Personalized Medicine and Rare Disease

For those with a rare disease but without a diagnosis, almost all medicine is “precision medicine.” Whatever drugs or treatments they take are flexible if the patient or their doctors think that the symptoms could be treated with better drugs. In many cases genome sequencing allows for more specific and personalized treatments, and precision medicine has many applications.

In cancer treatment precision medicine means changing the drugs used in chemotherapy not only based on the type of cancer, but based on the mutations that make the cancer dangerous. In drug development, precision medicine means finding new drugs that act as “keys” to certain “locks” in the body. In someone with a rare disease, a diagnosis could lead to a life-changing treatment. But for many, science has not yet found a cure.

Without knowing the cause of the disease, it can be risky to decide which treatments to try on a patient. Sometimes, patients and doctors have no choice but to guess and check. Often patients and their doctors go through the complicated process of reverse engineering a treatment based on whether drugs provide relief or not. For example, if your muscles don’t function properly, there could be many things wrong at the cellular level. Drugs that target the nerve interacting with the muscle might not work, but drugs that target the muscle cells might. With this information, you know a little bit more about the disease, but it can months or years to settle on an optimal treatment with this method.

For some patient’s with rare diseases, genome sequencing opens the door for treating the exact cause disease, not just the symptoms. Continuing the example from above, something as complicated as your muscles could have dozens of reasons for not working properly. If a diagnosis pointed to a malfunctioning protein, treatment could be targeted around that protein. This approach of finding targetable defects has been used successfully in cancer patients.

Precision medicine is being increasingly utilized in cancer treatment. Doctors may request that genome of someone’s tumor be sequenced, to see if a silver-bullet medication is available. This would allow them to avoid using chemotherapy. Cancer is caused by genetic mutations, so sequencing can give doctors important information about how the cancer might develop and behave with certain treatments.

Research into cancer genomes is at the forefront of modern efforts to study and cure cancer. Once sequenced, the mutations in a patient’s cancer can be compared to those in a large database built by researchers. This could yield insight into treatment; some cancer drugs work better against specific mutations, and some treatments are ineffective for similar reasons. If applicable, the chemotherapy doses, timing, and even the drugs involved can be adjusted for the best results.

For some types of cancer, the risk of getting a tumor is hereditary. Genes that normally suppress tumor growth can be mutated, and passed on each generation. Genome sequencing can reveal inherited mutations such as these. Especially for those with a prominent family history of a certain cancer, sequencing can help a patient make informed decisions about their lifestyle. These patients will have informed discussions with their doctors about the prohibitive measures they should undertake, and what they would want in the event that they do get cancer. Often patients who know that they are at risk will have frequent screenings for tumors and stay away from habits like smoking, which can further increase their risk.

Another aspect of precision medicine is drug development. Developing new drugs is very difficult, expensive, and time consuming. Researchers might go through millions of compounds before finding a very specific “key” to a target enzyme’s “lock.” Even when this search is aided by computer modeling, which shows scientists the shape of the enzyme and possible drug compounds that could fit inside, finding even one possible drug is a daunting task.

Once a research team finds a few compounds that can block the targeted enzyme, they are tested for safety, and eventually are given to humans in a clinical trial. This development process takes a lot of time and resources as tests slowly scale up in size from a petri dish to a human being. After years of these tests the drug may go to clinical trial, where patients can sign up to participate in a study of the drug’s effectiveness. Years and many more tests after this the drug may get government approval and released to the general public. If the drug is safe, and works well, it may be approved for clinical use by the FDA.

Some of the bottlenecks for precision medicine include the cost, as well as privacy concerns. These designer drugs are usually only effective for a small cohort of patients, so to recover costs put into developing the drug, a pharmaceutical company may charge much higher prices than for other medicines. Also, like other health data, genetic information is private information, so security must be maintained for all patients.

While Rare Genomics mainly helps people get their exomes sequenced, they also seek to form communities of patients with rare diseases to share their experiences and scientific information. Along with other partners, RG makes information more accessible to patients with rare diseases and their families and seeks to support them post-diagnosis through programs like RareREACH and Rare Share.

Precision medicine was a science fiction goal of the future a short time ago. Today the practice helps countless patients receive higher quality care. With genome sequencing, precision medicine has expanded its reach and shown its potential, and with new technologies constantly in development, I wouldn’t be surprised if it could do even more.

 

 

Genomics and the Genetic Revolution

Rare diseases are difficult to diagnose. Years of tests, even targeted genetic tests, could give negative or inconclusive results. If something is wrong with your body then something might be wrong with the proteins that make it run. If something is wrong with your proteins then something is likely missing or added or replaced in your genes. But - how do you find out what that is?

One of the only ways to find a one in three billion “letter” difference in the books of your chromosomes is through genome sequencing. Relatively, genome sequencing hasn’t been around for very long.

DNA sequencing hasn’t been around for very long either.

In the 1970’s the first DNA sequencing tools were developed, and using a gel base, charge differences, and plenty of copied DNA strands, a computer could be used to calculate the sequence of nucleotides present on a short section of DNA.

This incredibly powerful tool allowed scientists to gather exact information about genes instead of just making very educated guesses. Still, improvements were needed. When DNA sequencing became available scientists predicted a world of personalized medicine and gene therapy, but up until 2003 even the most optimistic considered the predictions science fiction.

Public interest in genome sequencing picked up during the Human Genome Project in the 1990’s, a U.S. government initiative like the Apollo moon missions. The project sought to work with the best geneticists around the world so they could sequence the first full human genome.

