Alexandra Ward, MA

This article was originally published in our sister publication 

Investigators evaluating a gene-editing strategy that seeks to reactivate developmentally silenced fetal hemoglobin (HbF, α2γ2) in order to replace defective sickle hemoglobin (HbS, α2βS2) in patients with 

 reported encouraging results in a late-breaking oral presentation at the 

American Society of Gene & Cell Therapy 25th Annual Meeting

 (ASGCT), held in Washington, DC, and virtually May 16-19, 2022.1

Findings from the early stage clinical trial targeting BCL11A erythroid specific enhancer to induce fetal hemoglobin suggest that disruption of the -115 BCL11A repressor binding site in the γ-globin gene promoters can stimulate therapeutically effective levels of HbF and is a promising approach for genomic SCD therapy.

First, the research team compared editing of BCL11A (-115) with ZBTB7A (-198) binding motifs to determine which target, when edited with the γ-globin gene promoters, would produce the most robust HbF induction.

“We electroporated Cas9-3xNLS ribonucleoprotein complexes (RNPs) into human primary CD34+ hematopoietic stem and progenitor cells (HSPCs) and attained high editing rates ranging from 76.2% to 85.7%,” investigators reported.

Investigators observed consistent and high indel mutations frequencies of 63.5% to 92.7% in all hematopoietic lineages with no apparent impairment of multilineage differentiation some 17 weeks after transplanting the edited CD34+ cells into immunodeficient 

They noted higher levels of HbF induction in erythroid progeny of CD34+ cells edited at the -115 γ-globin promoter target (31.8%) when compared with those edited at the - 198 ZBTB7A binding site (13%-18%).

The next step to further test the -115 γ-globin promoter editing approach in SCD patient cells was to edit plerixafor-mobilized CD34+ HSPCs from 1 healthy donor and 3 individuals with SCD.

“Seventeen weeks after transplanting edited cells into 

 mice, we observed consistently high rates of editing (75.1%) in all hematopoietic lineages, and substantial levels of HbF (27.6%) in erythroid progeny compared to controls (< 2.9%),” investigators reported. “Single cell western showed expression of gamma globin in a majority of edited erythroblasts (58%) compared to unedited controls (<6%). Moreover, RBCs derived from edited CD34+ cells from SCD patients exhibited significant 3-fold reduction in hypoxia-induced sickling.”

Lead author and presenter Varun Katta, senior research technologist at St. Jude Children's Research Hospital, reported that the team used CHANGE-seq discovery and rhAMP-seq validation and did not detect off-target mutations above background at 194 identified sites. Relying on PacBio-Hifi long-range sequencing, Katta and colleagues did note that a high-frequency large deletion occurred (4.9 kb) and resulted from simultaneous double strand beaks in HBG1 and HBG2 promoters.

“By digital droplet [polymerase chain reaction], we detected an average of 23.9% of this 4.9 kb deletion in engrafted cells at 17 weeks that has no apparent impact on erythropoiesis and HbF induction,” the team reported.

Next steps include plans for a future clinical trial in 2023 at St. Jude called the St. Jude Autologous Genome Edited Stem Cells (SAGES1) clinical trial.

Katta V, O’Keefe K, Wood R, et al. Genome editing of human hematopoietic stem cells to induce fetal hemoglobin for autologous cellular therapy of sickle cell disease. Presented at: American Society of Gene & Cell Therapy 25th Annual Meeting; May 16-19, 2022; Washington, DC. Accessed May 16, 2022. 

https://annualmeeting.asgct.org/global/am22/late-breaking-abstract-publication.aspx

Articles

In a late-breaking presentation at ASGCT 2022, investigators shared preclinical results of a gene-editing strategy that seeks to reactivate developmentally silenced fetal hemoglobin (HbF, α2γ2) in order to replace defective sickle hemoglobin (HbS, α2βS2).

Early Momentum for a Genomic Approach to Sickle Cell Disease Therapy

This article was originally published in ContagionLive.

How successful has the push for nursing homes to be used as a target for antibiotic stewardship efforts?

More than 3 million people receive care at these facilities each year in the US and many of the residents come directly from other health care settings. Because of this, there is a high prevalence of multidrug-resistant organisms and risk of adverse events from antibiotic use.

In research presented virtually at IDWeek 2021, investigators with the US Centers for Disease Control and Prevention (CDC) conducted a review of nursing home antibiotic stewardship citation deficiencies in order to improve implementation.

Here, presenting author Katryna Gouin, MPH, scientific data analyst with the CDC’s Office of Antibiotic Stewardship, details the top takeaways and clinical significance of the review.

Why are nursing homes a prime target in which to focus antibiotic stewardship efforts?

Nursing home residents are at high risk of infection and adverse events associated with antibiotic use including colonization and infection with antibiotic-resistant organisms and 

. An estimated 50-70% of nursing home residents will be prescribed 1 or more courses of systemic antibiotics in a year. Optimizing antibiotic prescribing in the nursing home setting is crucial to reduce the risk of adverse events from unnecessary or inappropriate antibiotic use. The Centers for Medicare & Medicaid Services (CMS) recognizes the importance of appropriate antibiotic use in this setting and requires antibiotic stewardship programs to be implemented in nursing homes. CMS requirements emphasize that nursing homes should develop and implement antibiotic use protocols and a system to monitor antibiotic use.

