GAN Gene Delivery

(Text in italics was added by web page admin.)

Dr. Steven Gray, from the gene therapy center at UNC at Chapel Hill, is leading Hannah’s Hope Fund’s gene delivery project. To date, no human has ever received a therapeutic gene to the spinal cord. The challenge is two-fold:

1) Get the viral vector ( a tool commonly used by molecular biologists to deliver genetic material into cells) across the Blood Brain Barrier (BBB), which is an extra protective layer surrounding the cells in the central nervous system (CNS);

2) Localize delivery with traditional lumbar puncture administration to the cord resulting in only a few cells treated. Because the GAN gene encodes an intracellular protein, not a secreted enzyme, it’s critical to treat as many cells as possible.

With gene delivery, scientists use a benign viral vector to transport healthy copies of genes to targeted cells. The virus infects the cells with a healthy copy of the gene that will, in theory, have life-long expression of a protein missing in the cells of subjects with GAN.  To date, longevity studies conducted at other academic institutions reveal AAV viral vector will express out for at least 12 years. (AAV: Adeno-associated virus is a small virus that is not currently known to cause disease and consequently the virus causes a very mild immune response. AAV can infect both dividing and non-dividing cells and may incorporate its genome into that of the host cell. These features make AAV a very attractive candidate for creating viral vectors for gene therapy.)

Clinical trials for a number of disorders of the brain have been long underway because viral vectors tend to spread in the cerebral spinal fluid along axonal pathways and multiple injections can be performed to achieve greater spread. With our novel route of administration of AAV serotype 9, (serotype: distinct variations within a subspecies of bacteria or viruses) subjects with GAN will likely be the first disease community to receive a therapeutic gene to the spinal cord.

Studies Demonstrate Hopeful Results

The first study HHF funded was to compare gene therapy viral vector serotypes and try different routes of administration to see if a new viral serotype would cross the BBB and give broad distribution throughout the cerebral spinal fluid that bathes the spinal cord.  We discovered AAV serotype 9 is crossing the BBB. 

We then funded a biodistribution study (the distribution of compounds within a biological system)  to see if we could increase spread of the viral vector throughout the cerebral spinal fluid. We learned AAV9 is transducing (the transfer of genetic material from one microorganism to another by a viral agent) 80% of nerve cells in the spinal cord with a healthy copy of the gene when administered via a novel route of administration.  We discovered that threading a catheter all the way up the spinal canal and releasing the viral vector at 3 loci allowed from broad distribution of the virus. These results are far better than expected.  Most geneticists feel if you can treat 10 to 15% of cells with a therapeutic gene, disease course can be dramatically altered. This biodistribution study conducted in collaboration with Dr. Nicholas Boulis, Emory University, indicates GAN gene delivery will very likely have significant impact on this disease and may completely halt disease progression.  It is anticipated that function may be restored to any nerve cell not yet dead.

Studies Underway

Therapeutic Level of GAN Gene Expression:

The studies underway now are to determine the therapeutic level of GAN gene expression. The human GAN gene promoter (the promoter facilitates transcription - transfer of genetic material) is too large to fit in the AAV viral capsid along with the full length GAN gene. Therefore, Dr. Steven Gray has had to engineer a promoter that’s small enough to accompany the full length gene.  When a promoter is truncated, expression is lowered.  This actually works in our favor since this protein is naturally expressed at low levels. However, preliminary results indicate the first promoter, called MeP, is not expressing enough to be therapeutic. 

Dr. Gray is tweaking the MeP promoter for greater expression and has also begun studies on two other truncated promoters to see if enough of the protein is being expressed to show rescue in cellular models of GAN. Once we have a promoter that reverses pathology in GAN cells in vitro, we will submit our Pre-Investigational New Drug packet to the FDA for feedback on the safety studies they will require us to conduct before we can begin a human clinical trial.

Because we’ve already shown in the animal model of GAN, (the GAN “knock-out” mouse), that pathological aggregates do not occur in the cells of old GAN mice that were treated with a higher expressing promoter at 3 months of age, we can save time and not have to repeat the mouse studies before submitting to FDA.  Unfortunately, we can’t use the high expressing promoter used in the mouse study in humans because it’s a single-stranded promoter and thus will only treat a few cells.  Double-stranded promoters are much more efficient and are used for human therapeutics. Also, it is anticipated that higher-expression of the protein in mice wasn’t pathological because mice have different neurofilament than humans.

We will tell the FDA we want to begin treating consenting adults based on 4 weeks safety (toxicology) data. The goal is to begin a trial Q2 of 2012. (Estimated cost of FDA required safety studies: $620,000.) 

We are applying for a joint Phase 1/Phase 2 trial to avoid having to reapply for Phase 2.  We plan to begin Phase 2, which is gene delivery to minors, based on 12 week safety data from Phase 1 subjects.

Natural History Study:

HHF is also funding a Natural History Study (NHS) on GAN.  This study charts the untreated course of the disease, with the goal of obtaining clinical outcome measures.  The outcome measures obtained from the NHS are used to measure efficacy of treatment during the clinical trial.  The FDA needs to know in advance how you plan to measure if an experimental therapy is reversing, slowing, stopping or having no impact on disease progression. (Estimated cost of NHS: $650,000.)

