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Genetics

High efficacy of exagamglogene autotemcel in achieving transfusion independence in β-Thalassemia

25 Apr, 2024 | 23:29h | UTC

Study Design and Population:

This open-label, single-group, phase 3 trial investigated the efficacy of exagamglogene autotemcel (exa-cel), a nonviral CRISPR-Cas9 gene-edited cell therapy, in patients aged 12 to 35 with transfusion-dependent β-thalassemia. Various genotypes were included, and participants underwent myeloablative conditioning followed by exa-cel infusion. The primary endpoint was to achieve and maintain transfusion independence.

 

Main Findings:

Of the 52 patients treated, 35 with sufficient follow-up showed that 32 (91%) achieved transfusion independence for at least 12 months, significantly surpassing the study’s efficacy threshold. The average total hemoglobin during this period was 13.1 g/dL, with fetal hemoglobin averaging 11.9 g/dL and widely distributed across red cells. The treatment’s safety profile was compatible with the expected outcomes of myeloablative conditioning and autologous hematopoietic stem cell transplantation, with no reported deaths or cancer developments.

 

Implications for Practice:

The successful achievement of transfusion independence in a high percentage of patients suggests that exa-cel is a promising treatment option for transfusion-dependent β-thalassemia. This study supports the potential for gene-edited cell therapies to significantly improve outcomes in genetic blood disorders. Continued monitoring and further research are recommended to fully understand the long-term implications and safety of such treatments.

 

Reference: 

Reference: Locatelli, F. et al. (2024). Exagamglogene Autotemcel for Transfusion-Dependent β-Thalassemia. New England Journal of Medicine. doi: 10.1056/NEJMoa2309673.

CRISPR-Cas9 gene editing in sickle cell disease shows high efficacy in preventing vaso-occlusive crises

25 Apr, 2024 | 23:21h | UTC

Study Design and Population: This phase 3, single-group, open-label randomized clinical trial investigated the efficacy of exagamglogene autotemcel (exa-cel), a nonviral CRISPR-Cas9 gene-edited therapy, in patients aged 12 to 35 years with severe sickle cell disease. The study included patients who experienced at least two severe vaso-occlusive crises annually in the two years prior to screening. The therapeutic intervention involved editing CD34+ hematopoietic stem and progenitor cells (HSPCs) and administering a myeloablative conditioning regimen with busulfan.

Main Findings: Of the 44 participants treated, 30 with sufficient follow-up demonstrated a significant response. Ninety-seven percent (29 of 30) remained free from severe vaso-occlusive crises for at least 12 consecutive months, and 100% (30 of 30) avoided hospitalization for these crises over the same period. The intervention showed a high safety profile, consistent with myeloablative busulfan conditioning and autologous HSPC transplantation, with no cancers reported during the follow-up.

Implications for Practice: The results suggest that exa-cel can effectively eliminate severe vaso-occlusive crises in patients with sickle cell disease, marking a substantial advance in treatment options. These findings may pave the way for broader application of gene-editing therapies in hematologic diseases, pending further research on long-term outcomes and safety.

Reference: Frangoul, H. et al. (2024). Exagamglogene Autotemcel for Severe Sickle Cell Disease. N Engl J Med, Online ahead of print. DOI: 10.1056/NEJMoa2309676.

Cohort Study: The impact of rare kidney diseases on kidney failure and survival rates in the UK’s RaDaR cohort

22 Mar, 2024 | 11:29h | UTC

Study Design and Population: This cohort study utilized data from the UK National Registry of Rare Kidney Diseases (RaDaR), encompassing 27,285 participants aged 0-96 years with 28 types of rare kidney diseases, recruited from 108 renal care facilities across the UK. The primary outcomes assessed were the cumulative incidence of mortality and kidney failure, compared with those of a general population with chronic kidney disease (CKD).

Main Findings: Over a median follow-up of 9.6 years, participants with rare kidney diseases exhibited a significantly higher 5-year cumulative incidence of kidney failure (28%) compared to the broader UK CKD population (1%, p<0.0001). However, they also showed better survival rates, with a standardized mortality ratio of 0.42. There was considerable variability in median ages at kidney failure and death, time from dialysis start to death, and time from diagnosis to reaching specific eGFR thresholds among different rare diseases.