Can you summarize the key findings of the citation review?

In our analysis, we performed a quantitative and qualitative review of antibiotic stewardship citation deficiencies issued to nursing homes between September 2018 through July 2019 across 44 states. We found that the 631 nursing homes that received an antibiotic stewardship deficiency citation were more likely to be for-profit or have small bed size (≤ 99) compared with the 14,841 nursing homes that did not receive a citation. After review of 318 randomly selected citation texts, we categorized the citations into 1 or more of 4 main categories based on the 

CDC’s Core Elements of Antibiotic Stewardship for Nursing Homes

 related to antibiotic prescribing were the most common citation (67%), identified by either missing antibiotic prescribing protocols, missing documentation of criteria for antibiotic initiation, reassessment, or review upon nursing home admission or re-admission. Deficiencies in antibiotic 

 accounted for 40% of citations, in which nursing homes were commonly cited for either missing or incomplete antibiotic or infection surveillance logs. Deficiencies in 

 were identified in 23% of stewardship citations, commonly as the absence of an antibiotic stewardship policy available at the facility. Deficiencies in 

 in which surveyors identified that healthcare professionals lacked appropriate antibiotic stewardship training, accounted for 13% of citations.

Were there any noticeable trends among nursing homes with a high number of citations?

Differences in the number of core element categories cited per nursing home may be related to surveyor variability and different reporting requirements by state and region. We limited this analysis to antibiotic stewardship citations and did not evaluate other types of citation deficiencies in nursing homes. Future evaluations of infection prevention and control citation deficiencies alongside antibiotic stewardship citations could help to identify nursing homes that need additional support in implementing stewardship and infection prevention and control programs.

What are some ways to improve implementation of antibiotic stewardship in nursing homes?

There are several barriers related to implementing antibiotic stewardship in nursing homes, including limited antibiotic stewardship expertise, high rates of staff turnover in this setting, and high medical complexity of residents.

We identified actionable opportunities to improve antibiotic stewardship program implementation in nursing homes, including:

All facilities should have an antibiotic stewardship policy available that highlights the commitment to program goals, accountable roles, and action steps taken to implement antibiotic stewardship.

Facilities should implement antibiotic use protocols, which was one of the most common reasons for antibiotic stewardship citations. Protocols requiring documentation of criteria for antibiotic initiation and reassessment should be integrated into nursing home workflows to improve adherence.

Nursing home staff should receive antibiotic stewardship training to implement the facility policy and prescribing protocols.

This evaluation also highlighted that additional resources are needed to support nursing homes to have a system to monitor antibiotic use, as required by CMS regulations, including:

Antibiotic use tracking and reporting resources – ideally tracking antibiotic use at the facility level should be automated using either electronic health records or long-term care pharmacy dispensing data because manual tracking of antibiotics is time intensive.

Training resources for nursing home healthcare professionals to interpret antibiotic use data and identify where further evaluation is needed and opportunities for improvement exist.

The study, “Review of nursing home antibiotic stewardship citation deficiencies to identify opportunities to improve antibiotic stewardship implementation, 2018-2019,” was presented virtually at IDWeek 2021, held September 29-October 3, 2021.

In research presented virtually at IDWeek 2021, investigators with the US Centers for Disease Control and Prevention conducted a review of nursing home antibiotic stewardship citation deficiencies in order to improve implementation.

Deficiencies Found in Nursing Home Antibiotic Stewardship Implementation

In a late-breaking poster presented at the 

American Heart Association (AHA) 2019 Scientific Sessions

 in Philadelphia, investigators in Sri Lanka add a randomized controlled trial to the evidence base of mechanistic studies supporting the use of propranolol in hypertension.

The randomized, double-blinded, placebo-controlled clinical APROPRIATE trial evaluated propranolol’s efficacy in patients with resistant hypertension at the National Hospital of Sri Lanka. Patients with a high blood pressure who were on 3 or more antihypertensives and diagnosed by ambulatory blood pressure monitoring (ABPM) were included in the study. Exclusion criteria included whitecoat hypertension.

Over a course of 3 months, a total of 108 patients were screened, with 40 randomized 1:1 to receive either the 40 mg of the study drug 3 times per day or matching placebo.

The primary outcome was systolic and diastolic blood pressure (SBP/DBP) measured in office and on ABPM.

Baseline characteristics were well-balanced between study arms, with a baseline mean SBP of 159.72 mmHg vs 158.00 ± 10.82 mmHg in the propranolol and placebo groups, respectively. Mean baseline DBP was 90.28 mmHg vs 89.00 ± 15.49 mmHg in the propranolol and placebo groups, respectively.

