Genetics & Rare Diseases
Phase 2 RCT: CRISPR-Based Therapy Reduces Attacks in Hereditary Angioedema
2 Jan, 2025 | 10:00h | UTCBackground: Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by unpredictable attacks of angioedema involving cutaneous tissues, the gastrointestinal tract, and, potentially, the larynx, posing a risk of asphyxiation. Current prophylactic treatments require frequent administration, often leading to suboptimal adherence and ongoing disease burden. NTLA-2002 is an in vivo CRISPR-Cas9–based therapy designed to permanently inactivate the KLKB1 gene in hepatocytes, thereby reducing plasma kallikrein levels and, hypothetically, lowering attack frequency in patients with HAE.
Objective: To evaluate whether a single intravenous infusion of NTLA-2002 (25 mg or 50 mg) would safely and effectively decrease HAE attack rates and reduce plasma kallikrein protein levels over a 16-week primary observation period, as compared with placebo.
Methods: This phase 2, randomized, double-blind, placebo-controlled trial included 27 adults with confirmed type 1 or type 2 HAE. Participants were assigned in a 2:2:1 ratio to receive a one-time dose of 25 mg or 50 mg of NTLA-2002 or placebo. The primary endpoint was the investigator-confirmed number of angioedema attacks per month from Week 1 through Week 16. Secondary endpoints included the number of moderate-to-severe attacks, use of on-demand therapy, adverse events, and changes in total plasma kallikrein protein levels (analyzed by immunoassays). Exploratory measures encompassed patient-reported outcomes using the Angioedema Quality of Life (AE-QoL) questionnaire.
Results: During the 16-week period, the mean monthly attack rate decreased by 75% in the 25 mg group and 77% in the 50 mg group relative to placebo (estimated rates of 0.70 vs. 0.65 vs. 2.82 attacks per month, respectively). Notably, 4 of 10 patients (40%) in the 25 mg group and 8 of 11 (73%) in the 50 mg group reported no attacks or further prophylaxis use after dosing. Placebo recipients showed only a 16% reduction from baseline. Adverse events were predominantly mild to moderate; headache, fatigue, and nasopharyngitis were most common. Infusion-related reactions occurred in a few patients but resolved without sequelae. A single transient grade 2 elevation in alanine aminotransferase was recorded in one participant given 25 mg of NTLA-2002. By Week 16, total plasma kallikrein levels decreased by 55% in the 25 mg group and 86% in the 50 mg group, with no meaningful changes in placebo.
Conclusions: A single intravenous infusion of NTLA-2002 significantly lowered attack frequency and reduced total plasma kallikrein levels in HAE. Most patients treated at 50 mg experienced no attacks, suggesting that long-term prophylaxis might be unnecessary for many. Longer observation supports durability, yet cost and potential long-term effects of gene editing warrant cautious interpretation.
Implications for Practice: If confirmed by larger phase 3 trials, this gene-editing approach could alter the management of HAE, reducing or eliminating the need for continuous prophylaxis. However, clinicians must weigh the high upfront cost, possible unpredictable immune responses, and the novelty of CRISPR-based therapies before integrating them into standard care.
Study Strengths and Limitations: Strengths include a placebo-controlled design, meaningful improvement in patient-reported outcomes, and robust plasma kallikrein protein reduction. Limitations are the small sample size, short primary observation period, and uncertain long-term safety in diverse populations.
Future Research: Ongoing phase 3 studies with larger cohorts and extended follow-up are essential to confirm safety, long-term efficacy, and cost-effectiveness.
Reference: Cohn DM, Gurugama P, Magerl M, et al. CRISPR-Based Therapy for Hereditary Angioedema. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMoa2405734
- Editorial: Musunuru K. A Milestone for Gene-Editing Therapies. New England Journal of Medicine. 2024; DOI: http://doi.org/10.1056/NEJMe2412176
RCT: Lipoprotein(a) and LDL-C as Independent Cardiovascular Risk Factors in Statin Trials
5 Nov, 2024 | 17:50h | UTCBackground: Low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) [Lp(a)] are both known risk factors for atherosclerotic cardiovascular disease (ASCVD). However, the interaction between Lp(a) and LDL-C levels in relation to ASCVD risk, especially in the context of LDL-C-lowering treatments like statins, remains unclear. This study aimed to clarify if LDL-C reduction impacts Lp(a)-associated ASCVD risk.
