!

!
UNIVERSIDAD!DE!PUERTO!RICO,!!RECINTO!DE!CIENCIAS!MEDICAS!
UNIVERSITY!OF!PUERTO!RICO,!MEDICAL!SCIENCES!CAMPUS!
ESCUELA!DE!MEDICINA,!SCHOOL!OF!MEDICINE!
!
!!

DEPARTAMENTO!DE!BIOQUIMICA!
DEPARTMENT!OF!BIOCHEMISTRY!

Lecture!Notes!(complement!to!presentation!slides)!MPRI!7119,!Fall!
2013!
Dr.!Ricardo!Rossell!
Lectures(58,(Novel(Therapies.(

!
Complex!diseases!are!caused!by!a!combination!of!genetic,!environmental,!and!
lifestyle!factors,!most!of!which!have!not!yet!been!identified.!Several!diseases!fall!into!
this!category,!including!several!congenital!defects!and!a!number!of!adultMonset!
diseases.!
!!
Regenerative*medicine!or!stem*cell*therapy*is!the!"process!of!replacing!or!
regenerating!human!cells,!tissues!or!organs!to!restore!or!establish!normal!function".!
*
Stem*cells!are!biological!cells!found!in!all!multicellular!organisms,!that!can!divide!
(mitosis)!and!differentiate!into!diverse!specialized!cell!types!and!can!selfMrenew!to!
produce!more!stem!cells.!
!
Stem!cells!are!capable!of!dividing!and!renewing!themselves!for!long!periods.!Unlike!
muscle! cells,! blood! cells,! or! nerve! cellswhich! do! not! normally! replicate!
themselvesstem! cells! may! replicate! many! times,! or! proliferate.! A! starting!
population! of! stem! cells! that! proliferates! for! many! months! in! the! laboratory! can!
yield! millions! of! cells.! If! the! resulting! cells! continue! to! be! unspecialized,! like! the!
parent!stem!cells,!the!cells!are!said!to!be!capable!of!longMterm!selfMrenewal.!
!
Types*of*stem*cells*
!
Embryonic*Stem*Cells*(ESCs)!are!unspecialized!cells!that!can!give!rise!to!
specialized!cells.!!They!are!capable!of!dividing!and!self!renewing!for!long!periods!
under!appropriate!conditions.!!These!cells!are!typically!taken!from!blastocysts!that!
are!not!implanted!for!pregnancy!(invitro!fertilization).!!They!are!usually!frozen!for!
future!use!by!the!couple!who!produced!them,!or!are!ultimately!discarded.!
!
Some!disadvantages!to!ESCs!are!!
(1) Hard!to!control:!They!may!pass!through!several!intermediate!stages!before!
becoming!the!cell!type!needed!to!treat!a!particular!disease.!

1!

(2) Rejected!by!the!immune!system:!The!immune!profile!of!the!specialized!cells!
would!differ!from!that!of!the!recipient.!
(3) Ethically!controversial:!Many!who!believe!life!begins!at!conception!say!that!
the!informed!consent!by!patient!donors!does!not!remove!the!ethical!stigma!
of!doing!research!on!human!embryos.!
!
Advantages:!!Virtually!unlimited!pluripotent!potential!!
!!
Adult*stem*cells!have!been!identified!in!many!organs!and!tissues,!including!brain,!
bone!marrow,!peripheral!blood,!blood!vessels,!skeletal!muscle,!skin,!teeth,!heart,!
gut,!liver,!ovarian!epithelium,!and!testis.!They!are!thought!to!reside!in!a!specific!area!
of!each!tissue!(called!a!"stem!cell!niche").!
!
Stem!cells!may!remain!quiescent!(nonMdividing)!for!long!periods!of!time!until!they!
are!activated!by!a!normal!need!for!more!cells!to!maintain!tissues,!or!by!disease!or!
tissue!injury.!
!
Umbilical*Cord*Stem*Cells*with!the!consent!of!the!parents,!blood!can!be!collected!
from!the!umbilical!cord!of!a!newborn!baby!shortly!after!birth.!This!does!not!hurt!the!
baby!or!the!mother!in!any!way,!and!it!is!blood!that!would!otherwise!be!discarded!as!
biological!waste!along!with!the!placenta!(another!rich!source!of!stem!cells)!after!the!
birth.!
!
The!umbilical!cord!blood!contains!haematopoietic!stem!cells!M!similar!to!those!found!
in!the!bone!marrow!M!and!which!can!be!used!to!generate!red!blood!cells!and!cells!of!
the!immune!system.!Cord!blood!stem!cells!are!currently!used!to!treat!a!range!of!
blood!disorders!and!immune!system!conditions!such!as!leukaemia,!anaemia!and!
autoimmune!diseases.!These!stem!cells!are!used!largely!in!the!treatment!of!children!
but!have!also!started!being!used!in!adults!following!chemotherapy!treatment.!!
!
Although!all!other!stem!cells!are!being!tested!clinical!use,!only!umbilical!cord!stem!
cells!are!routinely!used!to!treat!disease!today.!!
!
Induced*Pluripotent*Stem*Cells*were!first!generated!by!Shinya!Yamanakas!team!
at!Kyoto!University,!Japan!in!2006.!Yamanaka!used!genes!that!had!been!identified!as!
particularly!important!in!embryonic!stem!cells!(ESCs),!and!used!retroviruses!to!
transduce!mouse!fibroblasts!with!a!selection!of!those!genes.!Eventually,!4!key!
pluripotency!genes!essential!for!the!production!of!pluripotent!stem!cells!were!
isolated;!OctM3/4,!SOX2,!cMMyc,!and!Klf4.!*
**

