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.Dr. R.B. MaccioniProfessor of Neurology, F. Medicine, U Chile & Director INTERNATIONAL CENTER FOR BIOMEDICINE (ICC)
CENTRO INTERNACIONAL DE BIOMEDICINA
NEUROCIENCIA Y MEDICINA TRADUCCIONAL
- 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
Ruta de Presentacin
LOGROS RECIENTES DE ICC HACIA UNA SALUDABLE LONGEVIDAD
ICC se fund en 1989 y hoy est considerado como ...a world class center of excellence. ICC ha sido reconocido por el Programa Human Frontiers entre los 3 centros lderes en el mundo en desarrollo.
Descubrimientos sobre el rol del estrs oxidativo en el envejecimiento y en los trastornos neurodegenerativos. Mecanismos de transduccin de seales en la patogenia del Alzheimer (AD). La hipotesis revitalizada de la protena tau La teora de la neuroinmunomodulacin en el orgen de la enfermedad de Alzheimer Ingeniera de protenas y modelamiento molecular del complejo cdk5/p35. Avances en la comprensin gentica y la farmacologa de la AD. Desarrollo innovador de biomarcadores no invasivos para la AD Nutraceuticos en el tratamiento de la AD 564 publicaciones cientficas, mayoria ISI (7 papers destacados en portadas de revistas de alto impacto). Algunos papers reconocidos entre los ms citados en el tema a nivel mundial Cientificos de ICC obtienen importantes Premios a nivel Mundial por contribuiciones en este tema. 8 patentes de invencin en los ltimos aos
Compromiso ICC
Triple hlice de la innovacinTriple hlice de la innovacin
Industria Gobierno
Universidad
Investigaciones en ICC
Diagnstico
Enfermedad de Alzheimer
Biomarcadores Frmacos Anti Alzheimer
NeuropsicologaNeuroimagenes
- 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 commercialized
- Trademark in U.S.A. for the product BRAIN UP-10TM, nutraceutic formulae and dietary supplement recommended for cognitive improvement and to slow down brain aging. Author: Dr. Ricardo B. Maccioni and Constanza Maccioni.
PATENTES
Patentes de Chile en el sistema PCT.
Productividad cientfica y patentes (1999 2009)*
Pub/ao/millon hab. Patente/ ao/millon hab.Chile 117 0.8 Irlanda 670 67.0N. Zelandia 1.097 195.0Finlandia 2.300 253.0
Fuente: Base de datos de Conicyt www.conicyt.cl
Porqu el Alzheimer es un problema de salud pblica?
Su prevalencia aumenta drsticamente2/3 de los casos de Alzheimer y otras demencias viven en el mundo en desarrollo.
Ferri et al., 2005Kalaria et al., 2008
INT
ER
NA
TIO
NA
LC
EN
TE
R F
OR
BIO
ME
DIC
INE
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 pobrsimos resultados. La comunidad mdica y los cuidadores de esos pacientes estn preocupados por la falta de soluciones efectivas.
Facts:
Most common cause of dementia. Every year, 4.6 million new cases of dementia are reported worldwide.
One new case every 7 seconds. By 2050, will be 100 million people with dementia in the world.
ADI, 2008
Total worldwide societal cost of Alzheimers disease (2005)
US$ 315,4 billion
Latin America
Total cost US$ 13.8 billionsTotal cost per demented US$ 6905
Wimo A, 2007
Alzheimers DiseaseA public health emergency.