Baseline values upon ABPM were comparative across the propranolol and placebo groups—total mean SBP (148.58 +/- 7.16 vs 153.58 +/- 12.73; p = 0.141), DBP (84.34 +/- 6.83 vs 81.82 +/- 18,74; P = 0.575), mean awake SBP (151.68 +/- 6.28 vs155.77 +/- 12.21; p = 0.192), mean awake DBP (86.54 +/- 6.96 vs 87.85 +/- 7.31; p = 0.565 ), mean sleep SBP values (135.19 +/- 35.22 vs 147.60 +/- 20.01; p = 0.179) and mean sleep DBP (75.72 +/- 19.77 vs 80.05 +/- 10.02; p = 0.387).

After 3 months of either treatment or placebo, patients in the propranolol arm recorded a significantly reduced mean office SBP of 130.00 (+/- 13.24) mmHg vs 139.93 (+/- 14.17) mmHg (p = 0.046). Mean office DBP was 77.83 (+/- 9.65) mmHg compared with 82.66 (+/- 8.58) mmHg in the propranolol and placebo groups, respectively (p = 0.142).

In the propranolol group vs placebo, mean ambulatory SBP was 137.28 +/- 12.55 vs 149.17 +/- 12.51; (p = 0.08) and the DBP 79.40 +/- 5.52 vs 84.08 +/- 8.44 (p = 0.05). Mean change from baseline in DBP was 5.422 +/- 6.14 mmHg in the propranolol group vs -3.48 +/- 15.59 in the placebo (p=0.031).

Investigators found that the treatment arm also displayed reductions in mean ambulatory SBP, awake SBP and DBP, and smaller variations between awake and sleep ABPM, although these results were not statistically significant. Symptomatic sinus bradycardia led to cessation of the drug for 1 patient. 

In conclusion, the study supports the efficacy of propranolol in lowering blood pressure in patients with resistant hypertension compared with placebo. 

The poster, “Addition of Propranolol in Resistant Arterial Hypertension Treatment (APROPRIATE Study) - A Randomized, Double Blinded, Placebo Controlled Clinical Trial,” was presented Saturday, November 16, 2019, at AHA 2019.

Patients in the propranolol arm recorded a significantly reduced mean office SBP of 130.00 (+/- 13.24) mmHg vs 139.93 (+/- 14.17) mmHg (p = 0.046).

APROPRIATE Study: Propranolol Cuts BP in Patients With Resistant Hypertension

 demonstrated that icosapent ethyl (IPE) has the ability to reduce cardiovascular events by 25%, but investigators have yet to fully explore the mechanism of benefit.

A research team led by Matthew J. Budoff, MD, with LA BioMed, set out to evaluate whether the addition of IPE, along with diet and statin therapy, can lead to a greater change from baseline in plaque volume measured by serial multidetector computed tomography (MDCT) compared with placebo in patients with high triglycerides (TG).

In interim findings presented in a late-breaking session at the 

 in Philadelphia, the EVAPORATE study demonstrated that the addition of IPE significantly slowed coronary plaque progression as compared to placebo over 9 months for 4 of the 5 secondary end points.

However, the mechanistic study’s primary end point of progression rates of low attenuation plaque was not statistically significant as of the 9-month interim mark. The trial will continue to 18 months.

Patients with coronary atherosclerosis, according to MDCT (1 or more angiographic stenoses with ≥20% narrowing), were included in the prospective, randomized, double-blind, placebo-controlled, multicenter study. Inclusion criteria comprised age ≥45 years, fasting TG levels ≥150 mg/dL and <500 mg/dL, LDL-C >40 mg/dL and ≤100 mg/dL, and on stable statin therapy (±ezetimibe) for ≥4 weeks prior to qualifying measurements for randomization.

Exclusion criteria included severe (NYHA class IV) heart failure, contrast allergy, renal insufficiency (eGFR <60), and hypersensitivity to fish and/or shellfish.

Patients had no history of myocardial infarction, stroke, or life-threatening arrhythmia within the prior 6 months, and no history of coronary artery bypass grafting. Baseline characteristics were well-balanced between the treatment and placebo arms.

A total of 80 patients were randomized to receive either IPE 4g/d or placebo.

Investigators performed interim scans at 9 months and are currently following the group for an additional 9 months with MDCT at 0, 9, and 18 months.

The primary end point was progression rates of low attenuation plaque volume as measured by MDCT and defined as -50 to 50 HU, with secondary end points including plaque morphology and composition, markers of inflammation (Lp-PLA2), and LDL-C and HDL-C.

The 9-month interim analysis shows that IPE slowed progression by 21% for low attentuation plaque (p=0.469), 19% for total non-calcified plaque (p=0.010), 42% for total plaque (p=0.0004), 57% for fibrous plaque (p=0.011), and 89% for calcified plaque (p=0.001).

Investigators also demonstrated that progression rates on mineral oil placebo is similar to a non-mineral oil placebo cohort using same the methodology, scanner, and laboratory, showing that the outcomes were benefits of IPE and not a harm of mineral oil.

The study, “Effect of Icosapent Ethyl on Progression of Coronary Atherosclerosis in Patients With Elevated Triglycerides (200-499mg/dl) on Statin Therapy (EVAPORATE Study),” was presented Monday, November 18, 2019, at AHA 2019.

The addition of IPE significantly slowed coronary plaque progression as compared to placebo over 9 months for 4 of the 5 secondary end points.