Pro­ject status/ re­sults

Tar­get Dry AMD

The Tar­get Dry AMD ap­proach is a pro­gres­sion of Tar­get­AMD 1.0 ap­ply­ing the same treat­ment ap­proach (sub­ret­in­al in­jec­tion of pa­tient’s ge­net­ic­ally mod­i­fied Iris Pig­ment Ep­ithe­lial cells) and tech­no­logy for ge­net­ic modi­fic­a­tion (non-vir­al Sleep­ing Beauty trans­po­son sys­tem).

Here, a second thera­peut­ic pro­tein is pro­duced by the mod­i­fied Iris Pig­ment Ep­ithe­lial cells to re­duce reti­nal in­flam­ma­tion and oxi­dative stress (see the defin­i­tion of oxi­dative stress in Tar­get Dry AMD/Goals). Toge­ther, the thera­peut­ic pro­teins Pig­ment Ep­ithe­li­um-De­rived Factor (PEDF) and Granulo­cyte Mac­ro­phage-Colony Form­ing Factor (GM-CSF) are able to strengthen reti­nal cell sur­viv­al and to re­store a healthy reti­nal en­vir­on­ment and like that, in­hib­it de­gen­er­a­tion. The main ob­ject­ives of the pro­ject are the:

  1. De­vel­op­ment of a dry AMD dis­ease mod­el
  2. En­hance­ment of the safety of the cell product by us­ing trans­posase mRNA in­stead of DNA
  3. Prove of long-term stable PEDF and GM-CSF gene and pro­tein ex­pres­sion and se­cre­tion
  4. Ana­lys­is of in vitro ef­fi­ciency and safety
  5. De­term­in­a­tion of in vivo ef­fi­ciency
  6. Con­firm­a­tion of in vivo safety

In a fol­low-up pro­ject to be star­ted in spring 2024, the pre-clini­cal phase will be com­pleted be­fore com­pil­ing ex­per­i­ment­al data to build the dossier to Swiss reg­u­lat­ory au­thor­ity for clini­cal tri­al ap­prov­al.

With­in the pro­ject, we were able to con­struct a plas­mid car­ry­ing the GM-CSF gene and to trans­fect hu­man Reti­nal and Iris Pig­ment Ep­ithe­lial cells with three plas­mids cod­ing for the trans­posase, the PEDF and the GM-CSF gene. We de­veloped a re­pro­du­cible dry AMD dis­ease mod­el us­able for ef­fi­ciency stud­ies. Stable and ef­fi­cient trans­fec­tion was evid­enced by the in­crease of gene ex­pres­sion and pro­tein pro­duc­tion in trans­fec­ted hu­man Reti­nal and Iris Pig­ment Ep­ithe­lial cells. We could en­hance and con­firm the safety of the gene the­ra­py by us­ing the mRNA trans­posase amongst oth­ers by ex­clud­ing tu­m­ori­gen­i­city of ge­net­ic­ally mod­i­fied cells.

Target Dry AMD Project status/Results - soft agar colony formation

A po­ten­tial gen­o­tox­icity of trans­fec­ted Reti­nal and Iris Pig­ment Ep­ithe­lial cells will be ex­cluded in vitro, by Prof. Ivics by per­form­ing an in­teg­ra­tion site ana­lys­is.

Up to now, find­ings of this pro­ject have res­ul­ted in 4 peer-re­viewed (eval­u­ated by in­de­pend­ent sci­ent­ists) art­icles.