Objective: This meta-analysis examined whether LDL-C reduction with statins affects ASCVD risk mediated by elevated Lp(a) levels.
Methods: Data from 27,658 participants across six statin trials were analyzed, including both placebo and statin groups. ASCVD risk was assessed using multivariable Cox proportional hazards models with adjustments for various cardiovascular risk factors. The study evaluated continuous associations between Lp(a) levels, LDL-C levels, and ASCVD risk.
Results: Elevated Lp(a) levels were associated with higher ASCVD risk across all LDL-C levels, even among patients with the lowest LDL-C achieved through statin therapy. Statin-treated patients with Lp(a) >50 mg/dL exhibited a significantly higher ASCVD risk, even in the lowest quartile of achieved LDL-C (HR 1.38, 95% CI 1.06–1.79). The highest risk was observed in individuals with both elevated Lp(a) and LDL-C levels (HR 1.90, 95% CI 1.46–2.48).
Conclusions: Lp(a) and LDL-C are independent risk factors for ASCVD, with LDL-C lowering alone insufficient to mitigate the risk associated with elevated Lp(a).
Implications for Practice: These findings underscore the need for distinct strategies to manage patients with elevated Lp(a), particularly as LDL-C reduction alone does not fully address the associated ASCVD risk.
Study Strengths and Limitations: This study’s strength lies in its large participant pool and robust statistical analysis; however, variability in Lp(a) measurement methods across trials may limit precision.
Future Research: Investigations into therapies specifically targeting Lp(a) may offer additional ASCVD risk reduction beyond LDL-C lowering alone.
Summary of the review “Lipoprotein(a) and Cardiovascular Disease”
23 Sep, 2024 | 21:22h | UTCSummary of the review “Lipoprotein(a) and Cardiovascular Disease“
By Prof Børge G Nordestgaard and Anne Langsted
Key Takeaways for Practicing Physicians:
- Significance of Lipoprotein(a) [Lp(a)]:
- Causal Risk Factor: Elevated Lp(a) is a genetically determined causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve stenosis.
- Prevalence: Approximately 1 in 5 individuals globally have high Lp(a) levels, increasing their cardiovascular risk.
- Genetic Determinants and Ethnic Variations:
- Genetic Influence: Over 90% genetically determined with minimal lifestyle impact.
- Ethnic Differences:
- Lowest levels: East Asians, Europeans, Southeast Asians.
- Intermediate levels: South Asians, Middle Easterners, Latin Americans.
- Highest levels: Individuals of African descent.
- Sex Differences: Postmenopausal women have about 17% higher Lp(a) levels than men.
- Clinical Measurement and Interpretation:
- When to Measure:
- Once in a Lifetime: Recommended for all individuals to measure Lp(a) at least once.
- High-Risk Patients: Especially important in those with premature ASCVD, familial hypercholesterolaemia (FH), family history of elevated Lp(a) or early ASCVD.
- Stability of Levels: Lp(a) levels are stable after age two and are unaffected by most lifestyle factors.
- Interpreting Levels:
- Elevated Risk Thresholds:
- >30 mg/dL (≥62 nmol/L): Increased risk begins.
- >50 mg/dL (≥105 nmol/L): Clinically significant high risk.
- >90 mg/dL (≥190 nmol/L): Severe risk, comparable to FH.
- Elevated Risk Thresholds:
- Laboratory Considerations:
- Assay Selection: Use isoform-independent assays with standardized calibration.
- Reporting Units: Preferably in nmol/L; however, mg/dL is acceptable with appropriate conversion.
- When to Measure:
- Impact on Patient Care:
- Risk Stratification:
- Independent Risk Factor: High Lp(a) increases ASCVD risk independent of other lipids.
- Reclassification: Can reclassify patients into higher risk categories, influencing management decisions.
- Management Strategies:
- Current Limitations: No approved therapies specifically targeting Lp(a) reduction.
- Aggressive Risk Factor Control:
- LDL Cholesterol: Intensive lowering with high-intensity statins, ezetimibe, and PCSK9 inhibitors.