It will cost about $25,000 to treat each patient during the clinical trial. Subjects with GAN need a therapeutic gene delivered to the nerve cells in the brain and spinal cord, as do tens of thousands of people suffering from closely related neurological disorders.  Spinal Muscular Atrophy (SMA) is the leading cause of death in children by genetic disorder and there is no FDA approved treatment.  This disease community will also benefit from this gene delivery mechanism.   

Update from Lori Sames, 8/24/11: Preliminary data on one of the 3 gene therapy promoters being tested indicate it will be effective.  More studies are underway to confirm this result, and will take about 5 weeks. Please keep your fingers crossed that this will be our clinical promoter for out trial!

 

The highlight of my evening was when my cousin, Lori, introduced me to Ruth Shopmeyer.  For those of you who don’t know, Mrs. Shopmeyer is the angel who introduced Hannah’s Hope to Doris Buffett.  About a year before Ruth, who is now 86, ever heard of Hannah’s Hope, she saw Ms. Buffett on the CBS Morning Show discussing her Sunshine Ladies Foundation.  When Ruth heard about Hannah via one of the local Albany news reports, she remembered seeing Doris on the Morning Show but could not remember her last name.  She actually called CBS and asked them who was on their show a year ago discussing a charitable foundation.  Then with the help of her daughter, Ruth tracked down the Sunshine Ladies contact information.

Ruth wrote to Doris and mentioned that she understood how hard it was to lose one’s husband.  She also wrote about Hannah’s Hope and asked that the Sunshine Ladies consider supporting our cause.  Something in Ruth’s letter touched Doris’ heart, and her assistant reached out to Lori. 

Just in case you are a new HHF supporter, last year, the Sunshine Ladies agreed to provide a matching grant of $500,000 to Hannah’s Hope if we raised $500,000 in six months.  Thanks to our incredible supporters, we raised well over that amount!

What I told Ruth on Saturday night was that what she did not only helped HHF financially, she showed us that miracles are possible.  Ever since Lori and Matt decided that GAN was NOT going to be a death sentence, they have been in the business of creating miracles.  It is miraculous that a few months after learning of Hannah’s diagnosis, Lori and Matt created a 501C3 and held the first international symposium on GAN at Boston Children’s Hospital with researchers from around the globe.

It is miraculous that our lead researcher, Dr. Steven Gray of the UNC Chapel Hill Gene Therapy center has already found a treatment, and Hannah has already participated in the pre-trials baseline testing. 

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PRESS RELEASE
For Immediate Release
January 25, 2011
 
Hannah’s Hope to Host One of America’s Most Famous Philanthropists
 
Rexford, NY- Ms. Doris Buffett, sister of Billionaire Warren Buffett and founder of the Sunshine Lady Foundation, will be attending this year’s 2nd Annual Hannah’s Hope and Love Ball. Coincidentally, we will be celebrating Ms. Buffett’s birthday at our event, also.  The Sunshine Lady Foundation gave Hannah’s Hope Fund a $500,000 matching grant in August 2009 that resulted in a total fundraising effort of $1,123,000 last year.  The event is being held Saturday, February 12 at The Desmond Hotel, from 6pm-11:30pm. This black tie event is generously sponsored by Martin, Harding and Mazzotti LLP and Merrill Lynch’s Southern Saratoga office. 
 
We will have over 400 people in attendance and are featuring music by The Refrigerators, an elaborate silent auction, ice sculptures, open bar, carving stations, hors d'oeuvres, a jazz trio “Misty”, and martini and champagne bars.  Cost is $150 per person, and reservations may be made online at www.hannahshopefund.org .  For more information, please contact Lori Sames at 518-275-5359 or lorisames@yahoo.com . 
 
Hannah’s Hope Fund is inspired by Hannah Sames, a 6 year old girl from Rexford, NY who was diagnosed with Giant Axonal Neuropathy in March 2008.  HHF is now the only worldwide organization focused on curing this disease, and has connected GAN families from around the globe.  HHF is dedicated to curing GAN, a rare genetic disorder that slowly takes away one's ability to walk, use one's hands, speak, swallow and ultimately is terminal.  HHF is a family driven 501C3 Public Charity.  Our scientists have developed a gene therapy for GAN and we are funding the studies required by the FDA to begin a clinical trial. HHF is a completely volunteer organization with NO paid employees. Please join our mission and help us save these precious lives.

