Metagenomi Presents New Data on Novel Gene Editing Systems at the 26th American Society of Gene + Cell Therapy (ASGCT) Annual Meeting

– Company’s metage­nomics-derived gene edit­ing tool­box shows activ­i­ty, speci­fici­ty, and trans­lata­bil­i­ty for broad use in genet­ic med­i­cine development –

– Metagenomi’s CRISPR asso­ci­at­ed trans­posase (CAST) sys­tems designed for large, site-spe­cif­ic gene inte­gra­tions repro­ducibly achieved pro­gram­ma­ble trans­po­si­tion into mul­ti­ple endoge­nous sites in the human genome –

– First non-human pri­mate data using MG291, a nov­el type V CRISPR sys­tem, shows POC for ther­a­peu­tic gene knockdown –

Metageno­mi, a genet­ic med­i­cines com­pa­ny with a ver­sa­tile port­fo­lio of whol­ly owned, next-gen­er­a­tion gene edit­ing sys­tems, pre­sent­ed new data for its gene edit­ing pro­grams dur­ing the 26th Amer­i­can Soci­ety of Gene + Cell Ther­a­py (ASGCT) Annu­al Meet­ing. The pre­sen­ta­tions demon­strate enhanced effi­cien­cy of Metagenomi’s pro­pri­etary type V and type II nucle­as­es, first-in-class CAST sys­tems for large, tar­get­ed DNA inte­gra­tion capa­bil­i­ties, and nov­el base edit­ing sys­tems. In addi­tion, the Com­pa­ny pre­sent­ed proof of con­cept data in non-human pri­mates, show­cas­ing poten­tial ther­a­peu­tic trans­la­tion of Metagenomi’s lead nov­el nucle­ase technologies.

As an indus­try, we are on the precipice of incred­i­ble advances in genom­ic med­i­cine, but we need nov­el, effi­cient tools with edit­ing capa­bil­i­ties beyond the cur­rent stan­dard if we are to address the broad­est spec­trum of dis­eases,” said Sarah Noon­berg, Ph.D., M.D., Chief Med­ical Offi­cer of Metageno­mi. The data we pre­sent­ed this week fur­ther val­i­dates the pow­er of our metage­nomics-based dis­cov­ery approach in rapid­ly dis­cov­er­ing and opti­miz­ing nov­el next-gen­er­a­tion tech­nolo­gies that are high­ly tar­getable, spe­cif­ic and effi­cient. With a mul­ti­tude of gene edit­ing tech­nolo­gies, we can accel­er­ate their trans­la­tion to poten­tial­ly cura­tive ther­a­pies for a wide vari­ety of impor­tant diseases.”

The dis­cov­er­ies described in these pre­sen­ta­tions were enabled by Metagenomi’s exper­tise in metage­nomics and the Company’s pro­pri­etary dis­cov­ery plat­form. Metagenomi’s dis­cov­ery plat­form uses AI-enabled cloud com­put­ing to mine mil­lions of sequences from diverse envi­ron­ments cap­tured in its grow­ing data­base, ana­lyze their prop­er­ties, and opti­mize nov­el sys­tems for poten­tial ther­a­peu­tic applications.

Pre­sen­ta­tion Highlights

A Metage­nomics-Derived Gene-Edit­ing Tool­box Enables Effi­cient Genome Engi­neer­ing with Nucle­as­es and Base-Edi­tors in Pri­ma­ry Cells and In Vivo (Oral, Abstract #256)

Cur­rent tech­nolo­gies are lim­it­ed in abil­i­ty to tar­get var­i­ous sites in the genome and can some­times have off-tar­get effects, which may affect the safe­ty of poten­tial ther­a­peu­tics. Metageno­mi is iden­ti­fy­ing and devel­op­ing nov­el tools to over­come these lim­i­ta­tions. Instead of focus­ing on a sin­gle or few iso­lat­ed enzymes, Metageno­mi has curat­ed a library of type II nucle­as­es with diverse PAM tar­gets, and type V nucle­as­es, which show increased speci­fici­ty com­pared to exist­ing type II sys­tems, includ­ing Cas9. Com­pa­ny researchers have dis­cov­ered entire fam­i­lies of edit­ing sys­tems and used chimeric meth­ods to per­form PAM-inter­act­ing domain (PID) swaps between fam­i­ly mem­bers, which rapid­ly and sig­nif­i­cant­ly increas­es the tar­get­ing den­si­ty of the plat­form. In its total­i­ty, hav­ing a broad set of gene edit­ing tools is impor­tant for tar­get­ing any loca­tion in the human genome.

