Diseases of the Nervous System:
Part II
Neal G. Simon, Ph.D. Professor, Dept of Biological
Sciences Lehigh University
Mood Disorders: Medial Prefrontal Network & Amygdala
Price & Drevets (2010)
Alzheimer’s Disease
Ø An estimated 5.2 million Americans have Alzheimer's Disease
Ø 6th leading cause of death in the United States
Ø $226 billion: the direct costs of care in the United States in 2015
Ø In 2050: 14 million people will have AD
Ø In 2050: $1.1 trillion: direct costs
Alzheimer’s Disease: Symptoms
Ø Memory loss that disrupts daily life
Ø Challenges in planning or problem solving
Ø Difficulty completing familiar tasks
Ø Confusion with time or place
Ø Trouble with visual images and spatial relationships
Ø New problems with words when speaking or writing
Ø Mood and personality changes
Ø The cortex shrivels up, damaging areas involved in thinking, planning and remembering.
Ø Shrinkage is especially severe in
the hippocampus, an area of the cortex that plays a key role in formation of new memories.
Ø Ventricles (fluid-filled spaces
within the brain) grow larger.
The Alzheimer’s Brain: Gross Anatomical Changes
alz.org / braintour
The Alzheimer’s Brain: Microscopic Changes
Ø Alzheimer's tissue has many fewer nerve cells and synapses than a healthy brain.
Ø PLAQUES, abnormal clusters
of protein fragments, build up between nerve cells.
Ø Dead and dying nerve cells contain TANGLES, which are made up of twisted strands of another protein.
alz.org / braintour
TAU Tangles
A sec&on from the hippocampus of an Alzheimer’s disease pa&ent stained with a tau an&body (TNT1 – recognizes amino acids 2-‐18, see below). Note the classical triad of tau pathologies in AD, 1) neurofibrillary tangles (arrowheads), 2) neuropil threads (arrows), and 3) a neuri&c plaque (asterisk).
Alz.org; Kanaan
Clinical & Biomarker Changes in Dominantly Inherited Alzheimer’s Disease
Bateman et al (2012)
Ø Amyloid Hypothesis: 3 genes can cause altered processing (APP, PSEN1, PSEN2)
Ø Compared Carriers & Non-‐Carriers (n =128)
Ø Clinical, CogniOve, Imaging, & Biochemical Assessments
Ø Normalized against parental age of onset
Ø Follows ADNI protocols and standards
COGNITIVE MARKERS
Bateman et al., 2012
† Scores on the CDR-‐SOB range from 0 (cogni&ve normality) to 18 (maximal cogni&ve impairment).‡ P<0.01. § P<0.001. ¶ Scores on the Mini–Mental State Examina&on (MMSE) range from 0 (severe impairment) to 30 (no impairment). A score higher than 27 is considered normal. Scores on the Logical Memory subtest of the Wechsler Memory Scale–Revised range from 0 (no recall) to 25 (complete recall). ** P<0.05.
PUTATIVE BIOMARKERS I
§ P<0.001. ** P<0.05. ‡ P<0.01
Precuneus: § episodic memory, visual-‐spa&al abili&es, and motor ac&vity coordina&on strategies. self
percep&on, consciousness, and the execu&ve and working memory.
§ at rest, the highest metabolic rates, consuming more glucose than any other cortex
§ Part of Default Mode Network
thebrain.mcgill.ca
PUTATIVE BIOMARKERS II
§ P<0.001. ** P<0.05. ‡ P<0.01
Alzheimer’s Biomarkers: Comparison of Clinical CogniOve, Structural. Metabolic, & Biochemical Changes vs. EsOmated Expected Years for Symptom Onset
Bateman et al (2012)
Data shown are differences between mutaOon carriers and non-‐carriers
Brain scans show evidence of Alzheimer’s disease 20 years before symptoms arise (far left), 10 years before (middle), and after the onset of symptoms (right). Beta amyloid, a protein associated with the disease, is more visible in people who develop the disease (top row) than in those who don’t. The more color in the scan, the more beta amyloid is present in the brain.
Predicting Alzheimer's Disease: Biomarkers
Bateman et al (2012)
What Would You Do?
Drug Discovery and Development
October 13, 2015
Neal G. Simon, Ph.D. Professor
Department of Biological Sciences
Discovery and Preclinical Development
I. Background
II. The R&D Landscape
III. InnovaOon and TransformaOon
IV. Clinical Trials in CNS Drug Development
V. Drug Pricing
US FDA
Drug Development Process
Drug Development Process
Biopharmaceutical Drug Development: Attrition
Drug Discovery
Pre-‐Clinical
5 years 1.5 years 6 years 2 years 2 years
Clinical Trials FDA Review Large Scale
Manufacturing/ Phase IV
IND Subm
ided
NDA
Sub
mided
250 Compounds 5 Compounds 10,000 Com-pound
s
1 FDA Approved
Drug
Quelle: Burrell Report Biotechnology Industry 2006
Phase I 20-‐100 Volunteers
Phase II 100-‐500 Volunteers
Phase III 1000-‐5000 Volunteers
II. The Research & Development Landscape
Sources: Congressional Budget Office (CBO). Research and development in the pharmaceu&cal industry. www.cbo.gov/sites/default/files/cbofiles/gpdocs/76xx/doc7615/10-‐02-‐drugr-‐d.pdf. Washington, DC: CBO; October 2006. Accessed March 2014. Pharmaceu&cal Research and Manufacturers of America (PhRMA). PhRMA annual membership survey, 1996-‐2014. Washington, DC: PhRMA; 2015
Source:Tugs Center for the Study of Drug Development (CSDD). Cost of developing a new drug. Briefing. Boston, Mass.: CSDD. Pubished November 2014. Accessed March 2015.
R&D Cost Model per NME
Paul et al (2010). Nature Rev Drug Discovery
Private & Public R&D Spending
III. InnovaOon and TransformaOon
InnovaOon Models and TransformaOon
Hu et al (2007)
Thank you for your Ome and adenOon