Friday, October 9, 2015

NACFC 2015--Details from Day 1

This morning, the action began at 10 a.m. with a host of workshops.  Because there are always multiple interesting talks happening at the same time, Brock and I decided to divide and conquer to take in the most information.  Here are the most interesting nuggets from my morning.

I was anxious to hear the results of the European Gene Therapy Trials at the NACFC last year, but the UK team backed out last minute in order to complete their data collection process.  I was able to see their data earlier this year in a videotaped presentation by Dr. Alton, but this was the first time that the trial results have really been shared at a meeting like this, with the professional CF community at large. 

A Randomized, Double-blind, Placebo-controlled Trial of Repeated Nebulization of Non-viral CFTR Gene Therapy in Patients with Cystic Fibrosis.  Presented by Dr. Eric Alton

While research in the U.S. has been focused on the “small molecule” approach to treating CF, scientists in the UK have poured a tremendous amount of time and energy into gene therapy.  The UK CF Gene Consortium has been working for years on this project, and has encountered considerable obstacles along the way.  The most formidable challenge has been identification of an effective vector to transmit genes inside the lung cells of CF patients.  Many viral vectors were tested and abandoned due to the high inflammatory response they elicited (infection by virus is one way to breach the cell wall and gain access to the DNA held inside, but was found to cause too much collateral inflammatory damage to be an effective candidate).  Ultimately, a lipid (fat) vector was chosen to perform a phase 2b placebo controlled trial in humans.  Trial participants were asked to nebulize a gene therapy solution once a month (approximately 40 minutes to complete treatment). Ultimately, the study showed statistically significant improvements in FEV1.  

Patients exhibiting the most severe lung disease showed the least benefit from this treatment, and Dr. Alton hypothesizes that fibrosis and mucous barriers associated with more severe lung disease could be obstructing the interaction with lung tissue--preventing the transfer of the healthy gene.

Dr. Alton believes that this study, while modest in benefit, provides proof of concept that gene therapy should be further developed as a tool for treating CF.  The next steps would involve pushing the boundaries to see if further benefit might be obtained with higher dosages.  Also, if gene therapy is able to activate a small amount of CFTR in the lungs, there is the possibility that the chloride transport by this small amount of CFTR could be enhanced with the addition of a small molecule potentiator such as Kalydeco.

While gene therapy is an exciting concept, it is something that researchers have been working on for decades--basically since the discovery of the CF gene in 1989.  The treatment benefits seen in the trial were modest, but represent the greatest success to date using this approach.  Dr. Alton seems determined to continue down this road, but I have doubts... Personally, I think that the gene-editing or mRNA editing techniques (such as CRISPR-cas9 that we will hear about later in the conference) hold more promise as a way of actually changing an individual's genetic expression.  Just my opinion.  I was hoping for much better data after so many years of development.

Mesenchymal Stem Cell LL-37 in Cystic Fibrosis.  Presented by Tracey Bonfield

Human mesenchymal stem cells (hMSCs) come from bone marrow, and are able to differentiate and develop into many different cell types in the body.  There is no need to suppress the immune system to utilize hMSCs, making them an attractive candidate for therapy development.  

For this study, the CF mouse model was used to test how hMSCs might affect CF lungs.  The mice were infected with Pseudomonas aeruginosa and then treated with hMSCs.  The mice were followed for 10 days.  The data collected suggests that hMSCs exhibit both anti-inflammatory as well as anti-microbial properties.  The rate of Pa growth in the mice was decreased, and combination with an antibiotic treatment produced a synergistic effect (augmented the potency of the antibiotic).  

While this work is preliminary, this trial in mice shows measurable benefit, and further studies with hMSCs to treat CF lungs will be coming our way in the future.

Hormone Fluctuations Correlate with Respiratory Symptoms in Patients with Cystic Fibrosis. Presented by Raksha Jain.

Existing data has suggested that women with CF have worse health outcomes than men. Women demonstrate earlier colonization with respiratory pathogens and an increased exacerbation rate near ovulation.  This study examined the role that sex hormones play in CF.

This was an observational study where hormones were measured throughout the course of the menstrual cycle.  Inflammatory markers were measured, and patient reported data was collected as well.  Additionally, data was collected for women with CF who were asked to cycle on and off birth control pills--which function as an estrogen inhibitor.

The data they collected basically suggests that higher estrogen levels correlate to worse respiratory symptoms.  This was shown with an increased rate of exacerbation during the follicular phase of the menstrual cycle (when estrogen is highest).  It was also shown that suppression of estrogen with oral contraceptives trends toward reduced exacerbations, and should potentially be examined as a therapeutic option (this was a very small study, so these findings are suggestive rather than conclusive). 

