The FATE DNA editor released progerin, the protein associated with progeria, from the nuclear envelope in human cell organoids

The FATE DNA editor released progerin, the protein associated with progeria, from the nuclear envelope in human cell organoids

On August 31, a study in Nature Communications described FATE, a DNA editor that modifies a region of the LMNA gene. In neuromuscular organoids derived from human cells, this edit prevented progerin from acquiring the lipid modification that anchors proteins to the nuclear membrane. Signs of a DNA damage response then reappeared in muscle cells.

In Hutchinson-Gilford syndrome, commonly called progeria, cells produce progerin, a shortened form of lamin A, a protein in the inner layer of the nuclear envelope. Normal lamin A temporarily acquires farnesyl, a lipid modification that anchors the protein to the membrane, and loses it during maturation. Progerin lacks the site required for this final processing step, so the farnesyl group remains attached and keeps the protein at the nuclear envelope.

The authors compared two pairs of human cell lines that differed only in a region of the LMNA gene. In one pair, they corrected a variant found in a patient. In the other, they introduced the same variant into an initially healthy cell line. They used these cells to grow organoids in which muscle and neural tissues developed alongside each other. Progerin accumulated in the muscle compartment. After irradiation, 322 of 323 progerin-positive muscle cells did not develop γH2AX foci, which mark DNA breaks. 53BP1, a protein that should accumulate at these breaks, remained trapped at the nuclear envelope. This response remained intact in the neural compartment.

FATE replaces a single nucleotide in the region of LMNA that encodes the lamin A tail. This substitution prevents farnesyl from attaching to progerin. The edited organoids continued to produce progerin, but the protein became distributed throughout the nucleus. After irradiation, γH2AX and 53BP1 foci reappeared. In organoids carrying one nonclassical LMNA variant, FATE also released 53BP1 from the nuclear envelope and restored focus formation after irradiation.

The authors also packaged mRNA encoding the FATE editor into lipid nanoparticles and microinjected them into the muscle compartment of the organoids. After ten days, no more than 8,55% of the target region had been edited. In the same organoids, progerin became distributed throughout the nucleus, and γH2AX and 53BP1 again formed foci after irradiation.