The document discusses the author's research into Spinal Muscular Atrophy (SMA), a neurodegenerative disease. Through constructing hundreds of minigenes with deletions and mutations, the author discovered a rare genetic element called Intronic Splicing Silencer-N1 that inhibits SMN2 gene splicing. The author then developed novel antisense oligos to block ISS-N1 and allow production of functional SMN protein from SMN2. This work established antisense oligos as a potential treatment for splicing-related diseases. The author's findings led to a US patent application and informed the development of the first approved SMA treatment, Spinraza, by Ionis Pharmaceuticals.

1. I am a Ph.D. Scientist experienced in Neurobiology and Molecular Biology.
My research in the field of genetic disorder disease, Spinal Muscular Atrophy (SMA) has been
an important milestone in the field. SMA is a neurodegenerative disease and a leading killer of
the infants and toddlers. SMA is caused by defects in alternative splicing process on a very
important human gene called Survival of Motor Nueron “SMN1” thereby generating the non-
functional SMN protein. This protein is essential for survival of neuronal cells that are present in
the spinal cord. Absence of this protein destroys the motor neurons that control muscles
because of which muscles in the limbs, neck and chest become weak and the patient dies
within two years. My research discovered a novel way out to make the functional SMN protein
from the defective SMN2 gene by correcting its abnormal splicing via antisense -mediated gene
therapy.
In connection to this work, I have constructed hundreds of minigenes (US Patent Application #
20070292408) with deletion and mutations of DNA sequences in coding and non-coding
(intron) regions of SMN genes. I examined the effect of these individual mini genes on splicing
of SMN gene by introducing them various cell lines including SMA patient cells. Using this
approach, my trailblazing research has discovered, for the first time in the history of SMA
research, a rare genetic element in the Intronic region of SMN gene in collaboration with my
coworkers. This novel inhibitory element we named as “Intronic Splicing Silencer-N1” (ISS-N1).
This powerful element was proved to be one of the best drug target site for the cure of SMA.
Subsequently, I (with my Convectors at UMMS) have developed novel anti-sense oligos to block
the function of this inhibitory element so that a functional SMN2 protein could be produced.
Subsequently, I designed specific RNA molecule called antisense oligo that can be programmed
to bind specifically to ISS-N1 region of defective SMN2 gene. The antisense oligo successfully
caused the splicing machinery to include an important portion of SMN2 mRNA that is usually
skipped. My finding establishes that such antisense oligo molecules have strong potential
beneficial for treating a great diversity of splicing related human disease. My innovative work
related to cure of Spinal Muscular Atrophy has led to the US patent application # 20070292408.
My findings have opened a new avenue of investigation which has already proved very effective
for the treatment of SMA and serves as proof of principle for the use of similar RNA-based
splice-modulating molecules in other neurological disorders.
http://www.nature.com/scibx/journal/v2/n26/pdf/scibx.2009.1030.pdf
Our patent application (US Patent 20070292408 “Spinal Muscular Atrophy (SMA) Treatment via
targeting of SMN2 Splice Site Inhibitory Sequences”) was licensed from Univ. of Massachusetts
by “IONIS Pharmaceuticals” to develop their Drug – “Spinraza”.
Spinraza: not only the first-ever approved treatment for this disease, but also one that
addresses the underlying genetic cause of SMA. http://www.curesma.org/news/spinraza-
approved.html