A fascinating new genre of drugs – Antisense
oligonucleotides – is being developed for what were considered incurable
diseases. The US Food and Drug Administration (FDA) has now approved
Spinraza (nusinersen) for treatment of Spinomuscular atrophy (SMA). The
mechanism of action of this drug is worth understanding. The defect in
SMA is due to a mutation in the SMN1 gene. In humans, there
exists an alternative gene called the SMN2. This encodes a nearly
identical protein which differs from SMN1 by 11 nucleotides.
However, due to a single difference in exon-7 of SMN2 gene, there
is altered RNA-splicing of this transcript. The protein produced by this
gene rapidly degenerates.
In 2003, Adrian Krainer, a biochemist at the Cold
Spring Harbor Laboratory in New York, developed antisense
oligonucleotides (ASO), which is a short length of nucleotides which
could bind to the pre mRNA produced by the SMN2 gene. This
prevents splicing out of the exon-7. Hence a more stable protein is
produced. Initial studies in mouse models showed that intrathecal
injection of ASO led to increased production of SMA protein, and
improved strength. Subsequent human studies showed that 40% of children
injected with the drug showed improvement of motor milestones.
Additional clinical trials, though uncontrolled, continued to show a
positive response. FDA then assigned it a fast track designation,
priority review and orphan drug status.
Dosage recommendation is 12 mg intrathecally every 14
days for three doses. The fourth loading dose is given after 30 days of
the 3rd dose. Maintenance doses are continued every 4 months. The drug
is being marketed by Biogen, and the cost per dose will amount to $
125,000.
ASO, which modify mRNA transcription, are being used
for a range of diseases, including HCV, HIV, Ebola and CMV. An ASO
targeting the mRNA of GATA3 (a transcription factor that promotes Th2
responses) is being used for severe asthma. The antisense ODN mipomersen
(Kynamro), which targets the mRNA of Apolipoprotein B100, received
regulatory approval for use in humans with familial
hypercholesterolemia. (www.fda.gov 23 December 2016)
Youth Suicides in India
Youth suicides have reached crisis levels in India.
In the 1990’s when Australia faced a similar situation, a concerted
effort by the government saw a remarkable decline in suicide rates in
young people. The December 2016 issue of the Economic and Political
Weekly carries an erudite discussion of problem in India with
comparisons from Australia. There appears to be little public awareness
or concerted health policy to tackle this issue in India.
In Australia, between 1900 and 1990, teenage girl
suicides remained between 5-10 per lakh population. In young males, from
a low of 5.3 at the depths of World War II in 1943, rates rose steadily,
decade by decade. By the early 1980’s, the rate was almost 23 per lakh,
and by end of the decade it had reached over 33 per lakh.
It was finally labeled a ‘crisis situation’, and the
Australian government initiated a series of reports, which culminated in
the formulation of a national strategy for suicide prevention. After the
National Youth Suicide Prevention Strategy, suicide rates in Australia
plunged dramatically to an average of 11.9 per lakh in 15-19 year-olds
and 18.4 per lakh for young adult males in the age group of 20-24 years.
Youth suicides are preventable. About 80% of
teenagers contemplating suicide communicate their intention to a friend
or a family member. And only one in 40 attempts results in death. A
significant number never make a second attempt, and thus suicide
prevention programs can be very effective.
In broad terms, the youth and young adult suicide
rates in India were relatively constant at around 15 per lakh since
1967. However, the estimated all-India suicide rate in 2010 for males
aged 15–29 was 25.5 per lakh, and for females it was 24.9 per lakh.
Indeed, if we bear in mind the ‘15 per lakh equals crisis’ rule of
thumb, the young male suicide rates in 17 of the Indian states and
territories are near or well above that rate. Strangely, Puducherry has
the highest young male suicide rate in the world (82.7), far higher than
the leading country Lithuania (44.9). We all need to wake up, take
notice, and act. (Economic & Political Weekly 24 December 2016).
Healthcare Audit in Rural Madhya Pradesh
An audit of healthcare providers in rural Madhya Pradesh (MP) by
economists has revealed interesting data. In a study, highly trained
fake patients (called standardized patients) were coached to present
symptoms like normal patients for three diseases – angina, asthma and
dysentery. They made 1100 unannounced visits to public and private
health facilities in rural MP. Seventy percent of private health
providers, to whom these patients went, had no formal training, and
would be classified as quacks as per norms of the Medical Council of
India. The average time spent per patient was 2.4 minutes by public
health providers, and 3.7 minutes by private providers. A diagnosis was
provided by 26% and 43% of the public and providers, respectively; and
it was ‘correct’ in 15% and 13.5%, respectively. The per patient cost of
the public health care system was Rs 240, billed not to the patient but
to the exchequer. The per patient consultation fee was Rs 51 in the
private sector. The study concludes that most private providers "exerted
significantly higher effort than public providers" and "recommend
correct treatments equally often." This study provides valuable insights
into what is the quality of health care available at the grass root
level in India. (The Hindu 11 December 2016).