シンポジウム
47 今や主流になった神経難病の核酸医薬創薬の最前線
47 Update of oligonucleotide therapy as a major trend of drug discovery for intractable neurological diseases
座長：横田 隆徳（東京医科歯科大学 脳神経病態学分野） |
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| 2022年7月3日 14:00～14:30 沖縄コンベンションセンター 会議場B2 第5会場
4S05a-01
Current Status of ASO Therapy for ALS
*John Ravits(1)
1. University of California, San Diego
Keyword: SOD1, C9ORF72, FUS, ATXN2
ALS is characterized clinically by progressive weakness that is usually fatal over 3-5 years from respiratory failure and caused mechanistically by degeneration of motor neurons. Since clinical weakness is a direct read-out of neurodegeneration over a short time, ALS has become a fertile testing ground for proof-of-principle that ASOs will work in intractable neurological diseases. ASOs have versatile mechanisms of action that depend on modifications of chemical design and include transcript reduction by RNase H-dependent mechanisms and altered gene splicing by pre-mRNA binding. Most of the therapeutic strategies in the clinical trials in ALS have used the former (transcript reduction) and targeted genetic mutations which are thought to act through gain-of-function mechanisms. Thus far, there are three large scale trials in ALS: for SOD1, C9orf72, and FUS mutations. The phase 1 SOD1 trial showed SOD1 protein reduction (target engagement) but phase 3 trials did not meet the primary objective. However, positive trends were observed that suggested earlier intervention or longer treatments might have been effective. A current trial is underway recruiting asymptomatic/presymptomatic carriers of SOD1-mutations known to cause rapidly progressive disease. This trial is following the blood neurofilament longitudinally. This biomarker rises at the onset of disease and heralds clinical conversion and will determine when to start treatment. The clinical trial of an ASO targeting C9ORF72 in C9ORF72-mutated patients was stopped after completion of the phase 1 trial. The findings and reasons for not advancing to phase 3 are pending at this time (April, 2022). A pivotal clinical trial of FUS-mutated ALS has recently opened and expected to be completed in 2-3 years. The majority of ALS cases are sporadic, not genetic. These cases are characterized neuropathologically by both nuclear clearing and cytoplasmic aggregation of TDP-43. This suggests that loss of TDP-43 functions as well as gain-of-toxcity is critically involved and it cannot be targeted by a transcript reducing strategy. But interesting ASO work-around approaches for sporadic ALS patients have been identified and two of them are entering phase 1 clinical trials. One is targeting ATXN2 which is a TDP-43 co-partner that appears to be amenable to transcript reducing strategy. The other is targeting STMN2 which is a gene vital for axon regeneration but prematurely truncated by loss of TDP-43 function uncovering a cryptic exon in intron 1. Using a gene-splicing (rather than gene reducing) approach, the ASO will occupy a site on intron 1 of the STMN2 pre-mRNA to enable full transcript processing. Both these trials will take 2-4 years to complete. | | 2022年7月3日 14:30～15:00 沖縄コンベンションセンター 会議場B2 第5会場
4S05a-02
Integrating structure and function to guide development of therapeutic siRNAs for the central nervous system and beyond.