The first genome fully sequenced was of a bacteriophage, an organism so small that it is just a pocket of protein with DNA inside. That genome was about 5,000 “letters” long, and sequencing was completed in 1977.

To put this in perspective, the calculations done to first land a man on the moon were done on slide rules, by hand. That restriction would make the human genome project nearly impossible.

Computing is the lifeblood of genome sequencing. The rise in efficiency of sequencing and reduction in cost is proportional to the rise in computing power. During the human genome project from 1990 - 2003, the internet took off, the .com boom took hold of the economy, all while amazon, eBay, and google were just startups working out the right formulas. In the midst of this rapid development computers were used to catalog and interpret the billions of nucleotides in the human genome.

The first cellular organism’s genome sequenced was the H. Influenza bacteria in 1995. The genome was one million base pairs long. In 1996, the first eukaryotic genome, a single celled organism with 12 million base pairs, was sequenced, and in 1998 the first animal genome, a nematode worm, was sequenced.

Nine years after scientists set out to sequence the entire human genome, the first human chromosome was sequenced.

By 2003 the Human Genome Project was completed. It had cost 2.7 billion dollars and took 13 years to sequence the full three billion base pairs. Still, the project was both under budget and ahead of schedule by two years. Today, 99% of a person’s genes can be fully sequenced for a price of $1,000, and can be completed in less than 24 hours.

Since the rapid growth in genome sequencing technology, the time needed to analyze the large amounts of data is now the barrier. For genetic diseases, especially rare ones, there is often only one “letter” difference between a healthy gene and a dysfunctional one. Imagine getting a textbook on everything you want to know, but it’s written in a foreign language. The massive amount of data provided by genome sequencing is a boon to science, but only when it can be interpreted.

Personalized medicine and diagnostics for genetic diseases were always a goal for genome sequencing. Before that could become a reality, the cost and time spent on sequencing had to come down. This was accomplished with the rise in computing and a more selective sequencing approach, looking at only the exome, which contains the protein coding sections of the genome. Sequencing finally made its way into the clinic in 2010, and the occasional sequencing of cancer genomes to allow for targeted treatments began even earlier.

While the cost of sequencing itself has gone down significantly, the price tag doesn’t include the many hours that are spent by specially trained geneticists to find a diagnosis. Human analysis, even aided by a computer, has always been a bottleneck of time and resources in genome sequencing.

The Rare Genomics Institute was founded in 2011. Rare Genomics connects families to research institutions and seeks to help families of rare disease patients crowdfund the resources needed for exome sequencing. By furthering the reach of genetic testing, RG helps to make genome sequencing more accessible to those in need. By expanding the reach of genetic testing, the boundaries of medicine are pushed along the lines of the “science fiction” goals set out before DNA sequencing was even available. I wouldn’t be surprised if those “science fiction” goals of genome sequencing were right around the corner.

Allyson "Ally" Lark - October Rare Bear

Ally Rare Bear.jpg

Allyson “Ally” Lark celebrated her 6th birthday at the end of August. Her family hails from Manitoba, Canada, approximately three-and-a-half hours away from Winnipeg by car. As in the photo with her Rare Bear, Ally is a happy kid. Her mother Madelaine “Leni” Lark describes Ally as an, “energetic, kind, spunky, beautiful, lovely little girl” whose likes include “horses, penguins, music, dancing, spending time with her big sister Bethany and the rest of her family.”

Ally has also been diagnosed with some physical conditions, which include Global Developmental Delay (GDD), Hypotonia and Soft Neurologic Signs (SNS). By utilizing genomic sequencing, it is the hope that Ally’s family can find more answers concerning the details of Ally’s conditions. Ally’s genetics and metabolism doctor (Dr. Patrick Frosk of the Children’s Hospital Research Institute of Manitoba), posits that Ally’s physical features are indicative of a metabolic disorder. Though genetic testing has not yet yielded a specific name for the disorder that Ally has, it is the hope of Ally’s family that as new developments and discoveries are made, Ally’s genetic information may be referenced and a more definite diagnosis may be reached soon.

A frustrating aspect of receiving the diagnoses that the Larks did when Ally was just two years old is the uncertainty of the developmental potential of their child. By contacting the Rare Genomics Institute and having sequencing performed, it is the hope that at least some of that uncertainty can be removed.

Ally's mother Leni described receiving Ally’s diagnosis, “we were very scared as her future at that point was unknown. We did not know what her developmental potential would be, and we did not know what to do, or where to start.”

Ally’s condition is a recognized disability in Canada. However, living nearly four hours from the nearest city has impacted the ability of the Larks to get the one-on-one care their daughter needs. Leni notes, “Resources (here) are so minimal for kids with disabilities. It is up to families and schools/daycares to provide therapies. This is frustrating because we are not able to access crucial resources for Ally as much as we would like, particularly speech therapy and PT…Despite all of this, Allyson has made tremendous gains!”

Like many of us, Ally does not enjoy going to the doctor. But on Boxing Day 2016, her mother contacted the Rare Genomics Institute in an attempt to get Ally the care she needed through the use of whole genomic sequencing. Ally did not qualify for sponsorship of this kind of genetic testing in her home province. However, the Rare Genomics Institute was happy to help the Lark family. Having been selected to receive Whole Exome Sequencing for their daughter, the Larks saved out-of-pocket costs that could have totaled more than $20,000.

