More of the same? Voxelotor spawns a successor, but on what success does it build?

Ferrone, Frank A.

doi:10.1111/bjh.18785

Cited by 2 publications

(1 citation statement)

References 19 publications

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“…However, unlike in huHbA, the β-Glu6Val substitution in SCD promotes inter-tetrameric Hb interactions through a lateral contact with a hydrophobic pocket comprised of β-Ala70, β-Phe85, and β-Leu88 in a second Hb molecule (Fig. 1 a), which becomes surface-exposed by the R- to T-state conformational change, only then driving polymerization 37 – 39 . Hb polymerization is thought to occur through a double nucleation that begins with the formation of HbS fibers, followed by a nucleation of additional fibers on the surface of existing ones, resulting in RBC deformation and the subsequent deleterious effects of SCD.…”

Section: Introductionmentioning

confidence: 99%

Evaluating sheep hemoglobins with MD simulations as an animal model for sickle cell disease

Kuczynski,

Porada,

Atala

et al. 2024

Sci Rep

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Sickle cell disease (SCD) affects millions worldwide, yet there are few therapeutic options. To develop effective treatments, preclinical models that recapitulate human physiology and SCD pathophysiology are needed. SCD arises from a single Glu-to-Val substitution at position 6 in the β subunit of hemoglobin (Hb), promoting Hb polymerization and subsequent disease. Sheep share important physiological and developmental characteristics with humans, including the same developmental pattern of fetal to adult Hb switching. Herein, we investigated whether introducing the SCD mutation into the sheep β-globin locus would recapitulate SCD’s complex pathophysiology by generating high quality SWISS-MODEL sheep Hb structures and performing MD simulations of normal/sickle human (huHbA/huHbS) and sheep (shHbB/shHbS) Hb, establishing how accurately shHbS mimics huHbS behavior. shHbS, like huHbS, remained stable with low RMSD, while huHbA and shHbB had higher and fluctuating RMSD. shHbB and shHbS also behaved identically to huHbA and huHbS with respect to β2-Glu6 and β1-Asp73 (β1-Asn72 in sheep) solvent interactions. These data demonstrate that introducing the single SCD-causing Glu-to-Val substitution into sheep β-globin causes alterations consistent with the Hb polymerization that drives RBC sickling, supporting the development of a SCD sheep model to pave the way for alternative cures for this debilitating, globally impactful disease.

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Section: Introductionmentioning

confidence: 99%

Evaluating sheep hemoglobins with MD simulations as an animal model for sickle cell disease

Kuczynski,

Porada,

Atala

et al. 2024

Sci Rep

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The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease

Brothers,

Turrentine,

Akbar

et al. 2024

Blood

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Voxelotor is an inhibitor of sickle hemoglobin polymerization that is used to treat sickle cell disease. While voxelotor has been shown to improve anemia, the clinical benefit on the brain remains to be determined. This study quantified the cerebral hemodynamic effects of voxelotor in children with sickle cell anemia (SCA) using non-invasive diffuse optical spectroscopies. Specifically, frequency-domain near-infrared spectroscopy (FDNIRS) combined with diffuse correlation spectroscopy (DCS) were used to noninvasively assess regional oxygen extraction fraction (OEF), cerebral blood volume (CBV), and an index of cerebral blood flow (CBFi). Estimates of CBFi were first validated against arterial spin-labeled magnetic resonance imaging (ASL-MRI) in 8 children with SCA ages 8-18 y. CBFi was significantly positively correlated with ASL-MRI-measured blood flow (R2 = 0.651, p = 0.015). Next, a single-center, open label pilot study was completed in 8 children with SCA ages 4-17 y on voxelotor monitored prior to treatment initiation, and at 4, 8, and 12 weeks (NCT05018728). By 4 w, both OEF and CBFi significantly decreased, and these decreases persisted to 12 w (both p < 0.05). Decreases in CBFi were significantly correlated with increases in blood hemoglobin concentration (p = 0.025), while the correlation between decreases in OEF and increases in hemoglobin trended towards significance (p = 0.12). Given that previous work has shown that oxygen extraction and blood flow are elevated in pediatric SCA compared to controls, these results suggest that voxelotor may reduce cerebral hemodynamic impairments.

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More of the same? Voxelotor spawns a successor, but on what success does it build?

Cited by 2 publications

References 19 publications

Evaluating sheep hemoglobins with MD simulations as an animal model for sickle cell disease

Evaluating sheep hemoglobins with MD simulations as an animal model for sickle cell disease

The influence of voxelotor on cerebral blood flow and oxygen extraction in pediatric sickle cell disease

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