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1. Areas where new development tools could accelerate progress -- Formulation -- Glycosylation 2. Potentially important future areas of medical development -- Nanotechnology -- Tissue Engineering Other variables process 1 solvent 2 3 4 Impact of TransForm Technology Traditional

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1. Areas where new development tools could accelerate progress

-- Formulation

-- Glycosylation

2. Potentially important future areas of medical development

-- Nanotechnology

-- Tissue Engineering


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Other variables progress

process

1

solvent

2

3

4

Impact of TransForm Technology

Traditional

TransForm

# of F & F experiments

  • 200-20,000+

  • 10-20

Ability to explore F&F space more effectively and efficiently

Timing

  • 2 – 4 Weeks

  • 1 – 2 Months

Informatics;

data mining,

learning

  • Deep & iterative

  • Minimal


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Case Study: Ritonavir progress

  • 1.5 years after launch, converted into unanticipated form II polymorph

  • 50% less soluble

  • Abbott compelled to recall & reformulate

MPT 122 °C

MPT 125 °C

MPT 80 °C

MPT 97 °C

MPT 116 °C

Form I

Form II

Form III

Form IV

Form V

  • Within weeks at TransForm, using < 2g:

    • Both known forms identified & characterized

    • Found three novel, previously unreported forms

    • Novel, robust methods to make each form

Morissette et al. PNAS100, 2180 (2003).


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New Tools progress

  • Imaging

  • Informatics

  • Genomics

  • Proteomics

  • 5. Glycomics


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3 progress

B

N

R

A G C T A G C

-

-

C

H

O

S

O

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C

H

O

S

O

-

C

H

O

S

O

-

O

O

C

2

3

2

3

2

3

3

O

O

O

O

O

O

O

O

-

C

O

O

-

C

O

O

O

O

O

O

O

H

O

H

O

H

O

H

O

H

O

H

O

H

O

H

O

O

-

-

-

-

-

N

S

O

-

O

S

O

N

H

S

O

-

N

H

S

O

S

O

O

O

O

O

S

3

3

3

3

3

3

3

“Cracking the Code” of Sugars is

Analogous to the Sequencing of DNA

  • The sequencing of DNA has laid the foundation for biotechnology revolution

  • Like DNA and proteins, sugars play a central role in regulating basic biological activity, disease mechanisms, and drug action

  • Sugars exist as sequences of building blocks similar to DNA, but there has been a lack of adequate sequencing tools

  • Understanding of sugars is critical for polysaccharide drugs (e.g. Lovenox) and glycosylated proteins (e.g. Epogen)


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Inherent complexity of sugars has prevented comprehensive understanding

  • Structural complexity and information density

  • Lack of amplification

  • Heterogeneity

The Problem:

Lack of technology to and tools to sequence sugars has made it difficult to characterize and engineer sugars, and decipher their role in biology.


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ESI-MS understanding

NMR

Linkage information

Mass signatures

of groups

MALDI

-MS

Mass of chain

– chain length

Quantitative building block information

CE

Multiple Enzymes

Integration of Data

Convergence on unique solution to complex sequences

Sequencing Complex Polysaccharides [1999] Science 286: 537-542.Momenta Pharmaceuticals


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Future areas of medical development understanding

1. Nanotechnology

2. Tissue Engineering


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Prototype Device understanding

Silicon Nitride or Dioxide

Silicon

Active Substance

Cathode

Anode


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Implantable Drug Delivery System understanding

Battery-powered,

telemetry-controlled

implant

Design based on

pacemaker and ICD

microelectronics



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Pre-Clinical Studies Demonstrate understandingin vivo Release

  • Experimental Protocol

  • Implant microchips subcutaneously in rats

  • Release radioactive mannitol (388 ng/well non-metabolized sugar)

  • Collect urine and analyze for radioactive content

  • as an indicator of drug release


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hydrophilic block understanding

DNA

cationic block

polyplex

polymer-DNA complex

Polymer Therapeutics : Nanosized medicines

polymer-protein

conjugate

polymeric drug

or sequestrant

protein

Mw = 5 - 40,000 Da

~20nm

40-60 nm

5-15 nm

targeting residue

hydrophilic block

drug

linker

hydrophiobic block

drug

polymer-drug

conjugates

polymeric micelle

60-100 nm


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  • 1. How do you assess safety? understanding

  • 2. How do you characterize nanomedicines

  • --Biological

  • --Physical/chemical

  • 3. What animal models are appropriate?


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Annual Tissue Loss understandingEnd Stage Organ Failure (U.S.)

  • Over $500 billion in health care costs

  • 40 to 90 million hospital days

  • 8 million surgical procedures


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Bone understanding

Joint replacement 558,000

Bone graft 275,000

Internal fixation 480,000

Facial reconstruction 30,000

Cartilage

Patella 319,400

Meniscus 250,000

Arthritis (Knee) 149,900

Arthritis (Hip) 219,300

Small Joints 179,000

Tendon 33,000

Ligament 90,000

Skin

Burns, Sores, 3,650,000

Ulcers 1,100,000

Heart 754,000

Blood Vessels 606,000

Liver 205,000

Pancreas 728,000

Incidence of Organ and Tissue Deficiencies


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Biodegradable understandingPolymer Scaffold

In Vivo Implantation

New

Bone

Cartilage

Liver

Intestine

Ureter

In vitro Tissue Culture

Cells

Osteoblasts

Chondrocytes

Hepatocytes

Enterocytes

Urothelial Cells


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Cartilage Tissue Engineering understanding

BEFORE cell seeding

AFTER 2 weeks in culture


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System understanding

  • Modified PGA Tubes

  • 8 Weeks SMC Culture, then EC

  • Bio-Reactors – Pulsatile Radial Stress


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Medium understandingReservoir

Flow Direction

4 Bioreactors,

Assembled in parallel

20 cm

Pulsatile Pump

Compliance Chamber

Magnetic Stirplate


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Characteristics understanding

  • 50% Collagen

  • Rupture Strengths > 2000 mg Hg

  • Suture Retention – Strengths up to 90g

  • Demonstrates Contractile Responses to Serotonin, endothelin-1, and Prostaglandin F2α


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Human Embryonic Endothelial Cells Form Functional Blood-Carrying Microvessels

PECAM1

CD34


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  • How should safety be assessed? Blood-Carrying Microvessels

  • What are appropriate markers?

  • How do you determine appropriate function?

  • What are appropriate animal models?