Fur­ther­more, researchers describe how Metageno­mi has engi­neered one of its nucle­as­es into an ade­nine base edi­tor (ABE). This mod­i­fied nucle­ase achieved up to 95% A‑to‑G con­ver­sion in cul­tured cells and ~50% con­ver­sion in mouse hepa­to­cytes in vivo. In addi­tion, there was no detectable pre-exist­ing anti­body immu­ni­ty to Metagenomi’s nucle­as­es in a pan­el of serum sam­ples from 48 ran­dom­ly select­ed donors.

A Nov­el Type V CRISPR Sys­tem with Potent Edit­ing Activ­i­ty in Mice and Non-Human Pri­mates (Oral, Abstract #229)

Most gene edit­ing tools are based on the spCas9 nucle­ase, which is a mem­ber of the type II fam­i­ly of CRISPR sys­tems. Despite the obser­va­tion that type V CRISPR sys­tems exhib­it high­er speci­fici­ty and a dis­tinct PAM that enables access to genom­ic tar­get sites not pos­si­ble with Cas9, they have not been wide­ly used for in vivo gene edit­ing. In this pre­sen­ta­tion, Metageno­mi researchers describe the first use of MG291, a nov­el type V sys­tem with min­i­mal sequence iden­ti­ty to Cas12a/​cpf1, to per­form potent gene edit­ing in pri­ma­ry human cells in vit­ro, as well as in mice and non-human pri­mates (NHP) with high effi­cien­cy. This is the first report of NHP edit­ing with a type V nucle­ase and demon­strates effec­tive­ness for ther­a­peu­tic gene knockdown.

The MG291 mRNA sequence was opti­mized with the addi­tion of two potent human/​NHP guide RNA spac­ers and the ingre­di­ents encased in a liv­er-tar­get­ed lipid nanopar­ti­cle (LNP) infused into NHPs, which result­ed in on-tar­get edit­ing to as much as 55% of whole liv­er (esti­mat­ed 75% of hepa­to­cytes). There were no sig­nif­i­cant adverse effects or over­pro­duc­tion of inflam­ma­to­ry cytokines. Analy­ses for off-tar­get effects revealed high speci­fici­ty: no true off-tar­get sites were detected.

Tar­get­ed Inte­gra­tion to Endoge­nous Sites in the Human Genome Using CRISPR-Asso­ci­at­ed Trans­posas­es Dis­cov­ered from Nat­ur­al Envi­ron­ments (Poster, Abstract #1429)

A sub­stan­tial por­tion of genet­ic dis­eases are caused by sim­ple loss of func­tion, but inte­gra­tion of large seg­ments of DNA into tar­get­ed sites has his­tor­i­cal­ly been a chal­lenge. CRISPR asso­ci­at­ed trans­posas­es (CASTs) are a poten­tial solu­tion to this prob­lem, as these sys­tems have been shown to effi­cient­ly deliv­er large DNA por­tions into bac­te­r­i­al genomes.

Metagenomi’s nov­el CAST sys­tem is capa­ble of effi­cient trans­po­si­tion of a sub­stan­tial DNA frag­ment (2.5 kilo­bas­es) in vit­ro into E. coli and mam­malian cells. When deliv­ered to mam­malian cells, these CAST com­po­nents are expressed in an active form and local­ized to the nucle­us; researchers repro­ducibly achieved pro­gram­ma­ble trans­po­si­tion into mul­ti­ple endoge­nous sites in the human genome. This pro­vides proof of con­cept for poten­tial ther­a­peu­tic appli­ca­tion – and a crit­i­cal advance­ment for the gene edit­ing field.

About Metageno­mi
Metageno­mi is a gene edit­ing com­pa­ny com­mit­ted to devel­op­ing poten­tial­ly cura­tive ther­a­peu­tics by lever­ag­ing a pro­pri­etary tool­box of next-gen­er­a­tion gene edit­ing sys­tems to accu­rate­ly edit DNA where cur­rent tech­nolo­gies can­not. Our metage­nomics-pow­ered dis­cov­ery plat­form and ana­lyt­i­cal exper­tise reveal nov­el cel­lu­lar machin­ery sourced from oth­er­wise unknown organ­isms. We adapt and forge these nat­u­ral­ly evolved sys­tems into pow­er­ful gene edit­ing sys­tems that are ultra-small, extreme­ly effi­cient, high­ly spe­cif­ic and have a decreased risk of immune response. These sys­tems fuel our pipeline of nov­el med­i­cines. Our goal is to rev­o­lu­tion­ize gene edit­ing for the ben­e­fit of patients around the world. For more infor­ma­tion, please vis­it https://​metageno​mi​.co.