Patient Empowerment Program: A Rare Disease Podcast

Coming Together for the Nano-rare Patient

When Stan Crooke, M.D., Ph.D., ran Ionis and John Maraganore, Ph.D., ran Alnylam, they were partners that turned into rivals — and not always friendly ones — as they persevered to pursue an entirely new therapeutic space; RNA-targeted drug discovery and development. Now, the pair of drug discovery titans have united once again in support of Dr. Crooke’s n-Lorem Foundation—working to provide experimental personalized medicines to the rarest of rare disease patients (nano-rare) using the antisense oligonucleotide (ASO) technology he developed at Ionis. In this episode, Stan speaks with Dr. John Maraganore about John’s past, their former rivalry, and the optimism shared between the two with respect to the future of n-Lorem.Do you have a question that you’d like to ask Stan Crooke? Stan will be taking questions directly from you and other podcast listeners and dedicating an entire episode towards answering your questions! To submit a question for the upcoming Q&A episode, email podcast@nlorem.org with the subject line labeled “podcast question”. If you wish to be identified, mention your name in the email. If not, we will keep your submission anonymous. We cannot wait to hear from you!

Antisense (How We Do It at n-Lorem)

We’d like to thank our sponsor, Argonaut Manufacturing Services. Argonaut provides contract manufacturing and sterile fill-finish services for biopharmaceutical, diagnostics, and life science organizations. Argonaut’s expertise in sterile fill-finish is the last step in the complex process of providing personalized antisense oligonucleotide (ASO) medicines to nano-rare patients.When considering if the technology he led the creation of could be a viable way to develop a drug for a single patient, addressing their specific mutation, Dr. Crooke felt that he had to try, patients were dying without access to any treatment because they were just too rare. So began n-Lorem. As expected, developing an optimal ASO for a single patient is not an easy or simple process. Quality must lead every step and only optimal ASOs can reach patients.Learn our science and processes behind the discovery and development of personalized ASO medicines for each of our nano-rare patients. n-Lorem’s mission is to provide hope and potential help to nano-rare patients – for free, for life; a mission that was impossible just a few years ago. This enables the non-profit approach that we believe is the only way to address the needs of nano-rare patients. Thanks to our partners like Argonaut, we are able to provide hope and potential help to patients today and tomorrow.

Anna’s Story of Hope and Help

In this episode, Stan talks with Sonja and Dr. Neil Shneider, associate professor of motor neuron disorders at Columbia Medical School, about Sonja’s daughter, Anna. She is 17 years old and suffers an aggressive, fatal form of ALS. ALS is rare in teenagers, and this form of ALS is the worst of the worst. Sonja tells Anna’s story initial symptom onset, to diagnosis, and to Anna's response to ASO treatment. As a parent, Sonja reveals her full range of emotions during the duration of her daughter’s disease: puzzlement, pain, humility, and now optimism.

Why ASO Technology

What makes antisense oligonucleotides (ASOs) so special? Let’s first understand what an oligonucleotide is. An oligonucleotide is a short strand of synthetic DNA, or a nucleic-acid chain, usually consisting of up to approximately 20 nucleotides read from left to right. n-Lorem’s ASO technology is based on thirty years of innovation and investment to make ASOs drugs with optimal qualities. This technology is also uniquely beneficial for nano-rare patients due to its specificity and broad utility to address the myriad of mutations that nano-rare patients present. Each a unique program with a unique challenge.Compared to other drug discovery platforms, discovering and developing an optimal ASO is inexpensive, quick and can be used to treat diseases that are caused by many different types of gene mutations. ASOs are designed to bind precisely with RNA, modifying the process of creating a disease-causing protein. Thereby making ASOs highly specific and a powerful drug discovery technology for nano-rare patients, who need a therapeutic approach that targets their specific gene mutation.

Advocating for Rare Patients

In this episode, Stan speaks with Wendy Erler about her involvement in the treatment of patients with rare genetic disorders. From her start in the pharmaceutical industry, to her involvement with every major platform of drug development, to her position as vice president and head of patient advocacy at Alexion; Ms. Erler has always ensured that a patient's voice is heard.Learn more about Wendy Erler on twitter @wendy_erlerPlease like and subscribe so that we can reach more potential patients and their family.

Drug Discovery Platforms

There are three validated methods of discovering drugs – called platforms. Small molecule drugs (SMD), monoclonal antibodies (mAbs), and RNA-targeted drugs. SMDs are, you guessed it, very small! Remember that the size of chemicals is measured in units called Daltons, which is capitalized because it is named after the scientist who invented the term. The smallest chemical is a hydrogen ion, and it is 1 Dalton. Small molecule drugs are generally less than 500 Daltons. Because of this, they don’t carry much information and are not very specific in their ability to bind to proteins. A small change can alter the behavior of the drug almost entirely.mAbs are man-designed, biologically made proteins and typically, are 60-70 thousand Daltons. Clearly, they are in orders of magnitude larger than SMDs and, as you’d expect, they behave very differently from SMDs. Because mAbs contain more information than SMDs, they are generally more specific. Though mAbs are much larger than SMDs, only a little bit of information in the mAbs is used to specifically interact with their target and yet, all that chemical information in the protein can interact with many other things and thus cause problems.These are more specific than SMDs and can target a single site on a protein or chemical. RNA-targeted drugs, like antisense oligonucleotides (ASOs) and SiRNAs, use genetic information to target a specific site on an RNA. n-Lorem takes advantage of the specificity and versatility of ASO technology. ASOs are highly specific, and we can continuously learn from successes and failures of the technology to predict how the next one will behave. Discover the in-depth differences between the three platforms, their triumphs and failures in modern drug discovery, their benefits and limitations, and why gene therapy is not on the list of drug discovery platforms… yet.