Press Release: January 3, 2011  Hannah’s Hope Fund Wins Another $250,000 Pepsi Grant Rexford, NY- Hannah’s Hope Fund (HHF) has officially been announced as a finalist for the $250,000 Pepsi Refresh Everything Grant for the month of December.  HHF finished December as the #1 vote getter in the country for the $250,000 category.  Finalists are typically announced as grant recipients 3 weeks after the conclusion of the monthly contest and are posted on www.refresheverything.com.   HHF is a local charitable foundation founded by Matt and Lori Sames, parents of Hannah Sames.  Hannah was diagnosed with a rare, terminal disease called Giant Axonal Neuropathy in March 2008.  At the time, there was no concerted research, no funding and no hope.  Since then, Hannah’s Hope Fund has galvanized families from around the country and around the world.  Potentially, we are about 12 months away from a human clinical trial.  If the treatment developed at UNC Chapel Hill’s Gene Therapy Center is successful, it will save children suffering from GAN as well as other closely related diseases such as Spinal Muscular Atrophy and others.   HHF has raised over $2.3 million since its inception and needs to raise an additional $850,000 in 2011 in order to fund the necessary studies and surgeries for our human clinical trial.  For more information about Hannah’s Hope Fund or to learn how to donate, please visit www.hannahshopefund.org .   Media Contact Matt Sames Director of Hannah’s Hope Fund and Father of Hannah Sames 518-275-6040 mattsames@yahoo.com

This morning, HHF is at #1 in the Pepsi Refresh competition, and one of Hannah’s Mom’s friends emailed me to say, “Good people tend to attract the support and love of good people.  What all of you have done since the plan for HHF was hatched is just extraordinary.” Thoughts of “#1,” good people and Christmas lead to a thought about Hannah’s grand-father, my Uncle Earl or Uncle “Junior” as all of the cousins refer to him.  Uncle Junior was a football coach at my high school before I went there.  When I was a freshman and attending our family Christmas gathering, Uncle Junior walked by me wearing a football jersey with my high school’s name on the front (MAI for all of you Plattsburghians) and “Burnell” (our family’s last name) and the #1 on the back.  I jokingly said, “I want that shirt!”  He stopped in his tracks, peeled it off, leaving on only his undershirt in the bitter cold North Country.  Handing me the jersey, he said, “Now you can’t say I never gave you the shirt off of my back.”  Over 30 years later, that jersey hangs in my closet.  It has travelled with me to every dorm room and cramped grad school studio apartment, followed me to the South, saw me through my marriage and the birth of 2 kids, and now when I see it, it reminds me of one of the reasons I am determined to do all I can to help Hannah. When Uncle Junior handed me that shirt, he was bringing his generous spirit onto a physical plane that I could see and touch.  But he exemplified generosity in everything he did.  He would never hesitate to give someone the shirt off of his back, either literally or figuratively.  His children, one whom is Hannah’s Mom, Lori, grew up surrounded by that spirit and watching his example.  I absolutely believe what Lori’s friend emailed me this morning, “Good people tend to attract the support and love of good people.”  One of the reasons HHF is, and there’s no other word for it but miraculously successful in such a short amount of time is that Uncle Junior’s sprit of generosity surrounds his children, and now it surrounds their children.  When we give from our hearts with no strings attached, it creates something so much bigger than the gift we gave.  It creates an energy wave that radiates out from us encouraging everyone it hits to do the same.  And eventually that wave comes back to us, usually in ways we never could have imagined. I know Uncle Junior never could have imagined how handing me that shirt would teach me a lesson about giving that would one day inspire me to do everything in my power to save his grand-daughter.  But he didn’t do it because he wanted anything in return.  He did it from his heart. And that is the epitome of the Christmas spirit. Merry Christmas, Happy Hanukkah, Blessed Kwanzaa and wishes for a peaceful New Year. Heather Burnell Tutwiler

I know Uncle Junior never could have imagined how handing me that shirt would teach me a lesson about giving that would one day inspire me to do everything in my power to save his grand-daughter.  But he didn’t do it because he wanted anything in return.  He did it from his heart.

And that is the epitome of the Christmas spirit.

Merry Christmas, Happy Hanukkah, Blessed Kwanzaa and wishes for a peaceful New Year.
Heather Burnell Tutwiler

Hannah's Mom, Lori, titled this picture, "Hannah the Ham."  They were on their way to Chapel Hill and met up with a friend who asked Hannah to pose.

December 9, 2010 Note from BLOG Admin: Hannah has been in Chapel Hill this week with her parents for pre-clinical trial testing: Yesterday, Hannah had anesthesia for an MRI, NCV and LP to take CSF (cerebral spinal fluid).  Her back is a little sore.  She has no restrictions and will tells us if her back hurts.  She also had tons of evaluations (PT, OT, cognative, hearing, BAER).  We had a great meeting today with our scientists and the doctor overseeing the clinical aspects of our clinical trial and Natural Disease History Study on GAN, which began this week.  Hannah and 14 other kids will participate in the study over the next 24 months. The study charts the untreated course of the disease.  The FDA requires this data as proof that the treatment is effective and safe for long-term use.  The cost of this 2 year study is over $470,000. Each of the participating children will have 5 visits for the same testing and evaluations Hannah underwent this week.  Treatment can begin before all 5 visits occur.  The pre-treatment data sets are compared to post-treatment data to assess efficacy and safety of treatment.  The timeframe for beginning our clinical trial will depend on the FDA.  Scientifically, the next 10 weeks are very busy, as critical efficacy studies will be wrapping up.  We are having monthly conference calls with our scientists and will have a scientific meeting in NYC at the beginning of March.  All of this is possible because of the countless hours of support, your generosity and love.  THANK YOU. With gratitude, Lori & Matt