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Stop Making Sense: Antisense Therapies for Rare Diseases Show Promise

Publication date: 21 Apr 2019

Confounding conventional wisdom that the perfect translation of genetic information prevents disease, new approaches using antisense oligonucleotides (ASO’s) intentionally disrupt the normal information transfer process.  ASO's are short pieces of genetic material that have potential therapeutic effects when taken up by diseased cells.  For some disorders, the correct reading of the genetic code leads to the synthesis of abberrant proteins contributing to disease development. The introduction of an ASO alters the transfer of information such that the synthesis of a functional protein that counteracts disease symptoms is enhanced.  Two recent examples suggest that ASO therapies can be effective in the treatment of specific rare diseases.

Spinal Muscular Atrophy (SMA) is a neuromuscular disorder caused by a defective SMN1 gene unable to produce sufficient quantities of the protein SMN that promotes survival of motor neurons that control muscle movement. Degeneration of motor neurons lead to symptoms ranging from muscle weakness to severe paralysis and death. Spinraza™ is a FDA-approved ASO therapy used to treat SMA.  It enhances the synthesis of functional SMN protein from a related gene called SMN2 by altering the processing of its genetic message.  By doing so, SMN protein levels increase, motor neuron survival improves and the symptoms of SMA are alleviated.  In this situation, a “sense” message that contributes to the disease specifically binds to a complementary “antisense” RNA oligonucleotide that changes how the message is decoded and translated into protein.  The net effect is much like inserting a bypass for a broken zipper tooth to restore function.

The success and mechanism of action of Spinraza™ served as a model and inspiration for physicians treating Mila, a 6-year-old girl suffering from Batten Disease, an invariably fatal neurodegerative disorder.  There are different variants of Batten Disease, some of them with available treatments.  Mila´s variant had no approved treatment, but her case was special. She has an alteration in the CLN7 gene that prevents the production of a funcional MFSD8 protein.  In her situation, the genetic information necessary for producing the functional MFSD8 protein was present, but masked.  Her doctors applied the same concept used for Spinraza™ and pursued development of an ASO treatment for Mila that would allow her body to correctly read the CLN7 gene and produce a healthy MFSD8 protein.  They were able to obtain crowdfunding needed to support the research effort and to convince regulatory authorities to allow a custom therapy for an otherwise untreatable condition. Mila has been receiving her personalized medicine, appropriately named milasen, for some months and she has experienced an improvement in her symptoms.

Although this is certainly optimistic news, caution is needed in not over-extrapolating such results.  The genetic mutation in Mila was unique in that the genetic information required to produce the healthy protein was present, but masked. The tailor-made treatment only helped to reveal it.  In addition, Mila was extremely fortunate in that the physicians treating her had necessary research funding and were willing to invest it in her case.  The regulatory scenario was also very favorable⎼ the process was carried out under a “compassionate use” pathway and a “one patient trial” for Mila was approved. More typically, a randomized clinical trial is required in which portions of a study population are split between those receiving the experimental therapy and a placebo.

These circumstances make Mila´s case an extraordinary one.  However, after Mila´s success story, the same therapeutic approach is being sponsored by the Aashi Foundation for another girl affected by Batten Disease.   The promise of ASO’s in the treatment of rare diseases is being advanced one patient at a time.