The Lark’s experience with the Rare Genomics Institute has been a positive one. Though there is no answer at present as to why Ally has a developmental delay, her mother encourages all families in need of sequencing to reach out to Rare Genomics. Leni stated, “I would have regretted passing up this opportunity… (Rare Genomics is) great to work with! I was worried there would be a lot of red tape to go through as we are located in Canada and Rare Genomics is an American agency, but things went so smoothly.” The family’s plan now is to continue supporting their daughter any way they can. We at the Rare Genomics Institute are proud to have been a part of that support. If you or someone you know could benefit from whole genomic sequencing, please reach out to the Rare Genomics Institute via the links on this webpage.

Daryl Velez

The VanBrocklin’s are moving forward after Sequencing

As we pass the six-month mark as partners in the iHope program, it has already been so rewarding for us at Rare Genomics to see underserved families receive Whole Genome Sequencing in an effort to gain results and treatments for the conditions of their loved ones. We first shared the VanBrocklin story and video when they received their positive Whole Genome Sequencing results early this year.

I had the opportunity to interview the Van Brocklin family for the video at their home in Racine, Wisconsin, and came away very inspired. After visiting with Jami and Jonathan for just an afternoon, I was taken aback by all of the roadblocks that they have had to overcome in their search for answers for their children, Jasmine and Ronin. Now looking back months after receiving the sequencing results, we can see what a difference they have made.

The cost of copays, prescriptions and therapies for the VanBrocklin’s were well over $5,000 a year; in fact in 2016, they actually hit the threshold ceiling for medical tax deductions. With undiagnosed children, it was very difficult for the Van Brocklin’s to find any answers.  From a financial point of view, most insurance providers do not cover procedures like Whole Genome Sequencing, making it very difficult to acquire the comprehensive testing that is the key to unlocking these genetic secrets. From a parenting perspective, imagine having children with a disease that is unknown. It is impossible to start fighting a disease that you can’t even put a finger on.

Fortunately, both Van Brocklin children were able to take advantage of the iHope program and received results for their diseases. With Jasmine’s confirmed diagnosis for Ichthyosis Vulgaris, she has been referred by the Children’s Hospital of Wisconsin to their new pediatric genetic dermatologist.  This specialist possesses a much more thorough understanding of her condition. In Ronin’s case, with confirmed genetic testing findings of 16p11.2 microduplication he was able to obtain an official diagnosis of Autism. This diagnosis gives the Van Brocklin’s the option of specialized therapy, and also relieved concerns that his symptoms may have been due to a more significant health concern.

Our partners at Illumina, through the iHope program, have done a tremendous job working with us to provide underserved families with Whole Genome Sequencing testing and it has been a privilege of mine to be a small part of it.  If you are looking to be a part of the program, or if you have a family member that may qualify for the iHope program, please do not hesitate to join us in our search for answers.

Richard Bonds

Tenth Annual Rare Disease Day

The last day of February is a day to create awareness and let patients and affected with rare diseases be heard. This year, February 28th marks the tenth year of Rare Disease Day.

Rare Genomics (RG) participated last year, and we will again this year be a part of a day where rare diseases get the attention they deserve. This day patients worldwide stand together and make their voices heard, and RG wants to be a part of this.

What is Rare Disease Day?
Rare Disease Day seeks to raise awareness amongst both the general public and decision-makers about rare diseases and how living with these impacts patients’ lives.

Many different organizations participate in Rare Disease Day events. Rare Disease Day started in 2008 as a European phenomenon - but today it has expanded into be a worldwide phenomenon. Hundreds of patient organizations work to raise awareness for the rare disease community in their countries all year around, but on the last day of February they get extensive public and political attention.

The last day of February was chosen as Rare Disease Day since February 29th is the rarest day and only occurs every fourth year.

The official poster for Rare Disease Day 2017

Join us for Rare Disease Day
Rare Disease Day is an opportunity for RG to draw attention and awareness to rare diseases. The awareness is important in order to hopefully diagnose and cure many more patients with rare diseases in the future.

Please join us and participate in Rare Disease Day! Your donation to RG will help patients living with a rare disease. By donating to RG and being part of the tenth Rare Disease Day you contribute to a brighter future for the patients - a future without rare diseases.

Read more about Rare Disease Day and RG's participation here and donate by clicking the button below. Thank you!

Paper on Orphan Drug Development in China Published

Alice Cheng and Zhi Xie of the Rare Genomics Institute have published a open-access paper, "Challenges in orphan drug development and regulatory policy" in the Orphanet Journal of Rare Diseases.

Orphan drugs are pharmaceutical treatments developed to treat specific rare diseases. They aren't profitable for pharmaceutical companies to produce due to their extremely specific nature. Regulatory policies on orphan drug development are well-defined in the United States and European countries, but rare disease policies in China are still fluctuating. Pharmaceutical companies in China are de-incentivisted to pursue drug development for rare diseases due to a lack of clear definition and regulatory approval process. As a result, many rare disease patients in China pay out of pocket for international treatments.

Many grassroots movements have begun to support rare disease patients and facilitate research for the development of orphan drugs. The Chinese FDA has recently set new regulatory guidelines for drugs being developed in China, including an expedited review process for lifesaving treatments.

Cheng and Xie's paper compares orphan drug development and regulatory policy in China and the US. They find that due to political, economic, and cultural differences, China cannot simply base its policies on the American model. China's public healthcare system has the opportunity to take advantage of available data to create aggregated databases for diseases and genomic information, assisting epidemiology research.