2!

*
*
!
These!cells!are!not!clinic!ready,!but!are!a!goldMstandard!for!modeling!disease!and!for!
studying!mechanisms.!!!
*
*
Cancer*Stem*Cell*(Hypothesis)*are!a!subset!of!cells!within!a!tumor!that!can!selfM
renew!and!elaborate!tumor!heterogeneity.*Properties!of!a!Cancer!Stem!Cell!include:*
!Rare!(but!exceptions!exist)!
!Unlimited!proliferative!potential!
!Can!selfMrenew!
!Can!differentiate!(source!of!tumor!heterogeneity)!
!Highly!clonogenic!
!Can!initiate!tumor/metastasis!with!few!cells!
!Generally!but!not!always!drug/radiation!resistant!
*
*
Biochemical*Properties*of*Stem*Cells:!!
!
*

3!

*
The*Stem*Cell*state!is!controlled!by!the!genetic!expression!and!environmental!cues!
that!maintain!these!properties.!!They!can!also!be!altered!with!small!molecules!that!
intervene!in!the!cell!regulatory!cycle!
!

4!

!
!
!
Many*novel*treatments*are*being*generated**
ClinicalTrials.GOV!
!
!
MicroRNA,*siRNA*and*Gene*Repair!
!
Small!interference!RNAMbased!therapies!
!!
siRNAs!are!21Mbp!double!strand!RNAs.!siRNAs!are!designed!against!messenger!
RNAs!that!abnormally!overexpressed!in!several!diseases.!
!
!

!
MicroRNAMbased!therapies!
MicroRNAs!are!small!nonMcoding!RNAs!that!regulates!gene!expression!at!the!postM
transcriptional!level.!
!!

5!

!
!
!
!
!
!
!
!
!
Personalized*Medicine**
!
Adverse!reactions!to!prescription!drugs!are!killing!about!106,000!Americans!each!
yearM!roughly!three!times!as!many!as!are!killed!by!automobiles.!This!makes!
prescription!drugs!the!fourth!leading!killer!in!the!U.S.,!after!heart!disease,!cancer,!
and!stroke.!
!!
!Traditional!clinical!diagnosis!and!management!focuses!on!the!individual!patient's!
clinical!signs!and!symptoms,!medical!and!family!history,!and!data!from!laboratory!
and!imaging!evaluation!to!diagnose!and!treat!illnesses.!!
!!
People!metabolize!drugs!differentlyand!thus!have!different!pharmacological!and!
toxicological!responses!to!drugsbecause!of!variations!in!their!genes.!
!
!

6!

Personalized!medicine!involves!identifying!genetic,!genomic,!and!clinical!
information!that!allows!accurate!predictions!to!be!made!about!a!person's!
susceptibility!of!developing!disease,!the!course!of!disease,!and!its!response!to!
treatment.!
!!
!!
Benefits!to!personalized!medicine:!
!
Ability!to!make!more!informed!medical!decisions!
Higher!probability!of!desired!outcomes!thanks!to!betterMtargeted!therapies!
Reduced!probability!of!negative!side!effects!
Focus!on!prevention!and!prediction!of!disease!rather!than!reaction!to!it!
Earlier!disease!intervention!than!has!been!possible!in!the!past!
Reduced!healthcare!costs!
!!
Downside:!
!
Genetic!Discrimination!
Privacy!

7!