- PCSK9 Inhibitors: Lower Lp(a) by ~25% and reduce cardiovascular events.
- Lifestyle Modifications: Emphasize smoking cessation, healthy diet, physical activity, and weight management.
- Blood Pressure and Diabetes Management: Optimize control per guidelines.
- LDL Cholesterol: Intensive lowering with high-intensity statins, ezetimibe, and PCSK9 inhibitors.
- Avoid Unproven Therapies: Niacin is not recommended due to side effects and lack of cardiovascular benefit.
- Risk Stratification:
- Familial Hypercholesterolaemia (FH):
- Dual Risk: Elevated Lp(a) often coexists with FH, compounding cardiovascular risk.
- Screening: Measure Lp(a) in all patients with FH and consider cascade screening in families.
- Emerging Therapies:
- Gene-Silencing Drugs:
- Pelacarsen, Olpasiran, Lepodisiran: Lower Lp(a) levels by 80–98%.
- Administration: Subcutaneous injections, varying from monthly to quarterly.
- Small Molecule Inhibitors:
- Muvalaplin: Oral agent reducing Lp(a) by ~65%.
- Clinical Trials:
- Phase 3 Trials Ongoing: Evaluating cardiovascular outcomes with significant Lp(a) reduction.
- Potential Change in Practice: These therapies may soon provide effective options for patients with high Lp(a).
- Gene-Silencing Drugs:
- Practical Recommendations:
- Include Lp(a) in Lipid Panels: Encourage laboratories to add Lp(a) measurements to standard profiles.
- Patient Communication:
- Educate on Risks: Explain the significance of high Lp(a) and its genetic nature.
- Lifestyle Advice: Reinforce the importance of modifiable risk factor control.
- Family Screening: Consider evaluating first-degree relatives due to genetic inheritance patterns.
- Monitoring and Follow-Up:
- Re-measurement: Generally, one measurement suffices unless a significant event (e.g., menopause) occurs.
- Acute Phase Reactant Consideration: Be cautious interpreting levels during acute illness; recheck once stabilized.
Conclusion:
Elevated Lp(a) is a significant and prevalent cardiovascular risk factor that is largely genetic and stable throughout life. While direct treatments are on the horizon, current management focuses on aggressive modification of other cardiovascular risk factors. Measurement of Lp(a) should become a routine part of cardiovascular risk assessment, guiding more personalized and effective patient care.
RCT: Vutrisiran Reduces Mortality and Cardiovascular Events in Patients with Transthyretin Amyloidosis Cardiomyopathy
6 Sep, 2024 | 21:57h | UTCStudy Design and Population: This double-blind, randomized clinical trial evaluated the efficacy of vutrisiran in 655 patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM). Participants were randomly assigned to receive either vutrisiran (25 mg) or placebo every 12 weeks for up to 36 months. The study population included patients both with and without baseline tafamidis treatment.
Main Findings: Vutrisiran treatment significantly reduced the risk of death from any cause and recurrent cardiovascular events compared to placebo (HR: 0.72, 95% CI: 0.56–0.93, p=0.01). In monotherapy patients (no tafamidis), the hazard ratio was 0.67 (95% CI: 0.49–0.93, p=0.02). Vutrisiran also preserved physical function, showing less decline in the 6-minute walk test distance (mean difference: 26.5 meters, p<0.001) and quality of life (mean KCCQ-OS difference: 5.8 points, p<0.001). Adverse events were comparable between groups.
Implications for Practice: Vutrisiran offers a promising treatment option for reducing mortality, cardiovascular events, and functional decline in ATTR-CM patients. Its favorable safety profile supports its potential use in long-term management.
Randomized Clinical Trial: Aficamten improves peak oxygen uptake in symptomatic obstructive hypertrophic cardiomyopathy – N Engl J Med
27 May, 2024 | 20:24h | UTCStudy Design and Population: This phase 3, double-blind trial randomized 282 adults with symptomatic obstructive hypertrophic cardiomyopathy (HCM) to receive aficamten or placebo for 24 weeks. The primary outcome was the change in peak oxygen uptake, with secondary outcomes including changes in the Kansas City Cardiomyopathy Questionnaire score and New York Heart Association functional class.
