6 MARCH 2015 • VOL 347 ISSUE 6226 1069 SCIENCE sciencemag.org
differs greatly from the genetically based
tree of extant species; it does not recover
the extant platyrrhine family Cebidae and
misplaces many extant genera within their
Although platyrrhines almost certainly
rafted from Africa in the mid-Cenozoic, a
precise link between Amazonian
Perupithecus and any particular African taxon or
taxa remains obscure. The fragmentary nature of the new fossils, the use of a morphological data set with only dental characters,
and conflicts with genetic data raise doubt
about Bond et al.’s conclusions. Their tree
may minimize convergent evolution (
homoplasy) in the dentition, but it omits cranial
and postcranial characters for which their
proposed topology would increase homoplasy. Likewise, gene sequence data must
provide a framework for the placement of
extinct taxa when analyzed in combination
with living ones.
Perupithecus reveals tantalizing information that the niche of the earliest platyrrhines was very different from that of its
larger, more herbivorous living relatives. Its
small body size and molar structure suggest
insectivory (12). Coexistence with brachydont
rodents suggests that it was a forest dweller
much like Late Eocene African anthropoids.
This pattern contrasts with the adaptations
of the younger Branisella—a larger, more frugivorous, and possibly scansorial (climbing)
animal (13). Perupithecus’ presence in today’s
Amazon basin confirms that this region was
long the center of platyrrhine development
that still is largely unknown (14). ■
1. M. Bond et al ., Nature 10.1038/nature14120 (2015).
2. R. F. Kay, B. J. Mac Fadden, R. H. Madden, H. Sandeman, F.
Anaya, J. Vertebr. Paleontol. 18, 189 (1998).
3. M. Takai, F. Anaya, N. Shigehara, T. Setoguchi, Am. J. Phys.
Anthropol. 111, 263 (2000).
4. N. S. Upham, B. D. Patterson, Mol. Phylogenet. Evol. 63,
5. P. Perelman et al., PLOS Genet. 7, e1001342 (2011).
6. E. R. Seiffert, Evol.Anthropol. 21, 239 (2012).
7. C. D. Frailey, K. J. Campbell, Nat. Hist. Mus. Los Angeles
County Sci. Ser. 40, 71 (2004).
8. P.-O.Antoine et al., Proc. R. Soc. B Biol. Sci. 279,1319
9. O. C. Bertrand et al ., Am. Mus. Novit. 3750, 1 (2012).
10. E. R. Seiffert et al ., Science 310, 300 (2005).
11. D.E.Wildman,N.M.Jameson,J.C.Opazo,S.V.Yi, Mol.
Phylogenet. Evol. 53, 694 (2009).
12. R. F. Kay et al ., in Early Miocene Paleobiology in
Patagonia: High-Latitude Paleocommunities of the
Santa Cruz Formation, S. Vizcaíno, R. F. Kay, M. Bargo,
Eds. (Cambridge Univ. Press, Cambridge, UK, 2012), pp.
13. R. F. Kay, B. A. Williams, F. Anaya, in Reconstructing
Behavior in the Primate Fossil Record, J. M. Plavcan, C. van
Schaik, R. F. Kay, W. L. Jungers, Eds. (Kluwer Academic/
Plenum, New York, 2002), pp. 339–370.
14. R. F. Kay, Mol. Phylogenet. Evol. 82 (Pt. B), 358 (2015).
SUPPLEMEN TAR Y MATERIALS
RNA interference (RNAi)–based drugs harness endogenous posttranscrip- tional gene silencing pathways for therapeutic purposes. The goal is to turn down or shut off the expression of genes known to contribute to or
cause disease. RNAi “triggers” are typically
double-stranded RNAs (dsRNAs) of which
one strand has a sequence complementary
to that of a messenger RNA (mRNA), resulting in the reduction or elimination of that
an mRNA and its corresponding protein
product. The dsRNAs can be provided as
synthetic oligonucleotides or as genetic DNA
templates from which the RNAi triggers are
transcribed in the target cells (vector-based
transcriptional RNAi) (see the figure).
Key to the therapeutic utility of these
RNAi triggers is the ability to introduce
them into their target cells in the body.
Such delivery is typically facilitated by formulation into nanoparticles, simple conjugates, or viral vectors (see the figure). To
date, at least three delivery technologies
(liposomal nanoparticles, simple conjugates, and polyconjugates) have shown
highly persistent silencing of target gene
expession in the liver of humans and nonhuman primates, suggesting therapeutic
dosing frequencies as low as once-monthly
or once-quarterly (1–3).
There are two lead RNAi drug candidates
(ALN-TTR02 and ALN-TTRsc) in phase III
trials that target the disease-causing mutant
transthyretin (TTR) mRNA in the liver for
the treatment of familial amyloid polyneu-ropathy. Given that deficiency of the TTR
gene product is expected to be well tolerated
and the mutant TTR protein causes the disease, the target risk is low, and commercialization may happen as early as 2017
(ALN-TTR02). Beyond the TTR amyloidosis
candidates, there is an expanding pipeline
of RNAi gene targets in the liver. These include candidates for diseases ranging from
important public health issues (e.g., hepatitis B virus infection, common forms of metabolic and cardiovascular disorders, liver
cancer) to the rare and severe (e.g., triglycer-ide-related pancreatitis, primary hyperoxal-uria 1, α1-antitrypsin–related liver disease).
N-Acetyl-galactosamine (GalNAc) siRNA
conjugates targeting the liver have emerged
as an attractive delivery option offering the
prospect of infrequent (once-monthly or
even once-quarterly) subcutaneous dosing,
making them suitable for other common
chronic diseases such as type II diabetes
and hypercholesterolemia (2).
Although the liver is a favored organ for
delivery owing to its physiological role in
removing particles from circulation, it is
less clear whether new approaches aimed at
nonhepatic tissues will provide therapeutic
efficacy. These smaller nanoparticles, conjugates, self-delivering RNAi triggers, cationic lipoplexes, and transcriptional RNAi
methods hold particular promise for targeting cancer cells, phagocytic cells, vascular
endothelial cells, cell populations in the
kidney, cells in the back of the eye, and the
various cells types in the central nervous
system (CNS) (4).
For diseases requiring life-long treatment, as well as for the hard-to-reach
(e.g., CNS) tissues and/or tissues that rapidly turn over, such as blood-derived stem
cells, transcriptional RNAi methods currently have a practical advantage, because
of the prospect of persistent activity after
single administration. In addition, transcriptional RNAi may be a better match for
certain diseases where both the addition of
a normal gene, as well as silencing of the
endogenous mutated gene, are beneficial.
This would include diseases such as sickle
cell anemia (5) or the most common form
of α1-antitrypsin deficiency (6). However,
one disadvantage is that dosing is more
difficult to control with vector-transcribed
RNAi. Transcriptional RNAi candidates in
clinical development today address cancer,
HIV, and hepatitis C virus, as candidates
for α1-antitrypsin deficiency and neurodegenerative disorders approach the clinic.
This compares to over 20 synthetic RNAi
trigger clinical candidates.
It remains to be seen how the safety pro-
file from the largely short-term experience
By Dirk Haussecker1 and Mark A. Kay2
RNAi therapeutics are
emerging as a major drug
1 RNAi Therapeutics Consulting, Rastatt, Germany. 2 Pediatrics
and Genetics, Stanford University, Stanford, CA, USA. E-mail:
“Beyond the TTR
there is an expanding
pipeline of RNAi gene