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
Prdida de Neuronas Piramidales CDR 0.5 and 3.0
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 La hiptesis del amiloide llev a un camino equivocado que fren el avance en la solucin equivocado que fren el avance en la solucin
teraputica del Alzheimerteraputica del Alzheimer
NEURONAL MEMBRANENEURONAL MEMBRANE
EXTRACELLULAREXTRACELLULAR
INTRACELLULARINTRACELLULAR
GAMMA SECRETASE
BETA SECRETASE
ALPHA SECRETASEALPHA SECRETASE
CARBOXY CARBOXY TERMINUSTERMINUS
SOLUBLE APPSOLUBLE APP (sAPP)(sAPP)
BETA-BETA-AMYLOIDAMYLOID
NORMALNORMAL
ADAD
sAPPsAPP
BETA-AMYLOIDBETA-AMYLOID
BETA-AMYLOIDBETA-AMYLOID
sAPPsAPP
Dekosky, Kaufer & Lopez. In: Neurology in Clinical Practice, 2004:1901-1951
Aug.172010 - 9:07 am |179 views|
Eli Lilly Alzheimers Drug Made Patients Worse
By MATTHEW Abti-Beta amyloid
Patients taking an experimental Eli Lilly Alzheimers treatment worsened faster than those on placebo. The treatment also apparently caused skin cancer. Lilly says it will stop developing the drug, but will keep working on another, different Alzheimers treatment.The result is another setback for Alzheimer's research and should probably make scientists and investors think again about how little we know about this disease.
From Lillyspress release:In two pivotal Phase III trials, semagacestat was compared with placebo in more than 2,600 patients with mild-to-moderate Alzheimers disease. Lilly has now reviewed data from a pre-planned interim analysis of semagacestat studies. This interim analysis showed that, as expected, cognition and the ability to complete activities of daily living of placebo-treated patients worsened.
PROBLEMA A RESOLVER
NUESTRA HIPOTESIS DE TAUNUESTRA HIPOTESIS DE TAU
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
Maccioni et al, Arch Med. Res. 2001Fernndez et al., J. Alz. Dis. 2008 Rojo et al. Arch Med. Res. 2008
HMBG1
S100AGES
RAGE
TLR4
Endogenous Damage Signals
A peptideoligomers
Microgliaand astrocytes
Neuron Damage
ox-LDLNFk-
Degenerating neuron
Hyperphosphorylatedtau protein
Oxyradicals
Head injury
StatinsNSAIDsLong-term exposure to cholinergic agonists (?)
Deficiency in Bvitamins
Infections
Iron Overload
External Factors
Deleterious
TNFIL-1IL-6
Protective
High fat Intake
MechanicalDamage
Cell cycle activationwithout proliferation
Plasma membrane
Autotoxic diseases are different from autoimmune diseases
Autoimmune diseases involve the adaptive immune system. Aggressive and strike the young
Autotoxic disease are less aggressive and strike the elderly. Much more prevalent than
autoimmune diseases
We postulate that the major driving force in AD is neuroinflammation. Activation of the innate
immune system
Treatment with Antiinflammatory drugs reduces the risk of Alzheimer Disease
0.20.0 0.4 0.6 0.8 1.0
controlNSAIDS > 6 mos (.65)
NSAIDS chronic (.5)NSAIDS >2y (.42)NSAIDS > 2y (.4)
NSAIDS > 2y (.2) Int Veld et al 2001
Rheumatoid Arthritis (.16) McGeer et al 1990
Yip et al 2005
Landi et al 2004
Zandi et al 2002
Stewart et al 1997
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.
IL6
JAKs/STATs
MAPK
Egr-1 p35
cdk5/p35 Tau-p
IL-6 R
GLIA StressOxidativeBeta Amyloid
Neuron
p38
NMDA
Ca2+
SIGNALING CASCADE EXPLAINING HOW IL-6 INDUCES TAU PHOSPHORYLATION
Quintanilla et al., 2005; Orellana et al., 2006, Maccioni et al., 2010
23
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.
As que por qu no mezclamos Shilajit Andino con Vitaminas
del complejo B?
Publication of the Oxford Study on vitamins B in AD
VISTA AEROFOTOGRAMTRICA
DEL REA MINERA CONTENIENDO LOS
DEPSITOS DE SHILAJIT ANDINO EN LA REGIN
DE ATACAMA.