Main Findings: Aficamten significantly increased peak oxygen uptake by 1.7 ml/kg/min (95% CI, 1.0 to 2.4; P<0.001) compared to placebo. Improvements were also seen in all secondary outcomes. The incidence of adverse events was similar between the groups.
Implications for Practice: Aficamten shows promise in improving exercise capacity and symptoms in patients with obstructive HCM, potentially offering a new therapeutic option. Further research may confirm its long-term benefits and safety.
Reference (link to abstract – $ for full-text):
APA workgroup update maintains skepticism on pharmacogenomic tools for depression – Am J Psychiatry
25 May, 2024 | 19:47h | UTCA recent review by the American Psychiatric Association (APA) Council of Research Workgroup on Biomarkers and Novel Treatments revisits the use of pharmacogenomic (PGx) tools for selecting depression treatments. The review assesses new clinical trials and meta-analyses conducted from 2017 to 2022. Of the studies analyzed, few demonstrated significant efficacy in treatment response using PGx tools, with many suffering from methodological flaws such as lack of full blinding and insufficient control measures. Despite some trials showing promise, the overall evidence remains insufficient to support the widespread clinical application of PGx tools in managing major depressive disorder. The Workgroup reaffirms the 2018 conclusions and aligns with the U.S. Food and Drug Administration’s stance, recommending that future research should focus on more rigorous study designs and explore other potential benefits of pharmacogenomics, such as predicting rare adverse drug reactions.
Reference (link to abstract – $ for full-text)
Phase 1-2 Study: Safety and efficacy of EDIT-101 CRISPR-Cas9 treatment for CEP290-associated retinal degeneration – N Engl J Med
25 May, 2024 | 19:42h | UTCThis study evaluates the safety and effectiveness of EDIT-101, a CRISPR-Cas9 gene-editing therapy, in treating inherited retinal degeneration caused by CEP290 IVS26 variants. Conducted as a phase 1-2, open-label, single-ascending-dose trial, it involved 14 participants (12 adults aged 17-63 and 2 children aged 9 and 14) who received subretinal injections of EDIT-101. Treatment doses varied, with two participants at a low dose, seven at an intermediate dose, and five at a high dose. The primary safety assessment showed no serious adverse events or dose-limiting toxic effects. Notably, 64% of participants exhibited significant improvements in visual acuity, retinal sensitivity to red light, or mobility. Additionally, improvements in vision-related quality of life were documented in six participants. These promising results suggest that EDIT-101 is safe and potentially effective, warranting further investigation into CRISPR-Cas9 gene therapy for similar genetic retinal conditions.
Commentary on X:
Original Article: Gene Editing for CEP290-Associated Retinal Degeneration (BRILLIANCE) https://t.co/LgSs2RGBZv #ARVO2024 @ARVOinfo pic.twitter.com/WztX2OvzXM
— NEJM (@NEJM) May 7, 2024
Reference (link to abstract – $ for full-text):
Cohort Study: APOE4 Homozygosity as a Distinct Genetic Form of Alzheimer’s Disease with Early Biomarker Changes – Nat Med
25 May, 2024 | 18:55h | UTCThis cohort study investigated the impact of APOE4 homozygosity on Alzheimer’s disease (AD) by analyzing clinical, pathological, and biomarker data. The study utilized data from the National Alzheimer’s Coordinating Center and five additional large cohorts, comprising a total of 3,297 individuals for the pathological study and 10,039 for the clinical study. Results demonstrated that APOE4 homozygotes exhibited almost universal AD pathology and had significantly higher levels of AD biomarkers from age 55, compared to APOE3 homozygotes. By age 65, nearly all APOE4 homozygotes showed abnormal amyloid levels in cerebrospinal fluid, and 75% had positive amyloid scans, indicating a high biological penetrance of AD. These individuals also exhibited an earlier onset of symptoms, around age 65.1, and the progression and predictability of biomarker changes paralleled those observed in autosomal dominant AD and Down syndrome. However, in the dementia stage, amyloid and tau positron emission tomography scans showed no differences across haplotypes. The study concludes that APOE4 homozygosity represents a genetically distinct form of AD, underscoring the importance of tailored prevention strategies and treatments.
