes
RAGE
A peptide oligomers
Deficiency in B vitamins
TLR4 Infections NFk- ox-LDL Oxyradicals TNF IL-1 IL-6 Protective Plasma membrane Mechanical Damage Statins NSAIDs Long-term exposure to cholinergic agonists (?) Iron Overload
Maccioni et al, Arch Med. Res. 2001 Fernndez et al., J. Alz. Dis. 2008
Treatment with Antiinflammatory drugs reduces the risk of Alzheimer Disease control NSAIDS > 6 mos (.65) NSAIDS chronic (.5) NSAIDS >2y (.42) NSAIDS > 2y (.4)
NSAIDS > 2y (.2) Rheumatoid Arthritis (.16) 0.0 0.2 0.4 0.6
Yip et al 2005 Landi et al 2004 Zandi et al 2002 Stewart et al 1997 Int Veld et al 2001 McGeer et al 1990 0.8 1.0
Aggregated tau induces the release of proinflammatory cytokines IL-6 and TNF- . (Upper) Extracellular IL-6 in the conditioned media with ELISA protocol: (lower) ELISA of extracellular TNF- in GCM (A) Negative control buffer (B) 10 mg/mL aggregated tau (C ) 50 mg/mL aggregated tau
Exposure to activated glia conditionated media (GCM) for 24 h alter hippocampal neurons. A. Positive control with 1 mg/mL LPS. B. Exposure to conditioned media from glia treated with 50 g/mL aggregated tau. C. Exposure to conditioned media from glia treated with 10 g/mL aggregated tau and D. Negative control with aggregation buffer with arachidonic acid.
SIGNALING CASCADE EXPLAINING HOW IL-6 INDUCES TAU PHOSPHORYLATION Oxidative Stress NMDA
BetaAmyloid GLIA
IL6
IL-6 R
JAKs/ STATs
Neuron Ca2+
p38
MAPK
cdk5/p35
Tau-p
Egr-1
Quintanilla et al., 2005; Orellana et al., 2006, Maccioni et al., 2010
p35
Compuesto Andino (Shilajit Andino): Es un producto orgnico natural derivado de la descomposicin milenaria de plantas encontradas en Los Andes chilenos. Su principio activo es el cido flvico, contiene adems cidos hmicos selenio y minerales.
23
VISTA AEROFOTOGRAMTRICA DEL REA MINERA CONTENIENDO LOS DEPSITOS DE SHILAJIT ANDINO EN LA REGIN DE ATACAMA.
26
ICC GENERA BRAIN UP-10R ANDEAN COMPOUND PLUS VIT B COMPLEX Studies indicate that BrainUp-10: - Brain Up-10 is NEUROPROTECTOR - Brain Up-10 has neuritogenic activity - Brain Up-10 dos not have neurotoxicity (acute and chronic toxicity study) - Brain Up-10 no adverse effects in patients (Phase I). - Brain 10 improves cognitive performance (Clinical trials, Pilote
SOLUCION MEDICA
Tau antiaggregating activity
(A) TAU CONTROL (B) TAU + BRAINUP
(A) CONTROL
(B) + BRAIN UP
Neuritogenic action
BRAIN UP-10R
Cornejo et al., J. Alz. Dis. 2011
Inhibitory effect of fulvic acid over PHFs formation as monitored by Thioflavin assay (ThT) . A. Aggregation of tau fragment 4RMBD in the presence of Fulvic Acid at different concentrations. The IC50 value for inhibitory effect of Fulvic Acid was 37 M. B. Suggested model for the Fulvic Acid structure
BRAIN UP-10R
Study of the changes in the blood biomarker for platelets tau in relation to the treatment with formulation
+ Formulation +Placebo Ratio of HMW/LMW (for explanation please see ***) Mean SD Mean Group of the clinical trial AD Patients* CONTROL** Normal SD Mean SD
1.076 +/- 0.421 (1st. analysis) 1.107 +/- 0.239 (2nd. analysis)
Formulation group: 10 / N Placebo Group: 6 / N Control group: 7 * Patients incorporated into the study with pre diagnosis of mild to moderate AD and with incorporation criteria and informed consent signed and approved. ** Control subjects of the same range of ages of those incorporated as patients, from whom blood simples were extracted for the study to evaluate platelet tau. ***Ratio between oligomerized tau (HMW) and normal monomeric tau (LMW) (ratio of HMW/ LMW). This marker indicates that a significant increase in this ratio correlates with the level of cognitive impairment in AD. **** The blind was open. + Significant differences at the level of p<0.05
BRAIN UP-10R
En la evaluacin de sntomas neuropsiquitricos (Figura 4), destaca una clara tendencia a presentar menores alteraciones en el test NPI-12 en el grupo tratado con Brain-Up10R (valor p: 0,153).
Grupo
Placebo Brain Up10 100
Grupo
Placebo Brain Up10
50
80
40
60
Media NPI
30
40
NPI media
20
20
10
0
0
-20 0 12 24
12
24
Semana
Error bars: 95,00% CI
Semana
Error bars: 95,00% CI
Figura: Puntajes de los grupos placebo (azul) y tratado con Brain-Up10R (verde) en la evaluacin neuropsiquitrica mediante test NPI-12. Se aprecia un marcado efecto de Brain Up-10 R en aliviar los desordenes neuropsiquitricos del paciente, mayor estabilidad en la intensidad de los sntomas en los sujetos tratados con Brain Up-10R tanto en la evaluacin de frecuencia e intensidad de los sntomas (A), como en el grado de sufrimiento referido por el cuidador. Las barras de error corresponden a IC 95%.
tau
Tau-P
APP Variants
Tau-P
PROTEOMIC DETECTION
El Biomarcador Ideal
It should detect fundamental CNS pathophysiology of AD It should detect the presence of the disease itself, not the risk (e.g., APOE-4) It should be efficacious in pre-clinical stages It should be able to track disease progression, even from pre-clinical stages It should provide indication of treatment effectiveness It should be supported by clinico-pathological studies Better if it is non-invasive and inexpensive
*
pg/ml
** ***
(1)
Range: *345-951 pg/ml, **204-702 pg/ml, ***174-368 pg/ml. This study did not report S.D. and (1) did not include normal controls.
Clinical Phase
WWW.NEUROINOVATION.CL
METHODOLOGY
BIOMARKER
DIAGNOSIS TOOLS
Refs: Neumann, Farias and Maccioni, 2010; Farias, Slachevsky and Maccioni, 2012
CLINICAL TRIALS OF AD PATIENTS IN SANTIAGO (n= 346) Team: Drs. A. Slachevsky, C. Delgado, P. Prez, G. Farias, L. Guzmn & R.B. Maccioni
Correlacion del progreso de la AD con el biomarcador de tau plaquetario: covariables edad & educacin p<0.001.
Lansoprazole Thioflavina S
50 m
LNS
THS
C
ThS
D
LNS
Biosensor
AD-PHF
20
50
80 Time (s)
110
140
170
200
Thanks / Gracias