Implications for Practice: This study highlights the distinct trajectory of rare kidney diseases compared to more common forms of CKD, with higher rates of kidney failure but improved survival outcomes. These findings emphasize the over-representation of patients with rare kidney diseases in kidney replacement therapy cohorts and underscore the urgent need for targeted therapeutic interventions. Addressing this unmet need could significantly reduce the demand for long-term kidney replacement therapy, benefiting patients and easing healthcare system burdens.

Reference

Wong K, Pitcher D, Braddon F, Downward L, Steenkamp R, Annear N, et al. (2024). Effects of rare kidney diseases on kidney failure: a longitudinal analysis of the UK National Registry of Rare Kidney Diseases (RaDaR) cohort. The Lancet, 395(10223), P1234-P1245. DOI: https://doi.org/10.1016/S0140-6736(23)02843-X. Access the study here: Link

Clinical Trial Update | Long-term Givosiran treatment shows sustained acute hepatic porphyria symptom improvement

8 Aug, 2023 | 13:05h | UTC

Efficacy and safety of givosiran for acute hepatic porphyria: Final results of the randomized phase III ENVISION trial – Journal of Hepatology

Original Study: Phase 3 Trial of RNAi Therapeutic Givosiran for Acute Intermittent Porphyria – New England Journal of Medicine

 

Opinion | Regulating direct-to-consumer polygenic risk scores

7 Aug, 2023 | 14:59h | UTC

Regulating Direct-to-Consumer Polygenic Risk Scores – JAMA (free for a limited period)

 

Systematic Review | Rapamycin and rapalogs for tuberous sclerosis complex

25 Jul, 2023 | 13:43h | UTC

Rapamycin and rapalogs for tuberous sclerosis complex – Cochrane Library

 

Comparative Study | Genomic sequencing yields higher diagnostic results than targeted neonatal gene test in suspected genetic disorders

17 Jul, 2023 | 13:36h | UTC

Rapid Whole-Genomic Sequencing and a Targeted Neonatal Gene Panel in Infants With a Suspected Genetic Disorder – JAMA (link to abstract – $ for full-text)

Author Interview: Genomic Sequencing for Ill Newborns – JAMA

News Release: Genome sequencing highly effective at diagnosing genetic disorders in newborns and infants – Tufts University

 

Commentary on Twitter (thread – click for more)

 

Impact of newborn screening on severe combined immunodeficiency survival: results from a 36-year longitudinal study

14 Jul, 2023 | 12:45h | UTC

Measuring the effect of newborn screening on survival after haematopoietic cell transplantation for severe combined immunodeficiency: a 36-year longitudinal study from the Primary Immune Deficiency Treatment Consortium – The Lancet (link to abstract – $ for full-text)

News Release: Newborn screening facilitates early identification of infants with severe combined immunodeficiency – NIH/National Institute of Allergy and Infectious Diseases/News Medical

 

Commentary on Twitter

 

Case Series | Ambroxol therapy improves hematologic parameters in Gaucher disease patients

11 Jul, 2023 | 13:42h | UTC

Use of Ambroxol as Therapy for Gaucher Disease – JAMA Network Open

Editorial: Ambroxol as Therapy for Gaucher Disease—Ambitious but Ambivalent – JAMA Network Open

Commentary: Ambroxol Repurposing Improves Biochemical Markers in Gaucher Disease – HCP Live

 

Consensus Statement | Evaluation and management of deficiency of adenosine deaminase 2

30 Jun, 2023 | 14:53h | UTC

Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement – JAMA Network Open

Invited Commentary: Finding a Quorum in Deficiency of Adenosine Deaminase 2 Management – JAMA Network Open

 

Cohort Study | Coronary artery calcium score superior to polygenic score for CHD risk prediction

7 Jun, 2023 | 13:51h | UTC

Coronary Artery Calcium Score and Polygenic Risk Score for the Prediction of Coronary Heart Disease Events – JAMA (link to abstract – $ for full-text)

News Release: CT scan best at predicting heart disease risk in middle age: Scan beats genetics to gauge risk – Northwestern University

 

ASH 2023 Guidelines for management of venous thromboembolism | Thrombophilia testing

1 Jun, 2023 | 12:22h | UTC

American Society of Hematology 2023 Guidelines for Management of Venous Thromboembolism: Thrombophilia Testing – Blood Advances

