Cambridge Healthtech Institute’s 2nd Annual

RNA as a Drug Target

Expanding the Boundaries of Druggable Targets

September 16 - 17, 2020 ALL TIMES EDT

In the past year, the idea of targeting RNA directly with either a small molecule-like drug or with oligonucleotides has gone from an interesting idea to a viable business plan. It is expected that the FDA plans to make a decision on the first oral small molecule targeting splicing. Join us at the 2nd Annual RNA as a Drug Target conference, part of Discovery on Target, as we discuss not only the identification of specific and potent novel binders of RNA, but also the unique challenges that come with a novel drug target class.

Wednesday, September 16

SMALL MOLECULE RNA MODIFIERS

9:30 am

Targeting Structurally and Functionally Diverse RNAs with Drug-Like Small Molecules

John Schneekloth Jr. (Jay), PhD, Senior Investigator, Chemical Biology Laboratory; Head, Chemical Genetics Section, Center for Cancer Research, National Cancer Institute, NIH

The past twenty years have seen an explosion of interest in the structure and function of RNA and DNA. While some 80% of the human genome is transcribed into RNA, just ~3% of those transcripts code for protein sequences. Here, we discuss our group’s efforts to target RNA and DNA with drug-like small molecules using a small-molecule microarray (SMM) screening platform and the molecular basis for these interactions.

9:50 am

Discovery of Risdiplam, a Selective Survival of Motor Neuron-2 Gene Splicing Modifier for the Treatment of Spinal Muscular Atrophy

Hasane Ratni, PhD, Scientist & Project Team Leader, Medicinal Chemistry, F. Hoffmann-La Roche AG

SMA is an inherited disease that leads to loss of motor function and ambulation, and a reduced life expectancy. We have been working to develop orally-administrated, systemically-distributed small molecules to increase levels of functional SMN protein. Herein, we describe the discovery risdiplam that focused on thorough pharmacology, DMPK and safety characterization and optimization. This compound is completing pivotal clinical trials and is a promising medicine for the treatment of patients in all ages and stages of SMA.

Marla Weetall, PhD, Vice President, Pharmacology and Biomarkers, PTC Therapeutics

Utilizing small molecules to modulate splicing has emerged as a successful therapeutic approach to regulating protein expression. Here, three diseases where small-molecule splicing modulators can be utilized are described: spinal muscular atrophy; familial dysautonomia; and Huntington’s disease. For each of these indications, I will discuss the correlation between pharmacokinetics and pharmacodynamics, as well as the correlation between pharmacodynamics and efficacy.

Gregg Siegal, CEO, ZoBio

Modulation of enzymes that modify RNA (epitranscriptomics) is gaining interest in drug discovery. Gotham Therapeutics and ZoBio are developing inhibitors of YTHDF2, a multifunctional protein that selectively recognized 6 methyl-adenosine in mRNA thereby regulates protein expression. Results from fragment screening and hit evolution campaign will be presented.

 

10:50 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
John Schneekloth Jr. (Jay), PhD, Senior Investigator, Chemical Biology Laboratory; Head, Chemical Genetics Section, Center for Cancer Research, National Cancer Institute, NIH
Panelists:
Hasane Ratni, PhD, Scientist & Project Team Leader, Medicinal Chemistry, F. Hoffmann-La Roche AG
Marla Weetall, PhD, Vice President, Pharmacology and Biomarkers, PTC Therapeutics
Gregg Siegal, CEO, ZoBio
11:10 am Coffee Break - View Our Virtual Exhibit Hall
11:25 am

Protein Replacement with mRNA for Inherited Metabolic Diseases

Jingsong Cao, PhD, Principal Scientist, Rare Diseases & Metabolic Research, Moderna Therapeutics Inc.

Many rare inherited metabolic disorders are caused by deficiency of essential intracellular proteins (e.g. enzymes, transporters) responsible for maintaining proper homeostasis. Conventional protein replacement (e.g. enzyme replacement therapy or ERT) and gene therapy-based approaches are not an option for treating these disorders due to drug-delivery and efficacy/safety considerations. To develop new treatments for these diseases, we encapsulated nucleoside-modified, codon-optimized mRNAs, encoding these genes in lipid nanoparticles. Preclinical data demonstrating the efficacy and safety of our mRNA-LNP therapy for several rare metabolic disorders will be presented.

