CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

Abstract

BACKGROUNDTransthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODSAfter conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTSPreclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONSIn a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051.

Chromatin Alterations in Neurological Disorders and Strategies of (Epi)Genome Rescue

“…Consequently, there is a number of clinical trials worldwide to address the usefulness of CRISPR-Cas9-mediated genome modification [559]. A study published in June 2021, introduced a lipid nanoparticle-delivered CRISPR-Cas9 genome editing tool to treat individuals affected by transthyretin amyloidosis (ATTR amyloidosis), a life-threatening disease caused by progressive accumulation of misfolded transthyretin (TTR) [560]. This breakthrough finding will likely change the clinical management of monogenic diseases in the future, opening the possibility to edit genomes of patients attained by otherwise untreatable conditions.…”

Approaches to Enhance Precise CRISPR/Cas9-Mediated Genome Editing

“…TTR, which is primarily produced in the liver, was targeted with nanoparticle-encapsulated Cas9 mRNA and a single TTR guide RNA. Durable knockout was achieved in six patients without any major adverse events [11].…”

“…Similarly, another proof-of-principle study that achieved multiplexed editing of both the endogenous T cell receptor (TCR) and immune checkpoint PD-1 in chimeric antigen receptor (CAR) T-cells resulted in successful engraftment for at least 9 months without editing-associated clinical toxicities [10]. Recently, the feasibility of treating genetic diseases caused by single-gene mutations was established in a Phase 1 trial for transthyretin amyloidosis, a disease caused by the accumulation of misfolded transthyretin (TTR) [11]. TTR, which is primarily produced in the liver, was targeted with nanoparticle-encapsulated Cas9 mRNA and a single TTR guide RNA.…”

Update zu: COVID-19 und die Niere – Klinik

“…Rund ein Drittel der hospitalisierten Personen haben 6 Monate nach der akuten Infektion noch eine eingeschränkte Nierenfunktion (glomeruläre Filtrationsrate [GFR] <90 ml/min; [ 23 ]). Die Nephrologie steht hier vor der Herausforderung der langzeitigen Organprotektion, damit nicht eine Welle an chronisch Nierenkranken auf uns zurollt [ 24 , 25 ]. Mögliche Therapieansätze für Long/Post COVID sind die supportive Gabe von Erythropoetin aufgrund seiner positiven Wirkung auf respiratorische Reserve, Mikrozirkulation und andere Organfunktionen als Gegenspieler der überschießenden Entzündung und als Neuroprotektivum bzw.…”