The authors advocate for the five suggestions proposed by the National People's Congress and Chinese People's Political Consultative Conference of 2009:

  1. Establish a definition for rare diseases.
  2. Develop an orphan drug reimbursement system.
  3. Propose a clear and simple approval pathway for imported orphan drugs.
  4. Promte rare disease research through policy.
  5. Develop government-supported programs for rare disease patients.

Read the full paper from the Orphanet Journal of Rare Diseases.

Leading the Way: Marching Onward

At the Rare Genomics Institute, we understand that enacting change cannot happen unilaterally and that solving medical mysteries does not come without teamwork. We stand proudly at the forefront of the utilization of genomic sequencing for the purpose of identifying, treating and hopefully curing rare diseases. At the same time, we realize there are many other people outside of our organization who are just as fundamental to the fight against rare diseases as we are. The team at RG is inspired by those who dedicate their lives to helping others affected by rare disease. Here is one of their stories:

Research is the backbone of scientific discovery. Researchers do not often hone their craft in the spotlight: theirs is a task best suited at the lab bench, away from the public eye. It was, therefore, striking to come across a geneticist who works with the public on a daily basis as a pediatrician in my proverbial backyard at Columbia University. In December of 2016, I sat down with Dr. Wendy Chung to discuss her unique practice.

Dr. Chung holds both a PhD in genetics from Rockefeller University and an MD from Cornell University. The confluence of those pieces of education is not coincidental; “The year that I started my MD/PhD program was the year the Human Genome Project officially started. It became very clear to me that there was going to be a very unique opportunity in terms of being able to harness [that] power.”

Her interest in genetics in tow, Dr. Chung tailored her research and subsequent medical practice toward those who need genetic research most: children with rare diseases.

“A lot of individuals with rare disorders don't live to grow up,” Dr. Chung continued, “[However], it’s just been miraculous to me to be able to see how much things have evolved and changed in a very positive way: What I see now is that getting a diagnosis is much easier than it used to be. Now our energy needs to be focused on developing treatments. What drives me now is to figure out how we can get beyond the diagnosis and get to [those] treatments.”

Setting a Course:

The route that Dr. Chung’s lab takes toward diagnosis and treatment is somewhat irregular. Gene editing has been mentioned on the Rare Genomics Institute’s website before.

However, Dr. Chung edits the genes of model organisms (mostly mice) in order to test the reactions of those organisms to treatments before utilizing suggested treatments on humans. Dr. Chung’s practice is unique in that she and her team participate on both the research and practical implementation sides of the fence. She is actively both testing treatments and treating patients.

Dr. Chung stated, “We do everything we can in terms of clinical care and then we continue to march onward. If we don't find anything we can do clinically we cross over the fence into research mode and do everything we can on the research side. We can return information from the research study to [patients] and hopefully get them to a diagnosis faster and more effectively.”

Dr. Chung continued, “Because Columbia is a research institute, when we identify new conditions, we do our very best to help families connect to each other and to share information amongst clinicians. [We then] make that information freely available and accessible so that we can all learn together and try to understand mechanisms for why these conditions exist.” Dr. Chung detailed some of the limitations of more orthodox research methods, “If you're talking about cells in vitro, it’s a fine model for very basic molecules in terms of how they interact in a cell. But even if you make an organoid in terms of neurons in a dish, you can’t get that to function like a brain does. Maybe if you're lucky you'll get something that looks like a seizure from an electrical point of view, but often times you can’t get anything that approaches the right behavioral difference.”

Researchers at Columbia come to similar crossroads in Dr. Chung’s lab. “When it comes to mice or any other model organism,” stated Dr. Chung, “the mice may look basically fine, but the people, who have this same condition, they are clearly not fine.”

The two halves of Dr. Chung’s practice are united due to this complication. Though rodents inflicted with the same rare conditions as human patients may appear to function normally, Dr. Chung notes that mice do not read or write; they are not responsible for higher-order thinking challenges like those of a human. Therefore, sometimes, modeling is insufficient in both diagnosis and in research for treatment techniques for patients.

Next Steps:

The goal of Dr. Chung’s practice is, of course, not simply diagnosis but treatment. There are limitations to this goal, however. Research timelines often stymie a patient’s journey from diagnosis to treatment. Dr. Chung elaborates, “Treatment isn't something that comes a week after you get the diagnosis. It often takes several years to do that, but we're working with families to take that next step.”

Time is not the only limiting factor in the treatment of a patient living with a rare disease. Costs can be overwhelming for families. Accessibility is extremely important to the rare disease patient community and Dr. Chung’s team certainly recognizes the fact. Dr. Chung notes, “We take all types of insurance, whether it’s Medicaid or private insurance. We try to have enough capacity to try to deal with all of the different types of patients that would come in, whether they're kids or adults.”

“On the other hand,” Dr. Chung continued, “we also try to be realistic. If there are some individuals where, if we don’t think that there's a high enough probability that we're going to find something or help them even if we don't find an answer, we don't have them come halfway around the country.”

Working Together:

Dr. Chung’s patient population is wide-ranging in the geographic sense, and admission therein requires that only 3-5 patients are seen each week. Typical patients of the DISCOVER (Diagnosis Initiative: Seeking Care and Opportunities with Vision for Exploration and Research) Program “tend to be many of the same types of folks that you guys are working with at the Rare Genomics Institute” states Dr. Chung, “[these] kids may have neuro-developmental disorders or congenital anomalies or very rare or very early onset presentations of conditions that increase the probability that [their conditions may be] something hereditary.”

