.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

Correlacion del progreso de la AD con el biomarcador de tau plaquetario: covariables edad & educacin p

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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