Clinical Trials for One Patient

In this episode, Stan talks to Dr. Joe Gleeson about the role of genetics in neurology and pediatric patients with neurological conditions. Early in his training, Dr. Gleeson realized how prevalent it was that pediatric patients, especially those with neurological disorders, never received a diagnosis. Furthermore, in over half of these patients he felt that there were underlying genetic mutations causing these disorders. With the advent of genomic sequencing, now many of these mutations are identified, however few have any therapeutic options available. In this episode, the role of a genotype to define a phenotype is outlined and the need to shift our therapeutic approaches to be more action-orientated and addressing the underlying genetic cause not the symptoms. This requires a technology, like antisense, that is able to target a specific gene mutation. When asked why n-Lorem, Dr. Gleeson expresses significant optimism that n-Lorem will be able to address a number of these previously untreatable patients. Just diagnosing patients and treating symptoms is not enough, to make a meaningful impact on these patients, more needs to be done. Through n-Lorem many patients will now have the chance.

How Drugs are Used

Drugs are chemicals. They are like all other chemicals except that humans make a value judgement that a particular chemical (drug) will effect a desired change in a living organism. However, it’s important to note that a drug does what it does and there is no perfectly specific drug. So, drug effects always represent a mosaic of chemical interaction and effects. Each drug has properties that we humans hope will bring benefit to other humans. Those are the desired effects, but every drug produces effects other than the desired effect. Those are called side effects. But the drug doesn’t care – it just does what it does. In fact, often, what is a desired effect in one therapeutic setting, may be a side effect in another.As pharmacologists and physicians interested in treating patients with drugs, we are interested in several properties that all drugs have. These include the mechanisms by which the desired objective is induced, pharmacodynamics, the mechanisms by which the drugs may induce side effects, toxicology, and the mechanisms by which the body distributes and clears a drug from the body, pharmacokinetics. Put simply, we are interested both in what the drug does to the body and what the body does to the drug.Because drugs are chemicals and chemical reactions depend on collisions between two or more chemicals, drug effects are concentration dependent. We adjust the concentration of a drug in the body by adjusting the dose. All effects of drugs, with the possible exception of allergic reactions, are dose dependent. Therefore, we are interested in the doses that produce a desired effect and the doses that may produce undesired effects, or adverse events (side effects). A drug that produces a desired effect at a much lower dose than the dose required to produce an adverse event is usually considered a better drug. When we assess the difference between the dose that produces a desired effect and a dose that produces an adverse event, we are now analyzing a drug performance in a sophisticated way, and we are thinking about the term therapeutic index. This is the key parameter that you should always be thinking about when you use a drug.

A Diagnostic Odyssey: The UDN and n-Lorem’s Roles

Dr. Sessions Cole shares his career being a neonatal pulmonologist and his involvement in the undiagnosed diseases network, the UDN. Dr. Cole estimates that it can take up to 12 years to get a diagnosis for a patient with a rare genetic condition and that there could be as many as 30 million of these patients in the U.S. who are undiagnosed. The UDN is working to elevate the awareness of the diagnostic odyssey these patients undertake and diagnose up to one third of patients who are referred to the UDN. Dr. Sesh is part of n-Lorem’s access to treat committee (ATTC), the committee that evaluates and recommends patients to n-Lorem. Dr. Cole discusses the robust processes involved in the evaluation of each application to n-Lorem and the hope and value that n-Lorem is providing to nano-rare patients today.

Biological Systems & Chemical Networks

We are all chemical engines. So, what exactly is a chemical? Chemicals are anything that occupies space in the universe and exist in either a solid, liquid, or gas form – matter! Chemicals within living organisms are considered biochemicals and are organized into chemical networks (an integrated chemical process that establishes life and the maintenance of homeostasis). Homeostasis is simply a scientific term that means maintenance of the status quo. So, a healthy living organism must respond to its environment and manage different threats. The systems that are designed to ensure that the cell remains healthy are called homeostasis. Drugs are also chemicals. Drugs enter an organism and make their way through biological systems to interact with many chemicals. Sometimes those interactions lead to changes in the chemicals with which the drugs interact, altering one’s physiology or psychology. One must have a keen understanding of basic scientific terminology, these chemical networks, and biological systems to create drugs and use them to make a difference in all patient populations. Ready? Let’s get started.