RNA-based gene therapy requires therapeutic RNA to function inside target cells without eliciting unwanted immune responses. RNA can be ferried into cells using non-viral drug delivery systems, which circumvent the limitations of viral delivery vectors. Here, we review the growing number of RNA therapeutic classes, their molecular mechanisms of action, and the design considerations for their respective delivery platforms. We describe polymer-based, lipid-based, and conjugate-based drug delivery systems, differentiating between those that passively and those that actively target specific cell types. Finally, we describe the path from preclinical drug delivery research to clinical approval, highlighting opportunities to improve the efficiency with which new drug delivery systems are discovered. RNA therapies can be used to manipulate gene expression or produce therapeutic proteins. Here, the authors describe the growing number of RNA therapies and their molecular mechanisms of action. They also discuss the path from preclinical drug delivery research to clinical approval of these drugs. 

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Drug delivery systems for RNA therapeutics

Lumasiran (Oxlumo™) is a subcutaneously administered small interfering RNA (siRNA) targeting the mRNA for hydroxyacid oxidase 1 gene (HAO1; encodes glycolate oxidase) and was developed by Alnylam Pharmaceuticals for the treatment of primary hyperoxaluria type 1 (PH1). By silencing the gene encoding glycolate oxidase, lumasiran depletes glycolate oxidase and thereby inhibits the synthesis of oxalate, which is the toxic metabolite that is directly associated with the clinical manifestations of PH1. On 19 November 2020, lumasiran received its first global approval in the EU for the treatment of PH1 in all age groups. On 23 November 2020, lumasiran was approved in the USA for the treatment of adult and paediatric patients with PH1. This article summarizes the milestones in the development of lumasiran leading to this first approval.

Lumasiran: First Approval.

Therapeutics based on short interfering RNAs (siRNAs) delivered to hepatocytes have been approved, but new delivery solutions are needed to target additional organs. Here we show that conjugation of 2′-O-hexadecyl (C16) to siRNAs enables safe, potent and durable silencing in the central nervous system (CNS), eye and lung in rodents and non-human primates with broad cell type specificity. We show that intrathecally or intracerebroventricularly delivered C16-siRNAs were active across CNS regions and cell types, with sustained RNA interference (RNAi) activity for at least 3 months. Similarly, intravitreal administration to the eye or intranasal administration to the lung resulted in a potent and durable knockdown. The preclinical efficacy of an siRNA targeting the amyloid precursor protein was evaluated through intracerebroventricular dosing in a mouse model of Alzheimer’s disease, resulting in amelioration of physiological and behavioral deficits. Altogether, C16 conjugation of siRNAs has the potential for safe therapeutic silencing of target genes outside the liver with infrequent dosing. Lipophilic siRNA conjugates exert therapeutic activity in the mouse CNS. 

/pdf/expanding-rnai-therapeutics-to-extrahepatic-tissues-with-2xenhpsb.pdf

Expanding RNAi therapeutics to extrahepatic tissues with lipophilic conjugates

Safety, pharmacodynamics, and exposure-response modeling results from a first-in-human phase 1 study of nedosiran (PHYOX1) in primary hyperoxaluria

Background Primary hyperoxaluria type 1 (PH1) is a rare genetic disease caused by hepatic overproduction of oxalate that leads to kidney stones, nephrocalcinosis, kidney failure, and syste...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa2021712

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1

\n \n \n PH1 is a rare genetic disorder characterized by hepatic oxalate overproduction, leading to recurrent kidney stones, nephrocalcinosis, progressive kidney failure, and multiorgan damage from systemic oxalosis. There are no approved pharmacologic therapies for PH1. Lumasiran is a subcutaneously-administered investigational RNAi therapeutic that targets glycolate oxidase to reduce hepatic oxalate production. We report the first results from the six-month, double-blind period of ILLUMINATE-A, a randomized, placebo-controlled Phase 3 study to evaluate lumasiran in patients with PH1.\n \n \n \n Key inclusion criteria: age≥6 years, 24hr urinary oxalate (UOx)≥0.70 mmol/24hr/1.73m2, confirmed PH1 diagnosis, eGFR≥30 mL/min/1.73m2. Randomization: 2:1; lumasiran (n=26), placebo (n=13). Dosing: 3 mg/kg monthly×3, then quarterly. Primary endpoint: percent change in 24hr UOx excretion from baseline to month (M) 6. Primary comparison: least square (LS) mean treatment difference in percent change from baseline (average of M3-6).\n \n \n \n Lumasiran led to a statistically significant percent reduction in 24hr UOx excretion compared to placebo: the LS mean change from baseline to M6 (average of M3-6) was −65.4% with lumasiran and −11.8% with placebo (LS mean difference: −53.5%; p=1.7 × 10−14). Subgroup analyses of the primary endpoint showed a consistent effect of lumasiran across age, baseline UOx, eGFR, and concomitant pyridoxine use. Lumasiran led to statistically significant improvements in all hierarchically tested secondary endpoints, including: proportion of lumasiran-treated patients that achieved normalization or near-normalization of 24hr UOx at M6 (84% vs 0% of placebo-treated patients, p=8.3 × 10−7), and percent change in plasma oxalate from baseline to M6 (average of months 3-6) (-39.5%, p=2.9 × 10−8). There were no serious or severe adverse events. The most common adverse events related to lumasiran were mild, transient injection site reactions.\n \n \n \n Lumasiran resulted in clinically meaningful, rapid, sustained, and statistically significant reductions in urinary and plasma oxalate levels compared to placebo during the six-month double-blind period. Lumasiran has a favorable safety profile.\n

/pdf/lb002illuminate-a-a-phase-3-study-of-lumasiran-an-36gk6cuji1.pdf

Gesa Schalk

Papers

Lumasiran, an RNAi Therapeutic for Primary Hyperoxaluria Type 1

Lb002illuminate-a, a phase 3 study of lumasiran, an investigational rnai therapeutic, in children and adults with primary hyperoxaluria type 1 (ph1)