From bleeding edge to basics: an opinionated take on NEJM highlights for August and September 2021

The weird world of synthetic biology

In biology 101, one learns about the alphabet that translates DNA/RNA code into amino acids sequences ultimately resulting in proteins. Given that there are 64 possible triplet codons and 20 amino acids, multiple codons can map to the same amino acids. But this mapping can be reassigned including incorporating new amino acids – it has been done in E. coli with the promise of generating biologics with novel properties, although applications are not yet clear. A more practical application is to create strains of E. coli and perhaps one day mammalian cells, that are virus resistant. A virus’ DNA (or RNA) depends on host cell machinery for synthesis of viral proteins and, more generally, viral replication. To do so, it relies on the canonical mapping of codons into amino acids. If some codons, e.g., TCA for serine, are reprogrammed to be de facto stop codons (because there is no tRNA for it, and all the serines that used TCA in the host cell have been remapped to an alternate, e.g. TCT), viral replication will be stopped in its tracks.  If this can be carried over from E. coli to mammalian cells, it could become an important new tool to prevent viral contamination of cell cultures, the bane of biologics production. Sense and Sense Ability in a Synthetic Genetic Code


CRISPR vs. RNAi vs. ASOs

You’d think having three players in what is considered a rare disease (but maybe not so rare after all) is enough, but no, an Intellia-Regeneron collaboration is now challenging incumbents with approved therapies and they might well succeed. Recall that transthyretin amyloidosis (aTTR) is due to accumulation of misfolded transthyretin (TTR) which can be knocked down with either RNAi (Anylam) or ASOs (Ionis).  But there is another way to achieve the same result, albeit in a more radical (and permanent) manner using the CRISPR-Cas9 system to disrupt the TTR gene at the source. Given that TTR knock-out mice are healthy, it seems a reasonable approach, and in this study of 6 patients with aTTR, administration of targeted CRISPR appears to reduce TTR levels in a dose-dependent manner over a year. Measuring clinical effect will require a longer timeline and more patients (the study is on-going). Beyond aTTR, this suggests that any disease with ASO or RNAi therapies could also be considered for a CRISPR approach, the advantage being that it would be a one-and-done therapy, the disadvantage being that it is largely irreversible. CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis; Gene Editing — A Cure for Transthyretin Amyloidosis?


An incipient revolution in metabolic care

Looking at the last couple years, the biggest new thing coming down the pike for primary care are GLP-1 agonists such as semaglutide which not only greatly improve glycemic control in patients with diabetes, but also generate substantial weight loss in the overweight and obese without diabetes. A new entrant from Eli Lilly, tirzepatide, which has a dual mode of action as a GLP-1 agonist and at the insulinotropic polypeptide receptor, has now been tested in a head-to-head with semaglutide in Type-1 diabetes in a 2000 patient open-label randomized study. The results were spectacular, with corrections of HbA1c to near normal values and about 50% of patients who met a >10% weight loss target. Is tirzepatide truly better than semaglutide? That remains unclear as the semaglutide dose used was lower than the maximum possible; either way, both these drugs are extremely promising. As a reminder, the US obesity rate is above 40% and diabetes is above 10% and the costs associated with that must be in the several hundreds of billions. There is value there for new solutions.  Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes; Breaking New Ground with Incretin Therapy in Diabetes


Time is brain, but also money

For ischemic stroke, there is a very strong relationship between how quickly thrombolytics (t-PA) are administered after onset of symptoms and subsequent permanent neurological disability. A key bottleneck to rapid treatments is the need to rule-out hemorrhagic stroke which requires a CT scan. Mobile Stroke Units (MSUs) are an attempt to accelerate the process: these are enhanced ambulances with CT capability, staffed by professionals who have the expertise to give t-PA in the field. Now a randomized (but not blinded) study involving about 1000 patients who eventually received t-PA shows the benefit of this approach: the MSU group received t-PA 32 minutes earlier and ended up with minimal or no neurological disability at a rate of 55% vs. 44% in the traditional care group. However, there is no cost analysis – MSUs are expensive and stroke alerts were issued at about 10x the rate where a stroke intervention was possible. ICER – how about taking a look? Prospective, Multicenter, Controlled Trial of Mobile Stroke Units; Does My District Need a Mobile Stroke Unit?


Stopping or continuing antidepressants?

The standard approach to depression by primary care physicians is to try an antidepressant medication(s), but when the antidepressant works, has been used for several years, and the patient is stable, is it a good idea to stop? Despite inklings that relapses might be common, the only way to figure this out is through a randomized trial. In a UK study conducted with ~500 patients on antidepressants for at least 2 years who felt well, half discontinued their drug and half remained on therapy. In the discontinuation group, 56% had a relapse at 1 year against 39% among those who continued treatment (a nearly 50% relative increase).  While basic and perhaps unglamorous, these kinds of simple studies are incredibly valuable to healthcare. One wishes there would be more funding for those. Maintenance or Discontinuation of Antidepressants in Primary Care; The Pursuit and Maintenance of Happiness


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.