Reference (link to abstract – $ for full-text):
2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy – J Am Coll Cardiol
11 May, 2024 | 14:20h | UTCIn a significant advancement for the treatment of hypertrophic cardiomyopathy (HCM), the American Heart Association and the American College of Cardiology, along with other leading societies, have released updated guidelines to optimize patient care. Here are the essential updates and recommendations for practicing physicians:
1 – Updated Diagnostic Strategies: The guideline emphasizes the use of advanced imaging techniques and genetic testing to enhance diagnostic accuracy, enabling personalized treatment approaches.
2 – Risk Assessment Tools: Revised tools for sudden cardiac death (SCD) risk assessment are detailed, aiding clinicians in making informed decisions regarding the use of implantable cardioverter-defibrillators (ICDs).
3 – Management of Obstructive HCM: New recommendations for the pharmacological treatment of symptomatic obstructive HCM include the use of disopyramide and advanced therapies such as septal reduction when initial medication does not suffice.
4 – Guidelines on Exercise and Lifestyle: The guidelines provide a nuanced approach to physical activity, recognizing the benefits while outlining the risks for patients with HCM. Detailed advice is offered on managing competitive sports involvement and other lifestyle considerations.
5 – Multidisciplinary Approach: The guidelines advocate for a team-based approach involving specialized HCM centers, ensuring patients benefit from comprehensive expertise and the latest treatment modalities.
6 – Innovations in Treatment: Highlighting new therapeutic options like myosin inhibitors, the guidelines underscore their role in managing obstructive symptoms when traditional medications are inadequate.
7 – Special Populations: Detailed sections on the management of HCM in children and pregnant women, addressing the unique challenges these groups face.
These guidelines represent a cornerstone in the evolving landscape of HCM management, embodying a commitment to enhancing outcomes and quality of life for patients through evidence-based practices and collaborative care.
Reference (link to free full-text):
RCT: No significant benefit of adjuvant prednisone for patients with cystic fibrosis with exacerbations unresponsive to antibiotics – Eur Respir J
6 May, 2024 | 06:32h | UTCThis randomized, double-blind, placebo-controlled trial investigated the effectiveness of adjuvant oral prednisone in enhancing lung function recovery in patients with cystic fibrosis (CF) experiencing pulmonary exacerbations (PExs) unresponsive to initial intravenous (IV) antibiotic treatment. The study involved 173 participants, with 76 not achieving more than 90% of their baseline forced expiratory volume in one second (ppFEV1) by Day 7 of antibiotic treatment and subsequently randomized to receive either oral prednisone (1 mg·kg−1 twice daily, up to 60 mg/day) or placebo for an additional 7 days. Results showed that 50% of the prednisone group and 39% of the placebo group recovered over 90% of their baseline ppFEV1 by Day 14. However, the difference was not statistically significant (11% difference; 95% CI -11, 34%; p=0.34). Additionally, prednisone did not significantly prolong the time to the next exacerbation compared to placebo. This study concludes that adjuvant oral prednisone does not significantly improve lung function recovery or delay subsequent exacerbations in CF patients not responding to initial antibiotic therapy.
Reference (link to abstract – $ for full-text):
Randomized Crossover Trial: Prophylactic recombinant ADAMTS13 prevents acute events in congenital thrombotic thrombocytopenic purpura – N Engl J Med
6 May, 2024 | 06:22h | UTCThis study evaluates the efficacy and safety of recombinant ADAMTS13 compared to standard plasma-derived therapy in managing congenital thrombotic thrombocytopenic purpura (TTP). In a phase 3, open-label, crossover trial involving 48 patients, each participant underwent two 6-month prophylaxis periods, receiving either recombinant ADAMTS13 or standard therapy, followed by a switch to the alternate treatment. Results indicate that recombinant ADAMTS13 prevented acute TTP events during prophylaxis, with no events recorded, versus one event under standard therapy. Furthermore, recombinant ADAMTS13 was associated with significantly lower rates of thrombocytopenia and adverse events compared to standard therapy. The treatment increased ADAMTS13 activity to approximately 100% of normal levels, with no development of neutralizing antibodies. Overall, recombinant ADAMTS13 was found to be safe and more effective than standard therapy in preventing TTP events and manifestations.
