Mark Terndrup’s Post

In Nov 2023, the US Pharmacopeia issued Draft General Chapter <1040> Quality Considerations of Plasmid DNA as a Starting Material for Cell and Gene Therapies. In this article, USP's Rebecca Potts, the lead on the panel that developed this chapter, provides greater insight into: - Manufacturing standards - Facility standards - Quality management systems and qualification for GMP and non-GMP - Staff training - Stability studies https://lnkd.in/eaVsUB7d #dna #genetherapy #celltherapy #gmp

LucidQuest Strategic Insights (lqventures.com) >>> Gene&Cell Therapy >> CSL and uniQure’s three-year Hemgenix data show consistent effect in hemophilia B: With its $3.5 million price tag, CSL Behring and uniQure’s one-off hemophilia B gene therapy Hemgenix is one of the world’s most expensive therapies. On Friday, three-year follow-up from its registrational study offers a new look at the drug’s curative potential. The HOPE-B study tested a dose of Hemgenix in 54 men with the rare bleeding disorder. The treatment secured an FDA approval in November 2022 on the basis of topline results. In the 52 men who completed follow-up, the mean annualized bleeding rate (ABR) for the minimum six-month lead-in period of seven to 36 months post-treatment dropped by 64% (4.17 to 1.52). The number of bleeds among the men totaled 136 during the lead-in period. In year one, there were 55 bleeds, which dropped to 48 in year two and 37 in year three. “We may speculate that bleeding protection will be maintained as long as factor IX is expressed,” Wolfgang Miesbach, chair of the European Association for Haemophilia and Allied Disorders gene therapy working group, told Endpoints News in an interview. Factor IX is a clotting protein that’s missing or defective in hemophilia B, leading to spontaneous and prolonged bleeding events. Wolfgang Miesbach “[Bleeding protection] may even improve over time as we know that reduction in bleeds prevents compressor joint damage and subsequent bleeding risk,” Miesbach said. Patients’ mean factor IX activity level was 41.5 units/dL at one year but dropped to 36.7 IU/dL at two years before creeping back up to 38.6 IU/dL at three years. Research suggests that normal levels of factor IX sit between 50 and 150 units/dL but severe hemophilia B patients can present with levels below 1 unit/dL. Overall, 94% of patients remained free from continuous prophylaxis at the end of three years. Previous research conducted by St. Jude Children’s Research Hospital and UCL on a different AAV-based factor IX gene transfer therapy showed it was able to sustain factor IX levels for up to 12 years, Miesbach noted. So while there’s still a need for further follow-up to establish the long-term efficacy of Hemgenix, “it seems unlikely that factor IX expression will drop off suddenly,” he said. But one HOPE-B study participant saw its factor IX levels decline to the 2% to 5% range, resulting in the return of bleeding phenotype and resumption of prophylaxis at 30 months post-treatment. The patient had a history of more than 20 years of HIV, with the patient using antiretroviral therapy, and has chronically-treated depression. He had normal baseline liver function and liver elastography, Miesbach noted. “This loss of factor IX expression has not been seen with participants with a similar profile,” he said, adding there doesn’t seem… #lucidquest #genetherapy #celltherapy

Gene&Cell Therapy >> CSL and uniQure’s three-year Hemgenix data show consistent effect in hemophilia B: With its $3.5 million price tag, CSL Behring and uniQure’s one-off hemophilia B gene therapy Hemgenix is one of the world’s most expensive therapies. On Friday, three-year follow-up from its registrational study offers a new look at the drug’s curative potential. The HOPE-B study tested a dose of Hemgenix in 54 men with the rare bleeding disorder. The treatment secured an FDA approval in November 2022 on the basis of topline results. In the 52 men who completed follow-up, the mean annualized bleeding rate (ABR) for the minimum six-month lead-in period of seven to 36 months post-treatment dropped by 64% (4.17 to 1.52). The number of bleeds among the men totaled 136 during the lead-in period. In year one, there were 55 bleeds, which dropped to 48 in year two and 37 in year three. “We may speculate that bleeding protection will be maintained as long as factor IX is expressed,” Wolfgang Miesbach, chair of the European Association for Haemophilia and Allied Disorders gene therapy working group, told Endpoints News in an interview. Factor IX is a clotting protein that’s missing or defective in hemophilia B, leading to spontaneous and prolonged bleeding events. Wolfgang Miesbach “[Bleeding protection] may even improve over time as we know that reduction in bleeds prevents compressor joint damage and subsequent bleeding risk,” Miesbach said. Patients’ mean factor IX activity level was 41.5 units/dL at one year but dropped to 36.7 IU/dL at two years before creeping back up to 38.6 IU/dL at three years. Research suggests that normal levels of factor IX sit between 50 and 150 units/dL but severe hemophilia B patients can present with levels below 1 unit/dL. Overall, 94% of patients remained free from continuous prophylaxis at the end of three years. Previous research conducted by St. Jude Children’s Research Hospital and UCL on a different AAV-based factor IX gene transfer therapy showed it was able to sustain factor IX levels for up to 12 years, Miesbach noted. So while there’s still a need for further follow-up to establish the long-term efficacy of Hemgenix, “it seems unlikely that factor IX expression will drop off suddenly,” he said. But one HOPE-B study participant saw its factor IX levels decline to the 2% to 5% range, resulting in the return of bleeding phenotype and resumption of prophylaxis at 30 months post-treatment. The patient had a history of more than 20 years of HIV, with the patient using antiretroviral therapy, and has chronically-treated depression. He had normal baseline liver function and liver elastography, Miesbach noted. “This loss of factor IX expression has not been seen with participants with a similar profile,” he said, adding there doesn’t seem to be a specific set of features that make some… #lucidquest #genetherapy #celltherapy

