Suc­cess­ful Com­ple­tion of the Base-Lipid Pro­ject on Lipid Nan­o­particles (LNPs)

The bene­fits of ribo­nuc­leic acids (RNA) as drug can­did­ates encap­su­lated in lipid nan­o­particles (LNPs) are enorm­ous. Based on this tech­no­logy, a wide range of new ther­apies could be developed. The full poten­tial of these novel drugs can only be secured by improv­ing RNA deliv­ery through optim­ized LNP com­pos­i­tions, includ­ing novel lip­ids to obtain more stable, safe, and bio­de­grad­able drug deliv­ery vehicles (car­rier sub­stances) that ideally tar­get the dis­ease sites with pre­ci­sion. On this basis, the BASE-Lipid research con­sor­tium was foun­ded, which has received an over­all fund­ing of 13 mil­lion Euro from the Fed­eral Min­istry for Eco­nomic Affairs and Energy (BMWE/BMWK). The con­sor­tium brings together expert­ise from the Friedrich Schiller Uni­ver­sity at Jena and the Julius Max­imilian Uni­ver­sity at Würzburg, the star­tup NGP Poly­mers, the com­pany ISAR Bioscience, and major industry play­ers such as Evonik AG and Bayer AG.

To this end, cor­res­pond­ing syn­thesis steps and qual­ity ana­lysis meth­ods were invest­ig­ated and fur­ther developed to pro­duce new lip­ids and poly­mers of the required qual­ity, pur­ity, and quant­ity. Moreover, novel com­bin­a­tions of nuc­le­otides and lip­ids („oli­go­nuc­leotide-lipid-con­jug­ates“) were cre­ated. All these novel com­pounds served to estab­lish over a thou­sand dif­fer­ent mRNA-LNP for­mu­la­tions in the next step. To man­age the sheer num­ber of syn­thesis options for lip­ids and poly­mers, as well as the com­bin­at­or­ics for LNPs, the con­sor­tium relied on an iter­at­ive pro­cess. This allowed to guide and improve the devel­op­ment dir­ec­tions for sub­sequent rounds based on insights gained from pre­vi­ous syn­thesis and for­mu­la­tion rounds. The gen­er­ated LNPs were char­ac­ter­ized in detail and tested for sta­bil­ity, expres­sion, and tox­icity, among other factors. Super­ior prop­er­ties com­pared to the Comirnaty/Spikevax (BioNTech/Moderna) stand­ards were decis­ive cri­teria for the next iter­a­tion steps.

To under­stand the spe­cific char­ac­ter­ist­ics of the respect­ive LNPs, they were invest­ig­ated in human dif­fer­en­ti­ated cells—such as cent­ral nervous sys­tem (CNS), car­diac muscle, blood ves­sel wall, and vari­ous immune cells—as well as in co-cul­tures. This enabled very good repro­du­cib­il­ity of the res­ults, and served to replace many animal exper­i­ments, thereby avoid­ing them entirely. Based on the cor­res­pond­ing expres­sion pro­files, new LNPs were iden­ti­fied that enable sig­ni­fic­antly stronger tar­get expres­sion in the heart (car­di­omyo­cytes) or in the CNS/brain. Sev­eral of these LNPs showed markedly improved per­form­ance com­pared with pre­vi­ous gen­er­a­tions, sup­port­ing their suit­ab­il­ity for future applic­a­tions tar­get­ing the CNS.

Another mile­stone in the pro­ject was the dis­cov­ery of immun­omod­u­lat­ory LNP for­mu­la­tions, which favor­ably impact on immune cells in patients with autoim­mune dis­eases by improv­ing the body’s own inflam­mat­ory immune responses. Fur­ther­more, poten­tial poly­ethyl­ene glycol (PEG)-associated immune reac­tions in the gen­eral pop­u­la­tion could be avoided by using poly­oxazoline (POx) lip­ids instead of the pre­vi­ously used PEG lip­ids as stand­ard ingredi­ents. This enables sig­ni­fic­ant improve­ments in patient safety when admin­is­ter­ing LNP drugs, par­tic­u­larly with regard to repeated dos­ing or long-term medication.

The neces­sary doc­u­ment­a­tion for (pre-)clinical devel­op­ment of these new LNP for­mu­la­tions was sub­mit­ted to the reg­u­lat­ory agen­cies dur­ing a “Sci­entific Advice” meet­ing, thereby enabling clear plan­ning of the next steps for their use as drugs. The part­ners of the BASE-Lipid con­sor­tium will advance this devel­op­ment to make the first drug can­did­ates avail­able to patients in the near future.