Many of Dr. Chung’s patients are designated “N-of-1” or the very first patients to experience certain conditions. Dr. Chung clarified, “Although it’s not always the case, it’s not unusual for us to be an N-of-1 situation for a while. [These situations] don’t stay N-of-1 for very long, but they often start out that way.”

The uniqueness of her patient’s conditions often leads to frustrations in treatment. Dr. Chung notes that in terms of ultra-rare diseases, the challenges of both time and money weigh heavily on the patient population, “ultra-rare diseases are individually so rare that it is hard to be able to get the resources and the talented scientists to be able to dedicate all their energies for conditions that affect one in two million people, for example.”

Emphatically reinforcing why her organization is important in the many fights against rare conditions, Dr. Chung stated, “Unless every rare disease is blessed with a family who has gazillions of dollars they don't know what to do with, you can get stuck.”

But Dr. Chung’s team needn’t help families get un-stuck alone, “This is very much a partnership. Families really have to take up the cause and push things forward, especially when it comes to the ultra-rare disorders. If they don't, it's not like a lot of people are going to run to their assistance.”

Moving forward from diagnosis is a communal effort: it is up to all of us. Whether you’ve been inspired by the work of artists or you know someone living with a rare disease yourself, the work of doctors and researchers to help patients living with rare conditions cannot be completed without your help. Please consider suppporting ongoing rare disease research efforts. Let's march onward together.

CRISPR and Gene Therapy: An Overview of the Breakthrough Gene-Editing Tool

CRISPR has been in the news lately—for good reason. At Sichuan University, the first human patient is being treated with immune cells edited via CRISPR.

CRISPR has made effective gene therapy a realistic possibility for the near future. But how?

The structure of Cas9, from the National Institutes of Health (NIH).

The structure of Cas9, from the National Institutes of Health (NIH).

Targeting DNA with CRISPR

CRISPR is short for Clustered Regularly Interspaced Short Palindromic Repeats. The long name describes what it is: DNA segments from prokaryotes (single-cell organisms) with a series of short, repetitive base sequences punctuated by spacer DNA that originated from plasmids or phages (infectious agents). Palindromic repeats aren’t like palindromes in language; instead, they are a particular sequence of DNA that, when transcribed, can form a three-dimensional “hairpin” loop in RNA.

CRISPR DNA segments are part of a prokaryotic immune system, the CRISPR/Cas system. When plasmids and phages attack a prokaryote, inserting foreign DNA, this system resists. CRISPR associated proteins (Cas) use the foreign origins of CRISPR’s spacer DNA to identify the newly inserted sequences. Cas then copies these sequences and places them into an RNA molecule. Cas and this RNA molecule comb through the cell to find foreign DNA from plasmids or phages. When a match occurs, the portion of the RNA molecule copied from the spacer DNA locks on, allowing a Cas enzyme—Cas9, an endonuclease—to slice the foreign DNA. Now damaged from broken phosphodiester bonds, the plasmid’s or phage’s DNA can’t replicate within the cell.

The specific CRISPR/Cas system used in biotechnology is engineered from the CRISPR/Cas system in the bacteria that causes strep throat, Streptococcus pyogenes. When people talk about CRISPR, they’re referring to the whole CRISPR/Cas system, not just CRISPR as the DNA segments.

Using CRISPR to Cure

CRISPR can be used in gene therapy to treat diseases with a genetic component. Gene therapy uses genes themselves as a means to prevent or treat diseases. This can be done at a cellular level by inserting healthy genes, making a harmful gene inactive, or replacing a harmful gene with a healthy gene. Gene therapy uses a process called genome editing, which refers to any method that uses an endonuclease (molecular scissors) to cut DNA at a specific location in order to insert, remove, or replace a gene. Cas9’s ability to slice foreign DNA at targeted points makes CRISPR an effective tool for gene editing, and therefore, gene therapy.

When treating disease, scientists program CRISPR to detect a specific sequence that makes up a harmful gene. When that sequence is found, the DNA strand is unzipped and the harmful gene removed. In some cases, the DNA can repair itself. In others, scientists insert a healthy gene into the gap left by CRISPR. Gene therapy that occurs in somatic cells (body cells) facilitates treatment, as the gene’s intended function is restored.

Looking Forward

CRISPR isn’t foolproof, though; sometimes, Cas9 can cut DNA at the wrong place. However, CRISPR’s efficiency and overall accuracy allow it to overshadow earlier gene editing tools, like TALENs (transcription activator-like effector nucleases) and ZFN (zinc finger nuclease). Because of its programmable nature, it only takes a few days to engineer CRISPR to detect a specific sequence of DNA. With CRISPR, both copies of a gene—and both copies of multiple genes—can be edited at the same time.

Despite these qualities that make CRISPR the most efficient gene editing tool yet, both technical and ethical issues compound research. A significant technical hurdle is how CRISPR is delivered into individual cells. CRISPR must have direct access to a cell’s DNA to make repairs.

And even though CRISPR has already been used successfully in crops, mice, and mosquitoes, ethical questions arise when genetic engineering is applied to humans. This type of gene editing still poses risk: the crux of the decision to use gene therapy relies on weighing the risks of a genetic disease versus the risks of its potential cure. Even if ongoing research trials are successful, it will take years for CRISPR-enabled gene therapy to become a fixture of the clinician’s office.

