Alnylam Pharmaceuticals, Inc. · NASDAQ:ALNY
Alnylam Pharmaceuticals — HDSA 2011 Convention
34 slides from Alnylam Pharmaceuticals's conference presentation, June 2011
Slide 1: Developing RNAi Therapeutics Targeting Huntingtin with Direct CNS Delivery
Developing RNAi Therapeutics Targeting Huntingtin with Direct CNS Delivery 1
Slide 2: Presenter Disclosures
Presenter Disclosures Martin Goulet The following personal financial relationships with commercial interests relevant to this presentation existed during the past 12 months: Alnylam Pharmaceuticals Medtronic 2
Slide 3: HDSA informational use notice
The information provided by speakers in workshops, forums, sharing/networking sessions and any other educational presentation made as part of the 2011 HDSA convention program is for informational use only. HDSA encourages all attendees to consult with their primary care provider, neurologist or othe
Slide 4: Who Are We?
Who Are We? • Alnylam Pharmaceuticals – Biopharmaceutical company developing novel therapeutics based on RNA interference, a recently discovered naturally occurring process of gene regulation • CHDI – Not-for-profit virtual biotech company that is exclusively dedicated to rapidly discovering and dev
Slide 5: Our Mission
Our Mission Develop a treatment for Huntington’s Disease that uses a pump to deliver, directly into the person’s brain tissue, a drug that reduces the amount of the disease-causing protein in the brain. Let’s look at each of these items, then you’ll understand what we’re doing.... 5 5
Slide 6: Our Mission
Our Mission Develop a treatment for Huntington’s Disease that uses a pump to deliver, directly into the person’s brain tissue, a drug that reduces the amount of the disease-causing protein in the brain. Let’s look at each of these items, then you’ll understand what we’re doing.... 6 6
Slide 7: Understanding the Disease-causing Protein...
Understanding the Disease-causing Protein... 7
Slide 8: A gene = a section of DNA
DNA is copied to make RNA that is used for instructions on how to make Protein Proteins a gene = a section of DNA form structures, or do work, in our bodies. e.g. letters “CAG” messenger RNA mean “add the amino acid „glutamine‟ ” 8
Slide 9: Part of the HD Gene DNA sequence
(Part of ) the HD Gene DNA sequence – Too Many CAG’s Too Many Glutamines In Protein Causes The Disease CAG repeat region (here, 19 repeats) NM_002111 CAG, CAG, CAG, …. CAG 9
Slide 10: How Does The Expanded Huntingtin Protein Cause Disease?
How Does The Expanded Huntingtin Protein Cause Disease? • The expanded protein – Aggregates (clumps) of protein accumulate – Affects the way other genes in the cell are used... • “Transcriptional dysregulation” – Changes ability of the cell to produce energy (metabolism) – Makes the neuron more susc
Slide 11: What If We Just Turn Off Production of Expanded Protein?
What If We Just “Turn Off ” Production of Expanded Protein ? • 2000 – Ai Yamamoto, Columbia University – Conditional transgenic HD mouse • Expanded huntingtin gene artificially put into mouse, but in a form that only turns on when mouse fed a particular antibiotic – Turn on expanded protein mouse
Slide 12: What If We Just Turn Off Production Of Expanded Protein?
What If We Just “Turn Off ” Production Of Expanded Protein ? • Mice – Mutant mice expressing half the amount of huntingtin are normal • 1995 – Mabel P. Duyao, Massachusetts General Hospital • 1995 – Scott Zeitlin, Columbia University • Human – An individual with half the amount of huntingtin is norm
Slide 13: Our Mission
Our Mission Develop a treatment for Huntington’s Disease that uses a pump to deliver, directly into the person’s brain tissue, a drug that reduces the amount of the disease-causing protein in the brain. Let’s look at each of these items, then you’ll understand what we’re doing.... 13 13
Slide 14: RNA Interference
RNA Interference • Natural Normally, DNAWay To Reduce mRNA protein Production Of Protein 14
Slide 15: RNA Interference
RNA Interference • Natural Normally, DNAWay To Reduce mRNA protein Production Of Protein 15
Slide 16: siRNA Therapeutic
“siRNA Therapeutic” RNA interference targeting a specific mRNA in cells • RNA Interference – Fundamental mechanism built into all our cells: – Short, double-stranded molecule of RNA causes cell to “silence” its corresponding gene. • Normal function: – major player in development, gene regulation; so
Slide 17: Our Mission
Our Mission Develop a treatment for Huntington’s Disease that uses a pump to deliver, directly into the person’s brain tissue, a drug that reduces the amount of the disease-causing protein in the brain. Let’s look at each of these items, then you’ll understand what we’re doing.... 17 17
Slide 18: Finding The Drug: Alnylam's Screening Program