11:45 am

RNA Modulation of Translation of mRNAs for Novel Therapy in Neurodegenerative Disease

Jack Rogers, PhD, Director, Neurochemistry Laboratory, Associate Professor, Psychiatry-Neuroscience, Harvard Medical School and Massachusetts General Hospital

Our Neurochemistry Laboratory is advancing the therapeutic development of selective and potent alpha-synuclein (asyn), amyloid precursor protein (APP) and Prion protein (PrP) translation modulators. We discuss here the efficacy of key small molecules that alter translation rates of these disease associated proteins by the use of advantageous 5’UTR-directed repressor /reporters of the transcripts for their mRNAs (SNCA-mRNA, APP mRNA, PrP mRNA).  Our goal is to develop RNA directed molecules as neurotrophins for future treatments of Parkinson’s disease, as well as, neurodegenerative diseases that impair memory and cognition.

12:05 pm Session Break
12:45 pm Lunch Break - View Our Virtual Exhibit Hall

DIVERSE MODALITIES FOR MODULATING RNA TARGETS

1:15 pm

Antibody Targeting of Oncogenic mRNAs

Daniel Fernandes, PhD, DSc, CSO, CharlestonPharma, LLC

Recently, keen interest has been expressed at scientific symposia and in the scientific literature regarding RNA as a potential drug target in various diseases. Most of the efforts in targeting mRNA have focused on small drug molecules, since larger molecules often have difficulty in penetrating tumor cells. CharlestonPharma has developed a panel of human IgG1antibodies that bind to the nucleonin transporter on tumor cells in order to gain intracellular access. Once inside the tumor cell, the antibodies interfere with the stabilization of certain oncogenic mRNAs by nucleolin.

1:35 pm

TANGO (Targeted Augmentation of Nuclear Gene Output) for the Treatment of Genetic Diseases

Isabel Aznarez, PhD, Co-Founder, Vice President & Head, Biology, Stoke Therapeutics

TANGO uses antisense oligonucleotides (ASOs) to prevent naturally occurring, non-productive splicing, and increase productive mRNA and fully functional protein. We identified non-productive events in > 50% protein-coding genes. ASOs targeting these events lead to increased mRNA and protein in a dose-dependent manner. TANGO-ASO treatment of Dravet syndrome mice lead to protein restoration to near normal levels, significant reversal of the survival phenotype, decreased seizure frequency and increased numbers of seizure-free mice. 

1:55 pm Session Break
2:35 pm Refresh Break - View Our Virtual Exhibit Hall
3:00 pm Interactive Breakout Discussions - View Our Virtual Exhibit Hall

Join a breakout discussion group. These are informal, moderated discussions with brainstorming and interactive problem solving, allowing participants from diverse backgrounds to exchange ideas and experiences and develop future collaborations around a focused topic. Discussion topics and moderators will be listed on the website.

BREAKOUT: Using Diverse Modalities to Effectively Target RNA

Marla Weetall, PhD, Vice President, Pharmacology and Biomarkers, PTC Therapeutics
Isabel Aznarez, PhD, Co-Founder, Vice President & Head, Biology, Stoke Therapeutics
Daniel Fernandes, PhD, DSc, CSO, CharlestonPharma, LLC
  • Opportunities and challenges using small molecules to target RNA
  • Use of antibodies to target RNA
  • Advantages of using antisense oligonucleotides for modulating RNA pathways
3:35 pm Close of Day

Thursday, September 17

DECONVOLUTING RNA BIOLOGY

10:15 am

Translation Control Therapeutics: Discovery of Selective mRNA Translation Modulators

Yochi Slonim, Co-Founder & CEO, Anima Biotech, Inc.

