Editorial
Vision quest: gene therapy for inherited vision loss
Biomedical research and clinical trials are fundamentally
high-stakes endeavours, the results of which are often
portrayed in hyperbolic categories. Failed phase 3 trials are
called epic disappointments, while successful treatments
become game changers or magic bullets. Better still, they
receive US Food and Drug Administration (FDA) approval.
Jamie Grill-Blend Images/JGI
Nevertheless, there are few clinical success stories
that follow such an impressive narrative arc as Luxturna
(voretigene neparvovec-rzyl), which, on Dec 21, 2017,
became the first directly administered gene therapy
approved by FDA to treat children and adults with
confirmed biallelic RPE65 mutation-associated retinal
dystrophy. Mutations in the RPE65 gene can impair the
production of an enzyme critical to the retinoid cycle
and contribute to progressive vision loss, resulting
in complete blindness by childhood or adolescence,
once considered untreatable. A follow-on phase 1 trial
See Articles Lancet 2016; published by Jean Bennett and colleagues in The Lancet in
388: 661-72
See Articles Lancet 2017;
2016 showed that subretinal injection of a normal copy
390: 849-60 of the RPE65 gene via an adeno-associated virus vector
Tuberculosis: criteria for global leadership?
Tereza Kasaeva is to be the new Director of WHO’s
Global Tuberculosis (TB) Programme. She joins WHO
from Russia’s Ministry of Health. But instead of a warm
welcome, she will arrive in Geneva amid potentially
Denis Balibouse/Reuters
disabling controversy.
In December, WHO Director-General Dr Tedros received a
letter from a respected list of individuals and organisations
urging him to implement “a competitive, open process...
to identify an experienced, change-oriented leader...
to drive forward evidence-based guidance and advance
human rights in this pivotal moment on TB”. The
objective of such a transparent selection process was in
part “to solicit the input of various stakeholders, including
civil society”. WHO rejected their request.
Tedros has identified gender disparity among WHO
Directors as one of his most important organisational
challenges. He has already made several Director
appointments to address the gender and geographical
imbalances in leadership within the agency. But in the
case of Kasaeva, activists have raised questions about
her international expertise and experience. They are
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contralateral to a previously treated eye was safe and
yielded durable mobility and light sensitivity responses.
Importantly, this phase 1 trial also paved the way for
a successful phase 3 trial of voretigene neparvovec
reported by Stephen Russell and co-authors in The Lancet
in 2017, by prompting development, with FDA input, of
a standardised and clinically meaningful multiluminance
mobility test as a primary endpoint.
The story of voretigene neparvovec is an illustration
of the value of the iterative clinical trials process—each
phase providing value in determining the safety, efficacy,
and effectiveness of a treatment—but it is also symbolic
of a new era in gene therapy. Where previous explorations
had been limited to oncology, the application to
inherited vision loss is hope-inspiring and will spur novel
interventions for some of the most clinically challenging
conditions. It is worth acknowledging these triumphs
of ingenuity and perseverance not simply as failures or
successes but as validation of the biomedical research
enterprise itself. n The Lancet
frustrated that she was named without any external call
for candidates and that there was no consultation with
the broader TB community.
An additional anxiety is that Russia has a poor record
on TB and HIV. Her appointment may be regarded as
rewarding a country that does not deserve to be rewarded.
As one WHO Director told The Lancet, “Will [she] have
credibility or a mandate? Does this politicise the technical
side of the organisation?” By contrast, others, such as
Lucica Ditiu who leads the Stop TB Partnership, praised
Kasaeva’s appointment.
WHO’s reputation—indeed, its political leverage—
depends on the agency’s technical credibility. The sharp
divisions that Kasaeva’s appointment has created bode ill
for efforts to align the TB community during a year when
the disease will receive unprecedented attention at a
high-level meeting to be held during the 2018 UN General
Assembly. It will now be important for Kasaeva to reach
out to a sceptical TB community to reassure them of her
commitment to engage and build a powerful movement
for action on this still neglected disease. n The Lancet