LA REGION DEL ANDEAN COMPOUND
26
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 Phase II)
ICC GENERA BRAIN UP-10BRAIN UP-10RR
SOLUCION MEDICA
Tau antiaggregating activity(B) TAU + BRAINUP(A) TAU CONTROL
Neuritogenic action
(B) + BRAIN UP(A) CONTROL
Analisis morfomtrico de clulas del hipocampo expuestas a Brain Up-10
BRAIN UP-10R
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
Cornejo et al., J. Alz. Dis. 2011
BRAIN UP-10R
Study of the changes in the blood biomarker for platelets tau in relation to the treatment with formulation
Group of the clinical trial AD Patients* CONTROL**
+ Formulation +Placebo NormalRatio of HMW/LMW (for explanation please see ***)
Mean SD Mean SD Mean SDTime Zero (0 weeks) 2.967+/- 0.368 2.879 +/- 0.567 + 1.076 +/- 0.421 (1st. analysis)
Time 24 week 2.320 +/- 0.541 3.369 +/- 0.697+ 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
BRAIN UP-10R
NPI m
edia
50
40
30
20
10
Semana2412
0
0
Brain Up10PlaceboGrupo
Error bars: 95,00% CI
Med
ia N
PI
100
80
60
40
20
0
Semana2412
-20
0
Brain Up10PlaceboGrupo
Error bars: 95,00% CI
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).
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-10R 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 BIOMARKERS IN CSF
Anomalous brain tau.tau
Tau-P
PROTEOMIC DETECTION
APP Variants
Tau-P
Maccioni et al. (2006) Neurobiol Aging.
BIOMARCADORES UN PUENTE ENTRE LA CIENCIA BASICA Y LA CLINICA
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
Klunk WE. Neurobiology of Aging 1998; 19: 145-147
Niveles de (tau) en el CSF de pacientes con tres Niveles de (tau) en el CSF de pacientes con tres patologas neurolgicaspatologas neurolgicas
*
**
***
(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.
pg/m
l
AD: Alzheimers diseaseVaD: Vascular dementiaALS: Amyotrophic Lateral Sclerosis FTD: Frontotemporal Dementia
WWW.NEUROINOVATION.CL
Preclinical Phase Clinical Phase
(Diagnosis AD)
Time (in years)
Tau Oligomers
Biomarkers (e.g. Platelets tau.
Potential early diagnosis)
Deposits: Neurofibrilllary Tangles
Decline of Instrumental Activities of Daily Living
ESTRATEGIA BIOMARCADORES PARA DETECCION TEMPRANA AD
METHODOLOGYMETHODOLOGY
BIOMARKER
DIAGNOSIS TOOLS
VALIDATION CHILE(University Hospital)
VALIDATION USA (U. Pittsburgh)
DEVELOPMENT OF TECHNOLOGY
PROTOTYPE FOR THE DIAGNOSIS KIT
BIOMARCADOR NO INVASIVO DETECTA AD A NIVEL PRECLINICO
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
THS
LNS
ThS
A B C
D
LNS
LansoprazoleThioflavina S
50 m
Biosensor
Covalently inmobilized protein
Gold surface (50 nm)
Glass
Real time study of the interaction of LNS with tau filaments
Carboby methyldextran chains
Polymer Inmobilization conditions
PHF Buffer pH 2.95, 3hrs
Amyloid Buffer pH 4.46, 3hrs
-500
0
500
1000
1500
2000
2500
3000
3500
4000
-10 20 50 80 110 140 170 200
Time (s)
RU
SPR Lansoprazole with AD-PHFs (violet) and with fibrillary A (green)
AD-PHF
A
Nuestros esfuerzos estan orientados a mejorar la calidad de vida
Thanks / Gracias
PROPUESTAS PARA ACTIVAR EL DESARROLLO DE NUEVAS TECNOLOGIAS Y SU TRANSFERENCIA
1.- Capital Humano. En el mundo desarrollado son cientficos con experiencia en gestin.
2.- Polticas de estado en C&T. Los gobiernos han estado concentrados en emular un modelo de comercializacin clsico y desincentivan a los cientficos a participar y emprender
3.- Incentivo a la generacin de productos. Los fondos solo permiten comprobar hiptesis y no su proyeccin a la generacin de productos empaquetables.
4.- Necesidad de spin-offs. Incentivos en las universidades para transferir tecnologas.
5.- Redes para conectar con centros en el resto del mundo y provocar un spill over de buenas practicas internacionales al sistema.
6.- Atraer empresas y centros tecnolgicos del mundo hacia Chile (no es fcil porque stos no confan en la institucionalidad actual)
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