PKD Life - Summer 2022 - 22

THE RESEARCH REPORT
Can
ADPKD Be
Reversed?
Promising research in mice
suggests that it might,
but many unanswered
questions remain.
By Debra Gordon
E very now and again something happens in science
that amazes even the researchers behind
the study. Something like . . . reversing autosomal
dominant polycystic kidney disease (ADPKD)
in mice.
" It was unexpected and surprising, " says Stefan
Somlo, M.D., the C.N.H. Long Professor of Medicine
and professor of genetics at Yale School of Medicine,
about the study he and his team recently published
in the journal Nature Genetics. The research
was supported, in part, by the PKD Foundation.
The findings highlight the extraordinary discovery
that the kidney can adapt and change to
differing environments, and they also uncover
unexpected ways in which the genes responsible
for ADPKD regulate the organ.
SURPRISING RESULTS
Dr. Somlo's team first created a mouse model of
ADPKD that enabled them to inactivate the PKD2
gene responsible for about 15% of ADPKD. As might
be expected, the mice developed ADPKD. But when
they turned the gene back on, the kidney shrank
and the cysts disappeared. Even more remarkable
is that the kidney tubules-which filter out impurities,
minerals, and other nutrients from blood
22 PKD LIFE * SUMMER 2022
and which develop fibrosis,
or scarring, as a result of
ADPKD-returned to normal,
at least when the process was
initiated in the early stages of
ADPKD. The researchers got
the same results when they
deactivated and then reactivated
the PKD1 gene.
" The intent of the study
was to ask the question,
'What is the best-case scenario
one could hope for in
a therapy to re-express the
gene?' " Dr. Somlo says. The
expectation was that the cysts
would stop growing and slow
disease progression, much
like the only FDA-approved
treatment for ADPKD, tolvaptan,
does. " We didn't think
we could actually reverse the
disease, " he says.
It wasn't a slam dunk.
They found that if they reexpressed
the gene later in
the disease state, the cysts
disappeared and the kidney
shrank, but some of the fibrosis
remained.
NEW QUESTIONS
The findings also raised
numerous questions about
what polycystin, the protein
PKD genes make, actually
does. " It obviously exerts a lot
of control on the kidney that
we had no idea about, " he
PKD Life - Summer 2022

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