*Chantal Ferguson Ferguson(1,2), Julia Alterman(1,2), Ken Yamada(1,2), Dimas Echeverria(1,2), Bruno Godinho(1,2,3), Matthew Hassler(1,2,3), Neil Aronin(1,2,4), Anastasia Khvorova(1,2,4)
1. University of Massachusetts Medical School, 2. RNA Therapeutics Institute, 3. Atalanta Therpeutics, 4. Department of Medicine
Keyword: siRNA, oligonucleotide, chemically modified siRNA, neurodegeneration
Small interfering RNAs (siRNAs) and antisense oligonucleotides (ASOs) comprise a novel class of drugs that are programmable to silence any target gene. The development of chemical scaffolds that incorporate modifications to the endogenous sugar backbone, modifications to the diester linkages, and addition of bioconjugates has allowed for potent and reproducible efficacy of siRNAs in organs such as the liver. However, a clinical need remains to identify siRNA chemical structures that result in potent and sustained target silencing in the CNS, and that impact disease progression. Chemical engineering efforts resulted in divalent siRNAs (di-siRNA) development, which support robust and long-term efficacy in rodent and non-human primate (NHP) brains upon direct cerebrospinal fluid (CSF) administration. Here, we describe the rationale behind the develompent of di-siRNAs for CNS activity, the lessons learned from incorporating knowledge of CNS structure and function, and the lessons learned from previous research efforts and therapeutic oligonucleotide development. We further show the applicability of di-siRNAs to multiple targets relevant to the CNS and neurological diseases. | | 2022年7月3日 15:00～15:30 沖縄コンベンションセンター 会議場B2 第5会場
4S05a-03
血液脳関門通過を可能としたヘテロ2本鎖核酸
Blood-brain barrier penetrating heteroduplex oligonucleotide
*永田 哲也(1)
1. 東京医科歯科大学 脳神経病態学分野
*Tetsuya Nagata(1)
1. Department of Neurology and Neurological Science, Tokyo Medical and Dental University
Keyword: Blood-brain barrier, antisense oligonucleotide, heteroduplex oligonucleotide
Following the success of Nusinersen for spinal muscular atrophy, development of oligonucleotide therapy targeting the causative genes for many neurodegenerative diseases: Parkinson's disease, Alzheimer disease and familial amyotrophic lateral sclerosis is underway. On the other hand, antisense-oligonucleotide or siRNA do not migrate to the central nervous system (CNS) by systemic administration and are now generally administered by intrathecal injection. Therefore, we aimed to develop an antisense oligonucleotide drug that can cross the blood-brain barrier (BBB) by systemically administered. We first conjugated single-stranded antisense-oligonucleotide or our original heteroduplex oligonucleotide (HDO) with ligands such as lipids, and administered them intravenously to mice to investigate whether they have gene-repression effects and their distribution in the brain. In addition, we examined whether the effect was enhanced by multiple administration. As a result of screening, we confirmed that 4 types of ligands conjugated with HDO showed gene suppression effects in the mouse brain and enhancement by multiple administration. HDO were found to be distributed in the neuron by anti-phosphorothioate staining. In the experiment using dextran, no particular destruction of cerebral vascular endothelium was observed. Sufficient gene suppression was also observed in neurons and glial cells isolated from the brain by MACS. Central migration of HDO and gene suppression effects were also observed in rats. On the other hand, single-stranded nucleic acids conjugated with lipid showed no central migration and gene suppression effect. By selecting the ligand for HDO, it is now possible to cross the BBB and suppress genes expression in the CNS through systemic administration. We will aim for clinical application. | | 2022年7月3日 15:30～16:00 沖縄コンベンションセンター 会議場B2 第5会場
4S05a-04
アンチセンスオリゴを用いた神経疾患に対する個別化医療の取り組み
Precision medicine with antisense oligonucleotides for neurological disorders
*中山 東城(1,2)、Timothy W Yu(1)
1. ハーバード医科大学ボストン小児病院、2. 東京医科歯科大学大学院 医歯学総合研究科
*Tojo Nakayama(1,2), Timothy W Yu(1)
1. Harvard Medical School, Boston Children's Hospital, MA, USA, 2. Tokyo Medical and Dental University, Tokyo, Japan
Keyword: PRECISION MEDICINE, ANTISENSE OLIGONUCLEOTIDE, DRUG DEVELOPMENT, NEUROLOGICAL RARE DISEASES
Precision medicine leverages the patient’s genome to design therapies that results in improved outcomes. The relatively mature technology behind antisense oligonucleotides (ASOs) allows for truly personalized therapy, but requires coordination between families, health care professionals, industry, and regulatory bodies. Our work began with a pioneering effort in 2017, in which we developed and manufactured a genetically targeted, patient-customized medicine for a young girl with Batten Disease, a fatal neurodegenerative disorder, and began treating her with it, all in just one year’s time. This work was published in 2019 and has been the subject of extensive media coverage worldwide. Since this initial effort, our team has turned to develop additional genetic medicines for a host of rare diseases. Three of these efforts are in active clinical trials, and several more are progressing towards launch in the next one or two years. In these projects we have developed or are developing first-of-breed medicines for several genetic disorders: Batten Disease, Ataxia Telangiectasia, KCNT1 infantile epilepsy, and several others. In this session, we will discuss early forays in the application of ASOs as individualized medicine. Through these projects, we are pioneering novel approaches to the rapid development of treatments for rare diseases, an area of research that substantially contributes to the welfare throughout the world. | |
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