 

RCT | Effectiveness of genotype-specific tricyclic antidepressant dosing in patients with major depressive disorder

23 May, 2023 | 12:52h | UTC

Effectiveness of Genotype-Specific Tricyclic Antidepressant Dosing in Patients With Major Depressive Disorder: A Randomized Clinical Trial – JAMA Network Open

 

Commentary on Twitter

 

Review | Hereditary colorectal, gastric, and pancreatic cancer

18 May, 2023 | 13:43h | UTC

Hereditary colorectal, gastric, and pancreatic cancer: comprehensive review – BJS Open

 

Commentary on Twitter

 

M-A | Quality of life after risk-reducing surgery for breast and ovarian cancer prevention

9 May, 2023 | 14:21h | UTC

Quality of life after risk-reducing surgery for breast and ovarian cancer prevention: a systematic review and meta-analysis – American Journal of Obstetrics and Gynecology

 

Review | Lynch syndrome genetics and clinical implications

4 May, 2023 | 13:24h | UTC

Lynch syndrome genetics and clinical implications – Gastroenterology

 

Cohort Study | Risk of multiple morbidities across the lifespan in people with Down syndrome or intellectual disabilities

28 Apr, 2023 | 13:19h | UTC

Multiple morbidity across the lifespan in people with Down syndrome or intellectual disabilities: a population-based cohort study using electronic health records – The Lancet Public Health

 

Commentary from the author on Twitter (thread – click for more)

 

Large-scale study finds genetic causes for 41% of rare pediatric diseases

18 Apr, 2023 | 13:25h | UTC

Genomic Diagnosis of Rare Pediatric Disease in the United Kingdom and Ireland – New England Journal of Medicine (free for a limited period)

News Release: 5,500 people diagnosed with rare genetic diseases in major research study – University of Exeter

Commentary: Study endeavors to strengthen genomic diagnosis of rare pediatric diseases in the United Kingdom and Ireland – News Medical

 

Commentary on Twitter

 

Phase 2 RCT | Dersimelagon in erythropoietic protoporphyrias

17 Apr, 2023 | 13:05h | UTC

Dersimelagon in Erythropoietic Protoporphyrias – News England Journal of Medicine (link to abstract – $ for full-text)

 

Commentary on Twitter

 

Cohort Study | Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer

17 Apr, 2023 | 12:57h | UTC

Cancer surveillance as an alternative to prophylactic total gastrectomy in hereditary diffuse gastric cancer: a prospective cohort study – The Lancet Oncology (link to abstract – $ for full-text)

Commentary: Endoscopic Surveillance in Patients at Risk for Hereditary Diffuse Gastric Cancer – The ASCO Post

 

Cohort Study | Value of screening for the risk of sudden cardiac death in young competitive athletes

12 Apr, 2023 | 13:11h | UTC

Value of screening for the risk of sudden cardiac death in young competitive athletes – European Heart Journal

Editorial: Optimizing pre-participation screening to prevent tragedy in young athletes: moving from if to how – European Heart Journal

 

AAP Clinical Report | Health supervision for children and adolescents with Marfan syndrome

10 Apr, 2023 | 13:51h | UTC

Health Supervision for Children and Adolescents With Marfan Syndrome – Pediatrics

 

Commentary on Twitter

 

Review | Comprehensive care of women with genetic predisposition to breast and ovarian cancer

5 Apr, 2023 | 13:32h | UTC

Comprehensive Care of Women With Genetic Predisposition to Breast and Ovarian Cancer – Mayo Clinic Proceedings

 

Gastric Cancer: the combined impact of H. pylori infection and pathogenic gene variants

3 Apr, 2023 | 13:51h | UTC

Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer – New England Journal of Medicine (link to abstract – $ for full-text)

News Release: Helicobacter Pylori Infection Modifies the Risk of Gastric Cancer Associated with Germline Pathogenic Variants in Homologous Recombination Genes – ESMO

Commentary: H. Pylori Infection Negatively Modifies Genetically Increased Risk for Gastric Cancer – Physician’s Weekly

 

Commentary on Twitter

 

RCT | Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention

31 Mar, 2023 | 13:26h | UTC

Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial – The Lancet (link to abstract – $ for full-text)

 

Commentary on Twitter (thread – click for more)

 

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