The Journal of the Arkansas Medical Society Med Journal Feb 2020_Final | Page 17

ment. Neuromuscular scoliosis is often seen and
may need surgical correction. Intensive physical
and occupational therapy is important to main-
tain range of motion and decrease disability. Of-
ten orthotics and mobility assistance, for exam-
ple with a power or ultralight manual wheelchair,
are also needed. Patients with severely abnormal
swallowing may need feeding through a gastros-
tomy tube. Osteopenia also needs management
with supplements or medication like alendronate.
Airway obstruction in sleep may need to be man-
aged with a bilevel positive airway pressure (Bi-
PAP) device. However, even with intensive man-
agement, until very recently, the natural history
of the disease was that of gradual but inevitable
motor decline and usually early death.2,4,5
New Disease-Modifying Therapies
Happily, the bleak prognosis and natural history
of this disease may change with the availability of
disease-modifying therapies aiming to improve
motor function. Nusinersen is the first and only
such therapy currently approved by the U.S. Food
and Drug Administration. Considering the patho-
physiology of the disease, boosting SMN protein
production from SMN2 by promoting exon 7 in-
clusion is an obvious target. This is achieved by
nusinersen, a synthetic antisense oligonucleotide
(ASO). ASOs are lab-designed, short ribonucle-
ic acid (RNA) pieces that are a mirror-image of
the natural RNA that they bind to. Nusinersen
masks portions of the SMN2 messenger RNA
that inhibit the exclusion of exon 7. This allows
for the inclusion of exon 7 into the SMN2 final
mRNA transcript, resulting in production of more
full-length normal SMN protein. Nusinersen
improves motor function in all SMA types and
prevents disease onset/progression in pre-symp-
tomatic patients. ASOs do not cross an intact
blood–brain barrier, so the drug is injected intra-
thecally with the recommended treatment regi-
men of four loading doses: the first three doses
at 14 days interval, fourth dose 30 days after the
third dose, and maintenance dosing every four
months thereafter. Besides the obvious involved
process of drug administration and attendant dis-
comfort to the patient, side effects are relatively
minimal. The drug is eliminated by the body un-
changed in the urine. Prothrombin time, platelet
count, and urine proteins need to be monitored
prior to each nusinersen injection to screen for
development of clotting problems or kidney inju-
ry as mild thrombocytopenia and elevated urine
protein were noted in minority of patients treated
in the clinical trials. Although this medicine is not
curative, results are encouraging with about 50%
of the treated patients showing improvements in
the motor evaluation measures. 2,6
A gene therapy product for SMA awaits FDA ap-
proval. The best approach for treatment, consid-
ering the genetics of SMA, would be to replace
the absent SMN1 gene. The relevant genetic ma-
terial is delivered via a viral vector, Adeno-Asso-
ciated Virus 9 (AAV9). A single-dose intravenous
infusion of AAV9 vector containing DNA coding
for SMN protein resulted in longer survival, supe-
rior achievement of motor milestones, and better
motor function in patients with type 1 SMA than
in historical cohorts. 7 It is proposed that infants
will receive a one-time intravenous dose, and
older individuals a one-time intrathecal dose of
this product. Trial results are very encouraging.
Other potential therapies are undergoing trials.
Oral medication to boost SMN production from
SMN2 is being tested. SRK-015, a highly spe-
cific inhibitor of myostatin activation, is being
evaluated for efficacy. Research is underway to
identify potential modifiers in SMA, including the
gene plastin, which has been reported to modify
SMA symptoms in female patients, but not male
patients. Other cellular pathways such as the
mTOR, U12 splicing/stasimon, or the p38αMAPK
pathway that are altered in SMA and may contrib-
ute to how the disease develops, are also being
studied. 2,3,6
Conclusion
The recent advancements in the treatment for
SMA necessitates the care in a multidisciplinary
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