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Impact of a grant program to spur advances in sickle cell disease research.

ABSTRACT: More than 20 years ago, clinical trials and federal grant support for sickle cell disease (SCD) research were not on par with support for other genetic diseases. Faced with the opportunity to spur research and advance treatments for SCD, and at the recommendation of advisors, the Doris Duke Charitable Foundation (DDCF) offered an SCD research funding opportunity starting in 2009 through its Innovations in Clinical Research Awards (ICRA) program. Twenty-eight new grants of $450 000 for direct costs over 3 years and 7 renewals were awarded, for a total investment of $17 million. Only about half the research teams garnered follow-on funding directly related to their ICRA projects, but the financial return on the research investment was substantial (∼4 times the original $17 million or 300%). All but 1 of the ICRA investigative teams published original research reports that acknowledged DDCF as a source of funding; the median number of publications per team was 3. Major innovations in the diagnosis and treatment of SCD included but were not limited to a demonstration that genetic modification of BCL11A enhancer is a potentially important treatment modality, establishment that plerixafor mobilization is safe and effective for those with SCD, development and validation of a new diagnostic called SCD BioChip, and evidence that hydroxyurea treatment is safe and efficacious in African children. These outcomes show that relatively small research grants can have a substantial return on investment and result in significant advances for a disease such as SCD.

SUBMITTER: Escobar Alvarez SN

PROVIDER: S-EPMC8679676 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sickle-trait hemoglobin (HbAS) confers nearly complete protection from severe, life-threatening falciparum malaria in African children. Despite this clear protection, the molecular mechanisms by which HbAS confers these protective phenotypes remain incompletely understood. As a forward genetic screen for aberrant parasite transcriptional responses associated with parasite neutralization in HbAS red blood cells (RBCs), we performed comparative transcriptomic analyses of Plasmodium falciparum in normal (HbAA) and HbAS erythrocytes during both in vitro cultivation of reference parasite strains and naturally occurring P. falciparum infections in Malian children with HbAA or HbAS. During in vitro cultivation, parasites matured normally in HbAS RBCs, and the temporal expression was largely unperturbed of the highly ordered transcriptional program that underlies the parasite's maturation throughout the intraerythrocytic development cycle (IDC). However, differential expression analysis identified hundreds of transcripts aberrantly expressed in HbAS, largely occurring late in the IDC. Surprisingly, transcripts encoding members of the Maurer's clefts were overexpressed in HbAS despite impaired parasite protein export in these RBCs, while parasites in HbAS RBCs underexpressed transcripts associated with the endoplasmic reticulum and those encoding serine repeat antigen proteases that promote parasite egress. Analyses of P. falciparum transcriptomes from 32 children with uncomplicated malaria identified stage-specific differential expression: among infections composed of ring-stage parasites, only cyclophilin 19B was underexpressed in children with HbAS, while trophozoite-stage infections identified a range of differentially expressed transcripts, including downregulation in HbAS of several transcripts associated with severe malaria in collateral studies. Collectively, our comparative transcriptomic screen in vitro and in vivo indicates that P. falciparum adapts to HbAS by altering its protein chaperone and folding machinery, oxidative stress response, and protein export machinery. Because HbAS consistently protects from severe P. falciparum, modulation of these responses may offer avenues by which to neutralize P. falciparum parasites. IMPORTANCE Sickle-trait hemoglobin (HbAS) confers nearly complete protection from severe, life-threatening malaria, yet the molecular mechanisms that underlie HbAS protection from severe malaria remain incompletely understood. Here, we used transcriptome sequencing (RNA-seq) to measure the impact of HbAS on the blood-stage transcriptome of Plasmodium falciparum in in vitro time series experiments and in vivo samples from natural infections. Our in vitro time series data reveal that, during its blood stage, P. falciparum's gene expression in HbAS is impacted primarily through alterations in the abundance of gene products as opposed to variations in the timing of gene expression. Collectively, our in vitro and in vivo data indicate that P. falciparum adapts to HbAS by altering its protein chaperone and folding machinery, oxidative stress response, and protein export machinery. Due to the persistent association of HbAS and protection from severe disease, these processes that are modified in HbAS may offer strategies to neutralize P. falciparum.

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Impact of a grant program to spur advances in sickle cell disease research.

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