The take-away message--further study is warranted to determine if oral birth control pills may represent a way to improve the health status of women with CF through the suppression of estrogen.  

These 3 studies represent a tiny fraction of the discussions I saw today (I didn't even make it to my afternoon notes yet--but I have to be able to stay awake tomorrow)!  

After the morning session concluded at NACFC, Brock and I dashed over to the Volunteer Engagement Conference at the Renaissance to snag some lunch and connect with other CF families. I also had the privilege to speak about advocacy alongside Mary Dwight and Abi Green from the CFF, and my CFF National Advocacy co-chair Melissa Shiffman (who filmed an awesome advocacy video that I will be able to share when the link is made available).  Nothing inspires me to preach advocacy like spending my morning listening to the amazing scientific progress that is happening RIGHT NOW. 
I made it on and off stage without falling on my face--success!

 It makes me sick to my stomach to think about struggling with access barriers when we have so many wonderful opportunities speeding through the drug development pipeline.  I feel strongly that advocacy needs to be a priority for anyone who cares about the future of someone with CF, because progress means absolutely nothing in the absence of access.  I love analogies, and in my mind, we--the CF community-- are all piled in this homespun machine, moving closer and closer to the finish line (curing CF).  

Inside our machine are multiple interlocking gears that must mesh and spin simultaneously.  The awareness gear interacts with, and helps power fundraising--which leads to scientific investments--which ultimately bring new drugs and therapies into existence.  

The engine of our machine is humming along at breakneck speed!  BUT, there is another crucial juncture we must attend to, where all our inner gears interact with the axle (the ADVOCACY gear). This is the gear responsible for physically spinning the wheels to propel us forward.  If we fail to make that interaction with our system, our inner gears will be left to simply spin...while our machine goes NOWHERE.

You can imagine that it wouldn't take very long for those spinning wheels (and impatient families) to build up some intense heat.    

I believe that we MUST advocate to avoid a situation where the inner gears of our machine are held back by a structure that isn't ready/willing/capable to help us move those wheels closer to our goal. Imagine for a second that advocates HADN'T recently been successful at passing the Ensuring Access to Clinical Trials Act (EACT), and we had the money and science to move forward with exciting clinical trials--but barriers to trial participation stood in our way and slowed us down... I know that I would get hot under the collar in a hurry.  Knowing the passionately CF community the way that I do, I think we run the risk of some serious engine trouble in that situation. We can't let that happen.  

Advocate regularly to avoid engine trouble!
With that, I will close for tonight.  Tomorrow is another full day of workshops and symposium sessions.  Plus, I need to be at my best for lunch with Dr. Beall, and dinner with some of the best scientists in the world.  Stay tuned--we are just getting started!


  1. Quick note: your photo of the slide from the UKGTC presentation shows that the cohort with lower lung function showed significant improvement, whereas those with higher lung function did not show significant improvement. They theorize, again, as your slide shows, it's an issue of deposition. That issue would still be there in any non-viral vector that I know of; unclear to me that gene editing would have a mechanism of delivery that could overcome this?

  2. I look forward to hearing your CRISPR take, especially wrt ProQR. I couldn't make it this year.

  3. Couple of follow-on notes about the gene therapy trial
    in Robb's wake...

    -- Patients with severe lung disease were *excluded* from the trial because it was assumed that fibrosis etc would prevent the transfer of the gene.

    -- Patients who showed the *greatest* benefit were the most-severe group admitted... those with 50-70% FEV1 at outset. Their treatment effect was substantial, comfortably out performing Orkambi (for example).

    -- A less substantial treatment effect was observed in those with a starting 70-90% FEV1. And the most compelling hypothesis put forward for this is that the dose became too diffuse in those with a larger lung capacity / smaller airways open.

    That is why they are proposing a follow-on study with increased dose - with a higher dose concentration they expect the 70-90% group to show more substantial treatment benefit.

    Interesting adjunct: the proposed increased dose is safe... but it causes a brief temperature spike, which would have unblinded the study as it is such a tell-tale marker of the Real Thing. The next study will work to remain blinded while accommodating this treatment effect.

    My view on gene therapy at this stage is that its great merit is being a therapy that works for all mutation sets.

    The fact that lung decline was halted in the group receiving 'appropriate dose' (per above) is, to me, exciting - that arrested/slowed decline is exactly what we celebrate about Kalydeco for gating mutations.

    It's also worth noting that a viral vector has now been identified that seems appropriate for use in CF gene therapy and looks set to be vastly more effective as a delivery method that the liposome.