Preempting severe genetic disease
Around 2% of births come with a genetic disease, often with devastating impact. While some appear de novo (either from germplasm dominant mutations or from chromosomal accidents), a fraction are inherited (from the mother if X-linked, from both parents if autosomal recessive) and can be predicted (before conception) by gene sequencing parents. In a fascinating studied conducted across varied regions of Australia, 19,000 couples either intending to conceive or at an early stage of pregnancy (<10 weeks), were invited to to have their genome analyzed for the risk of an inherited genetic disease in their offspring; 9,107 couples accepted and were actually screened (with a significant trend toward higher education and higher income for the decision to enroll in this free study). Of those, 96% were determined to be low risk, 2% were high risk but already aware (e.g. based on family history), while another 2% were high risk but without prior knowledge. Of this last group, about 75% decided to take steps to mitigate the risk (e.g. undergoing IVF with pre-implantation genetic testing, or if they were already pregnant, do prenatal testing). Nationwide, Couple-Based Genetic Carrier Screening
Back to old ways: an attenuated vaccine for malaria
Attenuated vaccines have a long history but in the desire for more precise control, have been supplanted by a series of much more targeted methods. This has not worked with malaria for which the two approved subunit vaccines provide only limited protection. Here comes a new attempt with a genetically modified P. falciparum (named GA2) that lacks the ability to progress beyond the hepatic stage. In a Dutch study, 20 patients were “vaccinated” through infection with GA2 (comparator arms treated with GA1 or placebo), and underwent controlled human malaria infections (5 bites of infected mosquitoes each) to see if they had any protection. Those immunized with GA2 did (8 out of 9), and a determining factor appears to be cell-based immunity. Obviously, this is very early days, but top of mind are two questions: if there is truly immunity how long does it last? And is it possible to economically produce attenuated parasite at scale? Safety and Efficacy of Immunization with a Late-Liver-Stage Attenuated Malaria Parasite
A one-and-done for transthyretin amyloidosis?
Transthyretin amyloidosis (aTTR) is due to accumulation of misfolded transthyretin (TTR) and leads to cardiomyopathy and neuropathy. A variety of approaches have been used including RNAi (Amvuttra, vutisiran, Alnylam) to knock down production of TTR, but by far the most radical step is to disrupt the TTR gene with a CRISPR construct (previously described in these pages here). Intellia and Regeneron have now progressed NTLA-2001 (now named nexiguran ziclumeran, or “nex-z”) to a full-fledged phase 1b with 36 aTTR patients with cardiac symptoms. The results after 12 months of follow-up shows no trend to worsening of cardiac status (which one would expect in those patients absent treatment), and the serum TTR was down by 90% with no hint of any rebound (compare to vutisiran, which decreased serum TTR by about 80% in their phase 3). We will have to wait for the on-going phase 3 to confirm the benefit (NCT06128629 for those interested), but these results are certainly encouraging. There is a dictum in medicine (mostly repeated by surgeons): “nothing heals like steel” – perhaps someday we will be saying “no better fixer than CRISPR.” CRISPR-Cas9 Gene Editing with Nexiguran Ziclumeran for ATTR Cardiomyopathy
The quest for a functional cure to chronic Hepatitis B
Chronic Hepatitis B is an enormous global burden shortening many millions of lives due to cirrhosis or hepatocellular carcinoma. But like HIV, it is a clever, deeply rooted adversary whose eradication is nigh impossible due to hidden viral reservoirs. As with HIV, the goal has shifted to a functional cure, wherein immune control reduces viral load to an extremely low level without on-going therapy. Enters xalnesiran, an RNAi from Dicerna (licensed by Roche) that inhibits a range of RNA transcripts from HBV DNA. This was tested in a 48-week course of therapy in subjects with chronic Hepatitis B, alone or in combination with various immunomodulators (ruzotolimod or INF-α-2a). Patients were monitored for circulating HBsAg and HBV DNA for up to 48 weeks after treatment ended. The upshot: some patients achieved a functional cure at 48 weeks, but only those that started with low viral activity and who received the combo therapy (with immunomodulation). While applicability to a general patient population is doubtful, I view this as a proof of principle – there is hope the approach could work for others. At the same time, couldn’t the same thing be achieved with CRISPR rather than RNAi? Xalnesiran with or without an Immunomodulator in Chronic Hepatitis B
In which I have egg on my face (but I am not the only one)
As previously reported in this series, the anti-gout agent colchicine has been studied in cardiovascular disease and multiple trials had reported a benefit (COLCOT in post-MI patients and LODOCO-2 in CAD patients). I was convinced – the clinical data, the biomarkers, the putative mechanism of action were all compelling. The data were clear enough that the European Society of Cardiology changed its guidelines to include colchicine therapy with strength of evidence IIa (pretty good). In comes the results of the latest study, CLEAR, which compared colchicine to placebo in 7,062 patients post-MI (just like COLCOT), and… the result is nothing… colchicine did nothing for the cardiovascular event rate (but it did lower the C-reactive protein level in the treatment arm vs. the placebo arm which is how we know that this is not a blinding snafu). It’s mystifying. It’s also a reminder that there are reasons for the gold standard of conducting 2 (TWO) distinct RCTs in the same populations to establish a new standard of care. Colchicine in Acute Myocardial Infarction
The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.