Finding The Drug Alnylam’s Screening Program Starting Pool of Possibilities for siRNA against Huntingtin (all short DNA / RNA sequences along the HD gene) Eliminate the ones that might also suppress other proteins beyond Huntingtin Stability / Efficacy in cell experiments Chemical enhancements Distr
Slide 19: Screening in Cell Experiments
Candidate siRNAs Screening in Cell Experiments Normalized Huntingtin mRNA level (%) 100 screen 1 screen 2 80 60 40 20 0 cells with various candidate siRNAs cells without anti-huntingtin siRNA SFN, Oct 2009 19
Slide 20: Finding the Most Potent siRNA
Finding the Most Potent siRNA In Cell Experiments: How Much Suppression, With How Much siRNA? siRNA #1 siRNA #2 IC50 ~ 0.3 nM IC50 ~ 0.08 nM Normalized Htt mRNA level (%) Normalized Htt mRNA level (%) 90 90 75 75 60 60 45 45 30 30 15 15 0 0 0.01 0.1 1.0 10 0.01 0.1 1.0 10 siRNA concentration siRNA c
Slide 21: siRNA Reduce Amount of Expanded Protein In Cells From HD Patients
siRNA Reduce Amount of Expanded Protein (As Well As Normal Length Protein) In Cells From HD Patients GM04281 line GM04719 line 21
Slide 22: siRNA Can Reduce Amount of Huntingtin mRNA In Brains Of Laboratory Rats
siRNA Can Reduce Amount of Huntingin mRNA In Brains Of Laboratory Intrastriatal Infusion Rats (siHtt at 2,4, 8 and 15mg/mL and siLUC at 15mg/mL) Ipsilateral Striatum x for bDNA Day 0 Day 7 100 Normalized Htt/GAPDH 80 ** *** **p<0.01; *** p<0.001 vs. *** siLUC (% siLUC) 60 *** (ANOVA, Tukey posttest)
Slide 23: Our Mission
Our Mission Develop a treatment for Huntington’s Disease that uses a pump to deliver, directly into the person’s brain tissue, a drug that reduces the amount of the disease-causing protein in the brain. Let’s look at each of these items, then you’ll understand what we’re doing.... 23 23
Slide 24: How Does siRNA Get Into Rat (Or Other) Brain?
How Does siRNAGet Into Rat (Or Other) Brain? .... We Put It There, Directly. Rat brain Rhesus monkey brain 24
Slide 25: Direct Infusion Into Brain Using Catheter (Tube)
Direct Infusion Into Brain Using Catheter (Tube) SFN 2009 25
Slide 26: Direct Infusion of siRNA into Brains of Monkeys
Direct Infusion of siRNA into Brains of Monkeys Distribution of siRNA and correlation with Htt mRNA suppression Tissue % location Suppression of Htt mRNA 1 39% 2 28% 3 47% 4 51% 5 40% 14C-siHtt in NHP Brain Keystone: RNA Silencing., Jan 2010 26
Slide 27: Huntingtin mRNA Suppression and siRNA Distribution in Rhesus Monkey Brain
Huntingtin mRNA Suppression and siRNA Distribution in Rhesus Monkey Brain Consistent Htt mRNA Suppression Across Punches and Animals 160 150 Outliers indicated in 140 blue square box are % Htt mRNA Normalized to PBS from posterior slabs 130 (4 mm posterior to 120 infusion site) 110 100 90 80 70 60 5
Slide 28: Why Can't siRNA be a Pill, Or Given By Shot In Arm Or Needle In Vein?
Why Can’t siRNA be a Pill, Or Given – siRNA By Shot cannot readily In Arm Or Needle In Vein? survive digestive tract – Enzymes in serum can degrade siRNA in blood very quickly (although chemical stabilization methods exist) – Main reason: • Blood-brain barrier excludes large molecules such as siRNA
Slide 29: How Will People Receive Long-term Treatment?
How Will People Receive Long-term Treatment? Rat brain Rhesus monkey brain 29 29
Slide 30: Our Mission
Our Mission Develop a treatment for Huntington’s Disease that uses a pump to deliver, directly into the person’s brain tissue, a drug that reduces the amount of the disease-causing protein in the brain. Let’s look at each of these items, then you’ll understand what we’re doing.... 30 30
Slide 31: What will the therapy look like?
What will the therapy look like? – Surgical placement of one or more catheters (soft tubes) in brain – Pump implanted in abdomen (3.4” x 0.77”) – siRNA delivered to brain (droplets per day) from implanted pump – Pump periodically refilled through skin (e.g., by nurse, with a hypodermic needle) Medtr
Slide 32: So, Now You Understand Our Mission
So, Now You Understand Our Mission: Develop a treatment for Huntington’s Disease that uses a pump to deliver, directly into the person’s brain tissue, a drug that reduces the amount of the disease-causing protein in the brain. 32 32
Slide 33: How Long Before This Therapy Is Available?
How Long Before This Therapy Is Available? A While....We Have Lots More To Do, Yet..... • So far, we have – Identified siRNA that works with direct delivery to brain – Developed new catheter for better direct delivery to brain – Optimized parameters for good drug distribution in brain • Next steps –
Slide 34: The Progress We've Made So Far…
The Progress We’ve Made So Far… – Potent, selective siRNAs targeting Htt identified with bioinformatics (computers) and in vitro assays (cell experiments) – Chemically-modified siRNAs targeting Htt reduce Htt mRNA in relevant parts of the brain in rats • ~50% Htt mRNA silencing in striatum of rat •