Anima Biotech is advancing Translation Control Therapeutics, the first platform for the discovery of small molecule drugs that selectively control mRNA translation. Using patented technology that causes ribosomes to emit light pulses as they assemble proteins, we screen for drug candidates that decrease or increase translation with selectivity towards mRNAs, tissues, cells or pathways. We advance an internal pipeline of programs across therapeutic areas and in strategic collaboration with Lilly.

Jennifer C. Petter, PhD, Founder & CSO, Arrakis Therapeutics

RNA is upstream of all biology and presents a vast array of therapeutically attractive targets. Most therapeutic agents that bind directly to RNA are either antibiotics blocking bacterial ribosome function or oligonucleotides with their attendant pharmaceutical limitations. We have identified druggable RNA sub-structures in mRNA and orally available small molecules that bind to those structures selectively and thereby modulate mRNA function. I will describe recent results that support this larger mission.

10:55 am

Development of a Novel miRNA-Based Platform Technology for Cancer

Jingfang Ju, PhD, Professor, Program Director of Oncogenic Drivers and Mechanisms of Carcinogenesis, Stony Brook University

Treatment of pancreatic ductal adenocarcinoma (PDAC) remains a clinical challenge. We discovered that miR-15a suppresses Wee1, Chk1, Yap-1, and BMI-1, causing cell cycle arrest and inhibiting cell proliferation. We developed a miRNA-based platform by replacing uracil (U) in the guide strand with 5-fluorouracil (5-FU). In vivo we showed the therapeutic power of 5-FU-miR-15a alone or in combination with gemcitabine with near complete elimination of PDAC lung metastatic tumor growth.

11:15 am Session Break
11:35 am LIVE Q&A:

Session Wrap-Up Panel Discussion

Panel Moderator:
Jennifer C. Petter, PhD, Founder & CSO, Arrakis Therapeutics
Panelists:
Jingfang Ju, PhD, Professor, Program Director of Oncogenic Drivers and Mechanisms of Carcinogenesis, Stony Brook University
Iris Alroy, PhD, Vice President, R&D, Anima Biotech
11:55 am Coffee Break - View Our Virtual Exhibit Hall

PLENARY KEYNOTE PROGRAM

12:20 pm

PLENARY KEYNOTE: Tackling Undruggable Oncoproteins: Lessons from the VHL Tumor Suppressor Protein

William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics

VHL tumor suppressor protein (pVHL) inactivation is common in kidney cancer and upregulates the HIF2 transcription factor. PT2977/MK-6482 is an allosteric HIF2 inhibitor now in Phase 3 testing. Thalidomide-like drugs (IMiDs) bind to cereblon which, like pVHL, is the substrate-binding unit of a ubiquitin ligase. IMiDs redirect cereblon to destroy the myeloma oncoproteins, IKZF1 and IKZF3. We have developed new assays for identifying drugs that can destabilize oncoproteins of interest.

12:45 pm LIVE Q&A:

Plenary Keynote Discussion

Panel Moderator:
Stewart Fisher, PhD, CSO, C4 Therapeutics, Inc.
Panelist:
William G. Kaelin, Jr., MD, 2019 Nobel Laureate; Professor, Medical Oncology, Dana-Farber Cancer Institute; Investigator, Howard Hughes Medical Institute; Co-Founder, Cedilla and Tango Therapeutics
12:55 pm LIVE PANEL AND Q&A:

Plenary Keynote Discussion: De-Risking Early Drug Discovery

Panel Moderator:
Nadeem Sarwar, PhD, Founder & President, Eisai Center for Genetics Guided Dementia Discovery, Eisai, Inc.
  • Data Sciences
  • ​Novel Chemical Modalities
  • Investment and Partnering Models
  • COVID-19 Progress as Examples of Successful Partnerships
Panelists:
Anthony A. Philippakis, PhD, Chief Data Officer, Data Sciences & Data Engineering, Broad Institute; Venture Partner, GV
Stephen A. Hitchcock, PhD, Head, Research, Takeda Pharmaceuticals, Inc.
1:35 pm Lunch Break - View Our Virtual Exhibit Hall
2:05 pm Close of RNA as a Drug Target Conference





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