Sickle cell anemia modulators

Jonathan Milhomens dos Santos Lima, PhD student

What is SCA?
Adult hemoglobin HbA Sickle hemoglobin HbS

α β α S
α β α S
Adapted from: Kato et al, Nature, 2018.

The first “molecular disease”

 Inside the cell
Oxygenated vessel

Deoxygenated vessel

The first “molecular disease”

A complex pathophysiology Adapted from: Kato et al, Nature, 2018.
 Adapted from: Piel et al, NEJM, 2017

A complex pathophysiology
 Adapted from: Piel et al, NEJM, 2017

A complex pathophysiology
Course changing Management of
therapies complications

Adapted from: Kato et al, Nature, 2018

Management
What about gene therapy?

Management
 ↓pO2
↓Temperature
INDUCES POLYMERIZATION ↓pH
↑[HbS]
↑[2,3-DPG]
↓HbS O2 affinity

α-thalassemia
INHIBITS POLYMERIZATION HbF
Genetic background

Adapted from: Eaton and Bunn, Blodd, 2017.

Disease modulators
A tiny bit on the biochemistry

Adapted from: Eaton and Bunn, Blood, 2017.

Disease modulators
Ratio T/R of Hb allosteric
forms

Adapted from: Eaton and Bunn, Blood, 2017.

Disease modulators
Ratio T/R of Hb allosteric
forms

Adapted from: Eaton and Bunn, Blood, 2017.

Disease modulators
Ratio T/R - 2,3DPG

Shifts the equilibrium

towards T state

Adapted from: Eaton and Bunn, Blood, 2017.

Disease modulators
Ratio T/R - ↓2,3DPG

Increase polymer delay time in 3 ways:

↑ R quartenary state
↑ HbS solubility
↑ intracellular pH

Adapted from: Eaton and Bunn, Blood, 2017.

Disease modulators
HBSS/αThalassemia-trait

Steiberg and Embury, Blood, 1986

Disease modulators
HBSS/αThalassemia-trait

A- Normal HBAA control

B- HBSS/__α/__α
C- HBSS/αα/__α
D- HBSS αα/αα nonthalassemic

Steiberg and Embury, Blood, 1986

Disease modulators
HBSS/αThalassemia-trait
A B C D
A- Normal HBAA control
B- HBSS αα/αα nonthalassemic
C- HBSS/αα/__α
D- HBSS/__α/__α

Glader et al., J Lab Clin Med, 1985

Disease modulators
 HbF
α S
HbS
✘ Naturally present in adult sickle α S
patients
α γ
HbF
✘ Different hemoglobin configurations α γ

✘ Halt in HbS polymerization α S

HbSF
α γ

Adapted from: Eaton and Bunn, Blood, 2017.

Fetal hemoglobin and SCA

 Inside the cell Oxygenated vessel

↓[HbS]

Deoxygenated vessel

Disruption of
the
polymerizatio
n

Oxygenated vessel

Fetal hemoglobin and SCA

 SCA
Severe Moderate Asymptomatic
phenotype phenotype phenotype

Cells with no
F-cells Truly protected F-cells
HbF

The role of HbF as a modulator of SCA

 Genetic background
✘ Haplotypes

✘ SNPs

✘ Ancestry/genetic admixture

Disease modulators
 Piel et al., NEJM, 2017

Haplotypes
Ancestry/genetic admixture
and SNPs

Solovieff et al., Blood,

2012
Baharian et al., PLOS,
2016
Steinberg et al., NEJM, 2009

Disease modulators
Nongenetic factors

Disease modulators
 Obrigado!
Perguntas?

Você pode me achar aqui:

jonathan.lima@hemocentro.fmrp.usp.br