Overall, CRISPR is an accurate and powerful tool revolutionizing how gene editing and gene therapy are approached. As more research is completed, the full potential of this method can be revealed.

Rare Genomics Institute participates in #GivingTuesday again

 

Rare Genomics Institute was a part of the international movement #GivingTuesday last year, and now it is time to attend the international day of giving again. It is a day that brings nonprofits, donors, businesses and communities together celebrating generosity and the impact of giving back.

We are looking forward to participate again this year and fundraise resources, so we can continue and improve our important work on fighting rare diseases.

Last year, thanks to the support of all our amazing volunteers, we managed to raise almost $20,000 dollars between #GivingTuesday and the Year-End Campaign. We are excited about participating again this year, and we are confident that together and with all your help we will be able to meet 2016’s fundraising goal of $25,000 dollars.

The Year-End Campaign is divided in two parts. The first parts is from November 12 until November 29 (#GivingTuesday) and the second part from December 1 until December 31. We count on and hope for your help and the help of your friends and families this year.

Join Rare Genomics Institute’s participation in #GivingTuesday and celebrate generosity worldwide. Together we stand stronger and can make a huge impact. Thank you in advance and have a lovely November!

Leading the Way: Beyond the Diagnosis

Leading the Way: Beyond the Diagnosis

The Rare Disease United Foundation launched the Beyond the Diagnosis exhibit just two years ago. The idea was that portraits of those living with rare diseases could allow people to become more engaged with the rare disease patient community; that there is more to a person living with a rare disease than the diagnosis itself.

Read More

Shooting for the Moon in Honor of Mesothelioma Awareness Day

As Mesothelioma Awareness Day approaches, it's the perfect time to raise awareness about this rare form of cancer and the amazing potential for progress now in sight thanks to the Cancer Moonshot project. Established in 2004, Mesothelioma Awareness Day (September 26th) exists to bring funding and attention to mesothelioma, a rare yet aggressive and deadly form of cancer. So, how much can the Cancer Moonshot do to bring an end to Mesothelioma?

Mesothelioma

Mesothelioma is a rare form of cancer, with only about 2,000 to 3,000 new cases annually in the US. In cases of malignant mesothelioma, cancer cells form in the thin layer of tissue lining the abdomen, chest wall, or lungs, or, less commonly, in the testicles or heart. Long-term asbestos exposure is the primary cause of malignant mesothelioma in adults. This exposure puts not just the person who was originally exposed at risk, but also that person's family members. This kind of malignant mesothelioma typically takes 10 to 40 years to develop after exposure.

Pediatric mesothelioma is different in that it can spontaneously generate and does not necessarily have a link to asbestos exposure. In fact, most cases of pediatric mesothelioma seem to have no apparent cause, making prevention difficult. It is also exceedingly rare, as most cases of mesothelioma are in older adults.

The Cancer Moonshot and Data Siloing

In January of 2016, President Barack Obama announced the Cancer Moonshot project during his State of the Union address. The goal of the initiative is to double the amount of research progress in the fight against cancer by putting more money, cooperation, and focus on the most promising areas; by making more therapies available to more people; and by ensuring that the siloing of cancer research data comes to an end. The initiative is led by Vice President Joe Biden who directs the Cancer Moonshot Task Force; they are advised by the National Cancer Advisory Board (NCAB) and its working group, the Blue Ribbon Panel dedicated specifically to the Cancer Moonshot.

The issues that the Cancer Moonshot have identified are perhaps not surprising to anyone who is passionate about rare diseases generally or a specific rare disease such as mesothelioma. Nevertheless, they are notable and deserve our close attention.

First, the issue of siloing of data, research results, and scientific knowledge generally is a tremendous problem for all sufferers of rare diseases—people who make up about ten percent of the US population. While cancer immunotherapy, combination therapies, and genomics hold incredible promise for patients, siloing means a lack of access and progress.

As of the time the Cancer Moonshot was announced, only about 5 percent of American cancer patients participated in clinical trials for new treatments. Most of them don't have access to their own results and data. Furthermore, most oncologists simply don't have access to the latest advances in treatment research and technology.

Historically, the raw scientific data collected by researchers throughout the course of studies becomes the property of the institutions that the researchers work for. The end result is mountains of data locked away in each individual research institution, but no central repository from which truly groundbreaking conclusions and progress may spring. The need to detect biological and genetic patterns that could reveal the mechanisms that enable cancer to manifest and grow makes sharing and collaboration essential.

The Cancer Moonshot initiative has now identified one of its key goals: the creation of a National Cancer Data Ecosystem. This would be a free “one-stop shop” for research data on cancer available to patients and researchers alike. Patients could upload their own data and in turn receive information about their particular variety of cancer.

Collaboration is also going to be critical for making new treatments like immunotherapy more effective. Currently, only 20 percent of patients get the full benefit of immunotherapy treatments. Researchers hope that by pooling all existing knowledge about immunotherapy treatments and practices more effective forms of immunotherapy might be developed.

This kind of information sharing should also benefit genomics treatment projects such as the Collaborative Cancer Cloud. This project aims to create tailored gene therapies for each patient, and to do that it needs to access huge amounts of data on genetic mutations, cancer surveillance, and treatment effectiveness.

New Treatments Arising from Moonshot Research

In September 2016, the Blue Ribbon Panel reported back to the Vice President with recommendations for the rest of the Cancer Moonshot initiative. The report contains ten suggestions which will form the “research blueprint” for the rest of the project.

