Helen BLAU, et al.
Rapid Telomere Extension
Breakthrough R&D : nucleoside-modified
mRNA safely reverses 15 years of telomere aging in 1 week
Safe, Rapid Telomere Extension to
Prevent and Treat Hypertension
Blau, Helen M.
Stanford University, Stanford, CA, United States
We recently demonstrated a novel, uniquely-enabling drug for
telomere extension: nucleoside-modified mRNA encoding telomerase.
Our mRNA drug extends telomeres in six days by approximately
the amount by which telomeres shorten over 15 years of normal
human aging on average, and our drug is transient, being turned
over within a few days.
Uniquely, this approach has the potential to enable safe telomere
extension therapy, because it extends telomeres so rapidly that
the treatment can be very brief (a few days), leaving the normal
anti-cancer telomere-shortening mechanism intact immediately after
the brief treatment ends. Our drug does not integrate with the
genome, is non-immunogenic as it comprises the same modified
nucleosides recently discovered to comprise mature mammalian mRNA,
and can encode forms of telomerase which avoid post- translational
regulation enabling telomere extension even in slowly-cycling cell
populations such as some progenitors.
We and our collaborators are applying our drug to several
age-related conditions mediated by short telomeres: hypertension
and heart failure (Cooke and Blau labs), immunosenescence (Weyand
lab), and vascular dementia (Yesavage lab) (see supporting
letters). Each of these applications will be facilitated by this
project: here we propose to initiate translation of our drug
toward human studies by optimizing its intravenous delivery and
demonstrating its safety and efficacy. To optimize i.v. delivery
of our drug we will compare the best current and cutting-edge RNA
vehicles. In 2007 it was discovered that in the human body,
exosomes transport mRNA between cells via body fluids including
blood, and in 2011 autologous exosomes were used to deliver
nucleic acid via i.v. injection. We will test autologous exosomes
as vehicles for i.v. delivery of our drug. We will use our best
i.v. delivery method to extend telomeres of vascular endothelial
cells to prevent or treat hypertension in the short-telomere
mTERC-null mouse model of hypertension. Hypertension is the major
risk factor in heart failure, and mice with short telomeres
exhibit both hypertension and heart failure, and short telomeres
predict both conditions in humans. In both mice with short
telomeres and in humans, a key causative mechanism of hypertension
is excess endothelin-1 production by senescent endothelial cells,
and we (the Cooke lab) have shown that telomere extension prevents
endothelial cell senescence. Thus there is strong evidence
supporting the hypothesis that extension of endothelial cell
telomeres by our drug will help prevent or treat hypertension. We
will also test the safety of our drug by quantifying immune
response, tumor formation, and effect on lifespan in the
short-telomere hypertensive mice.
If successful, this work will initiate translation of our rapid,
safe telomere extension therapy toward the clinic for prevention
and treatment of hypertension and other age-related conditions by
us and our collaborators...
COMPOUNDS, COMPOSITIONS, METHODS, AND KITS
RELATING TO TELOMERE EXTENSION
US2014242154 / WO2014130909
[ PDF ]
Blau, et al.
Compounds and compositions for the transient expression of
exogenous telomerase activity in a cell are provided. The
compounds and compositions, which relate to a ribonucleic acid
coding for a telomerase reverse transcriptase, are useful in the
extension of telomeres in cells needing such treatment. Such cells
include, for example, cells that contain shortened telomeres and
cells from subjects that may benefit from telomere extension, for
example subjects that suffer from, or are at risk of suffering
from, age-related or other illnesses. Also provided are methods of
extending telomeres through the administration of the provided
compounds and compositions to animal cells, either in vitro or in
vivo, and kits including the compounds and compositions and
instructions for use.
The mission of CELLSCRIPT is to provide the best products and
technologies for making and using RNA for translation in cells for
clinical research and therapeutics.
Current products include kits for in vitro transcription, 5' RNA
capping using either a cap analog or capping enzymes, and 3' RNA
polyadenylation, as well as all-in-one kits for making capped,
poly(A)-tailed mRNA for translation in cells.
As documented in journal articles1–3 and patent applications, the
technologies on which INCOGNITO RNA kits and other products are
based were invented by Professors Katalin Karikó and Drew Weissman
at the University of Pennsylvania and exclusively licensed to
CELLSCRIPT for all fields of use. Drs. Weissman and Karikó showed
that INCOGNITO mRNA, besides being less immunogenic, is translated
into protein at much higher levels than the corresponding mRNA
that does not contain modified nucleosides, both in cultured cells
and in whole organisms. INCOGNITO-type - and m5C-modified mRNA
encoding KLF4, LIN28, cMYC, OCT4 and SOX2 that was repeatedly
transfected into somatic cells, such as fibroblasts and
keratinocytes, resulted in highly efficient generation of induced
pluripotent stem cells.
The delivery of protein-encoding INCOGNITO mRNA to cells in
culture or in vivo to an organism has the potential to produce a
therapeutic effect by compensating for a missing or defective
protein, overexpressing a desired protein, inducing a change in
cellular phenotype, or triggering a disease-specific immune
response. Thus, we believe INCOGNITO mRNAs will have many uses in
regenerative medicine, such as for: cell reprogramming; cell
therapies; cell, tissue or organ transplantation or repair; tissue
or organ engineering; enzyme replacement therapies; and
immunotherapies or immunomodulation therapies...
CELLSCRIPT recently introduced INCOGNITO™ RNA Transcription Kits
for in vitro synthesis of RNA that contains modified nucleosides,
such as pseudouridine (?) and/or 5-methylcytidine (m5C) in place
of the corresponding U or C canonical nucleosides (Figure 1).
These kits are so-named because the capped, polyadenylated and
nucleoside-modified RNA products (called "INCOGNITO mRNAs") are
disguised so they do not induce innate immune responses to the
same extent as the corresponding unmodified mRNAs when transfected
into mammalian cells that express a variety of RNA sensors...
RNA containing modified nucleosides and methods of use
KATALIN; WEISSMAN DREW
This invention provides RNA, oligoribonucleotide, and
polyribonucleotide molecules comprising pseudouridine or a
modified nucleoside, gene therapy vectors comprising same,
methods of synthesizing same, and methods for gene
replacement, gene therapy, gene transcription silencing, and
the delivery of therapeutic proteins to tissue in vivo,
comprising the molecules. The present invention also provides
methods of reducing the immunogenicity of RNA,
oligoribonucleotide, and polyribonucleotide molecules.
Inventor(s): ROWLEY PETER
The invention relates to nucleic acids encoding or comprising
interfering RNAs which target telomerase RNA or mRNA encoding the
telomerase reverse transcriptase (TERT). The invention includes
methods for inhibiting telomerase activity expression vectors, and
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