Monash researchers target gene variant for Sickle Cell Disease cure
A cure for sickle cell disease (SCD) may be possible from gene-editing that targets mutations in Krüppel-like factor 1 (KLF1) expression – a pathway linked to the switch from foetal haemoglobin (HbF) to adult haemoglobin (HbA) formation, Australian researchers say.
Researchers from Monash University were able to knockout KLF1 mutations via CRISPR-based editing – a DNA editing tool that allows researchers to locate mutated DNA variants, cut the DNA at that point and replace it with a new gene or gene fragment.
Investigators said that editing KLF1 may provide a way to target the ‘haemoglobin switching’ pathway and reactivate HbF in patients with SCD.
Following knockout of KLF1 in cells harvested from the peripheral blood of patients with SCD, investigators observed HbF levels at 40%-60%.
Lead investigator Dr Kevin Gillinder (PhD) said his team discovered two molecules, BCAM and ICAM-4 associated with vast-occlusive episodes in SCD, that were down-regulated in a KLF1 gene dosage-dependent manner. This suggested that reduced expression of both could provide additional benefit in treating SCD.
Together the findings indicated that editing KLF1 could provide ‘sufficient therapeutic benefit for patients with SCD’, the investigators said, though the gene-editing method would need to be explored in larger studies.
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Blood Groups linked to COVID-19 risk
ABO blood group may play a role in COVID-19 infection risk with group O being protective and group A conferring risks of higher disease susceptibility and severity, according to an international panel of haematology and pathology experts.
In a literature review published in Vox Sanguinis, the International Society of Blood Transfusion COVID-19 Working Group said the evidence supporting the association ranged from small observational studies, to genome-wide-association-analyses and country-level meta-regression analyses.
A number of hypotheses explaining the differences have been proposed – for example anti-A or anti-B antibodies present in group O individuals could bind to corresponding antigens on the viral envelope, neutralising the virus and preventing target cell infection. Another theory proposed that ABO type-associated variations in angiotensin-converting enzyme-1 activity and levels of von Willebrand factor (VWF) and factor VIII could also influence adverse outcomes, particularly in group A individuals who express high VWF levels.
But while evidence supporting such associations was ‘growing’ the Working Group said there was currently insufficient data for guiding policy based on the strength of available studies.
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High thrombotic events with CDK 4/6 inhibitors for breast cancer
Higher rates of thrombotic events in women with breast cancer on CDK 4/6 inhibitors have been reported in real-world practice compared to rates reported from clinical trials, according to US researchers.
Investigators at Oregon Health & Science University looked at rates of thrombosis in more than 260 adult breast cancer patients prescribed palbociclib, ribociclib, or abemaciclib.
The retrospective analysis revealed a much higher rate of events during treatment or within 30 days of CDK inhibitor discontinuation than reported in clinical trials with arterial thrombosis comprising over one-third of events. The highest incidence was with palbociclib followed by ribociclib, according to the study.
Researchers reported 29 thrombotic events occurring in 26 (9.8%) women. Of these events, 72% were venous and 34% were arterial. The 1‐year incidence of thrombosis was 10.4% overall, 10.9% on palbociclib, 8.3% on ribociclib, and 4.8% on abemaciclib.
Haemoglobin less than 10 g/dL was a statistically significant predictor of thrombosis (HR 3.53, P: .014) researchers note adding that thrombosis was associated with reduced overall survival (HR 1.28, P: .128, median 7.3 months) compared to not having a CDK‐associated clot (median 35.7 months).
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