AAV gene therapy suffers from the presence of preformed immunity against the AAV vectors in ~30-60% of patients. Here, Smith et al. develop a bifunctional enzyme called IceMG that can mitigate both IgG and IgM preformed neutralizing antibodies. Specifically, one end of IceMG has a domain which degrades IgG and the other end has a domain which degrades IgM. In this way, humoral immunity might be temporarily suppressed to allow AAVs to deliver beneficial genetic cargos. As an aside, I am developing a different approach (vaultAAV) to circumventing anti-AAV preformed immunity. I can envision my vaultAAVs and Smith et al.'s IceMG enzymes having complementary roles in addressing various medical situations. #genetherapy #syntheticbiology #proteinengineering https://lnkd.in/giHWwHQc

Re-dosing with CRISPR/Cas9-edited gene via LNP delivery. Data presented at the Peripheral Nerve Society annual meeting this week. These are proof-of-concept data collected in tandem with clinical trials, hopefully giving future alternatives if one administration does not yield sufficient edited gene product. #CRISPR #geneediting #CGT https://lnkd.in/gJW8wdqK

I am thrilled to inform about our recent publication " Diuretic effects of Hecogenin and Hecogenin acetate via aldosterone synthase inhibition" in Q1 journal with an impact factor of 4.1. In this study we have found that the Hecogenin (HEC) and Hecogenin Acetate (HA), steroidal saponins derived from Agave sisalana, exhibit significant diuretic effects through downregulating aldosterone synthase gene expression. Additionally, They also impact genes involved in cortisol, corticosterone, and steroid synthesis, suggesting potential therapeutic implications for cardiovascular and metabolic disorders. Full study is online now https://lnkd.in/dmUr96bp.

Bovine bFGF, encoded by the FGF2 gene, is a member of the fibroblast growth factor (FGF) family. Recombinant Bovine bFGF (recombinant bbFGF) is a recombinant protein that introduces the bbFGF gene into an E. coli expression system to induce large-scale expression.  It has the same biological activity as the bovine basic fibroblast growth factor. Basic fibroblast growth factor (also known as basic FGF, bFGF, FGF2, FGF- β, or heparin-binding growth factor) is a pleiotropic cytokine and one of the prototypic members of the heparin-binding FGF family. In vivo, the basic fibroblast growth factor is produced by a variety of cells, including cardiomyocytes, fibroblasts and vascular cells. Basic fibroblast growth factor regulates a variety of processes, including cell proliferation, differentiation, survival, adhesion, exercise, apoptosis, limb formation and wound healing.  #growthfactors #fgf #bfgf #biology #biologicals #biopharmaceutical https://lnkd.in/ehJakRCN

Effect of MCH1, a fatty-acid amide hydrolase inhibitor, on the depressive-like behavior and gene expression of endocannabinoid and dopaminergic-signaling system in the mouse nucleus accumbens https://lnkd.in/edh4eBX4

🌟 Exciting times ahead in the Cell and Gene Therapies (CGT) market for Hemophilia A and B! 🌟 In 2023, the CGT market for Hemophilia A and B soared to $12M with significant therapeutic expansions. 🚀 🌐 Our latest report dives deep into the competitive landscape, clinical trials, and future projections. 📊 Discover insights from key opinion leaders across the 5EU, US, and China. 🔍 We analyze unmet needs, regulatory challenges, and the reimbursement environment. #lifesciences #pharmaceuticals #biotechnology #cellandgenetherapy #hemophilia

'Here, we trace this success to two streams of research conducted over the past 60 years: the discovery of the transfection properties of lipoplexes composed of positively charged cationic lipids complexed with nucleic acid cargos and the development of lipid nanoparticles using ionizable cationic lipids. The fundamental insights gained from these two streams of research offer potential delivery solutions for most forms of gene therapies.' https://lnkd.in/dVEkVWe4