Reference (link to abstract – $ for full-text):
RCT: Beta-blockers post myocardial infarction showed no benefit in patients with preserved ejection fraction
30 Apr, 2024 | 13:40h | UTCThis randomized, open-label clinical trial conducted across 45 centers in Sweden, Estonia, and New Zealand examined the impact of long-term beta-blocker treatment in patients with acute myocardial infarction (AMI) who had undergone coronary angiography and had a preserved left ventricular ejection fraction (LVEF ≥ 50%). The study involved 5020 patients, predominantly from Sweden, with a median follow-up of 3.5 years. Participants were randomly assigned to receive either a beta-blocker (metoprolol or bisoprolol) or no beta-blocker. The primary endpoint was a composite of death from any cause or new myocardial infarction. The results showed no significant difference in the primary endpoint between the beta-blocker group (7.9%) and the no–beta-blocker group (8.3%) with a hazard ratio of 0.96 (95% CI, 0.79 to 1.16; P=0.64). Additionally, no significant differences were observed in secondary endpoints such as death from cardiovascular causes, myocardial infarction, or hospitalizations for atrial fibrillation and heart failure. Safety endpoints were also comparable between the groups. Overall, long-term beta-blocker treatment did not confer a reduction in risk for the primary composite endpoint or improve secondary outcomes in this patient population.
Commentary on X:
Original Article: Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction (REDUCE-AMI trial) https://t.co/z1NNeAK9Mm
Editorial: Routine Beta-Blockers in Secondary Prevention — On Injured Reserve https://t.co/NzlExH0LZm #ACC24 pic.twitter.com/8Jqpj2dM6E
— NEJM (@NEJM) April 17, 2024
Reference (link to abstract – $ for full-text):
RCT: Olezarsen effectively reduces triglyceride levels and pancreatitis episodes in familial chylomicronemia Syndrome
28 Apr, 2024 | 16:47h | UTCThis phase 3, double-blind, placebo-controlled trial evaluated olezarsen in 66 patients with familial chylomicronemia syndrome. Participants received 80 mg or 50 mg of olezarsen or a placebo subcutaneously every 4 weeks for 49 weeks. The study found significant reductions in fasting triglyceride levels at the 6-month mark in the 80 mg olezarsen group compared to the placebo (-43.5 percentage points), with a similar trend observed in apolipoprotein C-III levels. Furthermore, the incidence of acute pancreatitis was significantly lower in both olezarsen groups compared to placebo by the 53-week endpoint. The findings suggest olezarsen as a potent therapy for reducing triglyceride levels and preventing pancreatitis in this population.
Reference (link to abstract – $ for full-text):
High efficacy of exagamglogene autotemcel in achieving transfusion independence in β-Thalassemia
25 Apr, 2024 | 23:29h | UTCStudy 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:
CRISPR-Cas9 gene editing in sickle cell disease shows high efficacy in preventing vaso-occlusive crises
25 Apr, 2024 | 23:21h | UTCStudy 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.
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 | UTCStudy 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 | UTCOriginal 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 | UTCRegulating 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 | UTCRapamycin 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 | UTCRapid 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)
1/n With respect to my colleagues involved in the GEMINI study that was just published, I am worried about the danger of a major message from this report:https://t.co/hkUeRd2nsb
— John Greally (@greally) July 14, 2023
Impact of newborn screening on severe combined immunodeficiency survival: results from a 36-year longitudinal study
14 Jul, 2023 | 12:45h | UTCMeasuring 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)
Commentary on Twitter
Findings from a 36-year longitudinal study provide direct evidence that newborn screening for SCID has been the primary driver of improved survival in new-born babies in the USA and Canada since 2010.
Read the full article: https://t.co/TAAcPztpF9 pic.twitter.com/cOxvNNJmb9
— The Lancet (@TheLancet) July 12, 2023
Case Series | Ambroxol therapy improves hematologic parameters in Gaucher disease patients
11 Jul, 2023 | 13:42h | UTCUse 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 | UTCInvited 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 | UTCCoronary 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