The development of nucleic acid therapeutics for neurological diseases is rapidly evolving, with nusinersen approved and more than 10 nucleic acid drug candidates in clinical development for use in disorders of the CNS. Dozens more nucleic acid drugs for neurological targets are at the stage of early preclinical development.
There is a significant cross-talk in platform technology development for neurological diseases. A single AAV capsid that gives broad delivery to the brain may be used to deliver many cargo genes to treat different diseases. Similarly, if a chemical modification pattern is functional and nontoxic for one antisense oligonucleotide, it is an ideal starting point for the development of others (though of course there is still some selection and optimization required). We have recently coined the term “dianophore” to describe the ensemble of molecular features that determine the distribution and pharmacokinetic parameters of a drug. This term is contrasted with the pharmacophore, which is the ensemble of molecular features that determine target recognition and modulation .
By way of illustration, it took many years of focused work for Ionis and Biogen to obtain the first approval of nusinersen as an antisense oligonucleotide for use in the CNS. But using the same chemical modification pattern as was used in nusinersen, the group of Timothy Yu (Harvard Medical School) was able to develop a custom drug for a single pediatric patient with Batten disease in a matter of months . Thus, we expect that the pace of development of nucleic acid therapeutics for neurological diseases will continue to accelerate in the coming years.
There is also a significant cross-talk in terms of gene targets between different neurological conditions. Although the initial trigger of neurodegeneration is different in each disease, in many cases, downstream pathways of neurodegeneration and inflammation are shared and, thus, one target may be applicable to the treatment of multiple genetically distinct diseases. The most advanced nucleic acid drug candidates are focused on well-defined monogenic diseases such as spinal muscular atrophy, ALS, and HD. But a major advantage of nucleic acid therapeutics is the ability to simultaneously address multiple targets because oligonucleotides of many sequences can have similar pharmacokinetic properties. This is likely to be particularly important for the treatment of complex neurodegenerative disorders including AD and PD. It is even more likely to be required for therapeutics in the fields of neuro-oncology and trauma.