Cancer Immunotherapy in Focus

Ideally, the body's natural immune system works to prevent cancer by detecting and destroying cells that are abnormal. However, cancer cells can sometimes avoid being detected and destroyed by the body's immune system. They have several ways of avoiding the defenses of the human immune system:

  • Some cancer cells make it harder for the immune system to see them by reducing the expression of tumor antigens on their surface;
  • Some cancer cells inactivate immune cells by expressing proteins on their surface; and
  • Some cancer cells can both promote their own proliferation and survival and suppress immune response by inducing surrounding cells to release immune suppressing substances.

Knowing these tactics employed by cancer cells, researchers have pursued the field of cancer immunology, which has emerged over the past few years. The new techniques for treating cancer created in this field, called immunotherapies, all have the common goal of increasing the strength of immune responses to tumors. Immunotherapies can do this in several ways, but most methods boil down to countering specific cancer cells that suppress immune responses, providing man-made immune components, or stimulating smarter or stronger immune system responses generally.

So far immunotherapy is more effective against some kinds of cancer than others; for those varieties, immunotherapy alone may be enough treatment. For cancers that are less responsive to immunotherapy, at least so far, immunotherapy can still boost the effectiveness of other treatments when used in combination with them.

Several broader research questions related to cancer immunotherapy remain, and these too will be pursued as part of the Cancer Moonshot initiative:

  • Why is immunotherapy effective in certain patients with one type of cancer but not in others who have the same type of cancer?
  • How can we expand the use of immunotherapy to more varieties of cancer?
  • How can we increase the effectiveness of immunotherapy by combining it with other treatments like chemotherapy, targeted therapy, and radiation therapy?

Kinds of Cancer Immunotherapy

Once you understand the many kinds of cancer immunotherapies already under development, it is easy to see why the Cancer Moonshot experts find this area so promising. Here are the kinds of cancer immunotherapy that exist today.

Adoptive Cell Transfer

In adoptive cell transfer, an experimental form of immunotherapy, some patients with very advanced cancers have been completed cured. These patients primarily suffered from blood cancers. ACT works when T cells from inside the tumor of a patient, called tumor-infiltrating lymphocytes (TILs), are collected. Those TILs are then tested to see which show the greatest recognition of the patient's tumor cells. Those selected are then grown into large populations in the laboratory and activated by cytokines, immune system signaling proteins. Finally, the treated TILs are infused into the bloodstream of the patient.

This works because the most successful T cells are multiplied and put back to work. With greatly increased numbers they can then shrink or even kill off the tumors.

A similar method is called CAR T-cell therapy. This works by collecting T cells from the blood and then genetically modifying them to express CAR, a chimeric antigen T cell receptor protein. Then, as in the other ACT technique the modified cells are grown into large populations and reintroduced into the patient. Once inside the patient, these new CAR T cells attach to the surface of the cancer cells and attack them.

Monoclonal Antibodies to Treat Cancer

The immune system can attack invading substances like cancer cells by manufacturing many antibodies, proteins that sticks to antigens, specific proteins carried by enemy cells. Once so “marked” by the antibodies the entire immune system can get involved and fight the cells that contain that antigen.

Monoclonal antibodies (mAbs) are antibodies designed to target a particular antigen like those found on cancer cells. Scientists can make these mAbs in large numbers in labs, and these can be used to treat some cancers. In fact, more than one dozen mAbs have been approved to treat various cancers by the US Food and Drug Administration (FDA).

Naked monoclonal antibodies are the most common kind of mAbs used to treat cancers. These work without any radioactive material or drug attached to them.

Conjugated monoclonal antibodies, also called labeled, loaded, or tagged antibodies, are joined to either a radioactive particle or a chemotherapy drug so that the mAbs can be used to locate cancer cells and take the treatments directly to them. This helps lessen the damage caused by these treatments to healthy cells.

Radiolabeled antibodies are joined to small radioactive particles. These are used in radioimmunotherapy (RIT). Chemolabeled antibodies, also called antibody-drug conjugates (ADCs), are mAbs that carry drugs, usually chemotherapy drugs. Both of these are types of conjugated monoclonal antibodies.

Bispecific monoclonal antibodies are drugs that contain two different mAbs; this allows them to attach to two different proteins simultaneously.

Some therapeutic antibodies bind to cancer cells and cause apoptosis or cell death. In other cases, the binding antibody is recognized by specific immune cells or proteins, which then cause the cancer cells to die by cytotoxicity.

Immune Checkpoint Modulators

Obviously, to work properly the immune system must be able to distinguish between normal, healthy cells and “invader” cells. It needs “checkpoints” to do this. Checkpoints are molecules on some immune cells that must be activated or inactivated in order to prompt an immune response. Cancer cells can sometimes avoid or use these checkpoints to avoid detection or attack; this is why treatments that target checkpoints are promising.

There are two kinds of cytokines, proteins that normally modulate or regulate the activity of the immune system, that are being used to enhance the human immune response to cancer: interferons and interleukins. Some of these proteins activate white blood cells like dendritic cells and natural killer cells.

Researchers are also working to develop more drugs that target checkpoint proteins on T cells such as PD-1 or PD-L1. These checkpoint proteins act as “off switches” for the immune system and are intended to protect healthy cells. However, these are also found on some cancer cells, a defense mechanism against attack.

Benefits of Immunotherapy

Cancer immunotherapy offers some clear benefits. First of all, it has the potential to fight many different types of cancer. Because it enables an effective response from the human immune system, effective immunotherapy would provide a universal cure for cancer. Immunotherapy is already effective against many varieties of cancer, including some that have resisted traditional treatments like chemotherapy and radiation (melanoma, for example).

Effective cancer immunotherapy is more likely to produce long-term cancer remission because it “trains” the immune system to fight and remember cancer cells. Longer lasting remissions could well be the result of the human “immunomemory.” Furthermore, many clinical studies on cancer immunotherapy have already demonstrated long-lasting beneficial results.

Cancer immunotherapy is less likely to produce as many terrible side effects as chemotherapy and radiation do. This is because it is more targeted and protective of healthy cells. Typical immunotherapy side effects resemble the symptoms of fighting off infection, such as fever, inflammation, and fatigue, although some immunotherapy carries with it more severe side effects mimicking symptoms of autoimmune disorders.

In all, the potential benefits of successful cancer immunotherapy are tremendous.

Conclusion

On the eve of the 12th Mesothelioma Awareness Day, the Cancer Moonshot has provided a new sense of hope and progress. With its focus on cancer immunotherapy and enhanced cooperation and access to information, the Cancer Moonshot reveals an intelligent approach that has an ambitious yet realistic goal. Mesothelioma awareness advocates hail the Cancer Moonshot as a commitment even to rare forms of cancer that are often overlooked, because the benefits are clearly going to be felt by our community.

From a rare disease perspective, the Cancer Moonshot model is particularly appealing. Will a success in this area provide a new paradigm for a more collaborative fight against rare diseases in the future?

Karla Lant is a freelance writer and editor who volunteers for the Rare Genomics Institute.

Rare Genomics is a finalist for the 2016 Drucker Prize!

The winning nonprofit organization, which receives a $100,000 grant, will be announced on September 30. The Rare Genomics Institute was selected from 50 semifinalists—out of 500 applicants—after completing mini-courses that covered innovation and nonprofit performance. Rare Genomics answered questions on our current organizational practices and how we could implement the new ideas that were presented through the mini-courses.

The Drucker Prize, formerly known as the Peter F. Drucker Award for Nonprofit Innovation, has been awarded since 1991. Winning organizations represent the Drucker Institute's definition of innovation: "change that creates a new dimension of performance." Nonprofits are judged on effectiveness, the difference their programs can create in the lives of people they serve, and their innovative impact.

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BeHEARD 2015 Winner Update: Progress on Rare Skin Disorders

Heather Etchevers, a research scientist at the French National Institutes of Health, is a two-time winner of the BeHEARD competition for support for her research on identifying mutations that lead to giant congenital melanocytic nevus (CMN), a pigmented birth defect of the skin that requires surgery to remove.

In 2013, Heather was selected to receive a supply of JumpStart TAQ ReadyMix, a PCR reagent, from Sigma Life Sciences, which led to her lab finding the mutation responsible for CMN in eight patients. Heather was also able to use leftover reagent supplies for ongoing research to identify the genetic cause behind a second rare disease, cutaneous arteriovenous malformations. Her lab was able to eliminate one of four likely genes as a potential cause, a result that was written up for journal publication. During 2015, Heather was awarded $10,000 worth of existing mouse models from The Jackson Laboratory’s live repository, from which she selected six defined lines.

Heather and her team, “…are looking forward to using a so-called reporter mouse strain to monitor the activation of a particular signaling pathway in individual cells. With the animal model and cellular tools we are developing at the moment, [we will] develop innovative approaches to curing the worst effects of CMN syndrome (cancer, neurological deterioration) and managing the ones with psychosocial impact, such as a strikingly different appearance, relentless itchiness or otherwise less than fully functional skin.”

"It's always a tremendous challenge to attract research funding for rare diseases - even more so when we are carrying out fundamental studies in mechanisms and causes", says Heather. "RGI BeHEARD did just that - the fact that an award was attached made our research more visible and attractive for other funders."

DNA Dash

Rare Genomics Institute Calgary Executive Vyoma Shah talks about her personal experience with RGI and the DNA Dash in an interview with Global News Calgary.

BeHEARD 2015 Winner Update: Progress on Opitz C Syndrome

Dr. Roser Urreizti is a postdoctoral fellow at CIBERER, Universitat de Barcelona (Spain). Roser’s work focuses on searching for the gene or genes responsible for Opitz C Syndrome, by means of whole exome sequencing and functional studies. One of the distinguishing features of C Syndrome is a condition in which the skull is a triangular shape, primarily due to premature closure of the cranial sutures. The disease is also characterized by mental retardation, loss of muscle tone, abnormalities of the sternum, facial palsy, webbed fingers and/or toes, contractures, short limbs, heart defects, failure of one or both testicles to move down into the scrotum, (cryptorchidism), abnormalities of the kidneys and lungs, deformity of the lower jaw, and seizures.

In the 2015 BeHEARD Competition, Roser was awarded whole exome sequencings from Euformatics, which allowed her team to confirm that they had found the genetic cause behind the disease.

“In the patients analyzed by the Euformatics platform, we have identified the disease-causing mutation,” says Roser. “We have already started functional studies for every one of the genes associated with the diseases. None of them had been previously associated with Opitz C syndrome. We hope we will be able to test therapeutic approaches (molecular chaperones) in one year in a near future. We have started a collaboration to test selected FDA approved drugs on a patient's cells in a search for therapies once the functional studies confirm the relation between the mutation and the disease.”