Finding the Genetic Cause and Therapy for Adhd, Autism and 22q: A Journey Into Precision Medicine That Could Affect Millions Worldwide

Development

PROLOGUE: WHY I WROTE THIS BOOK

I am not a physician and I am not a scientist.  I am a lawyer by trade and a serial entrepreneur by inclination.  I am a doctor because I have a doctorate in philosophy.

I have the very good fortune of having two wonderful friends and neighbors, Hakon Hakonarson and Philip Harper.  As a result of this relationship, I have been able to participate in a great adventure involving finding the genetic cause and treatment regimen for attention deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD) and 22q11.2 deletion syndrome (22q), and potentially other diseases.  I am grateful to these two friends for providing me the opportunity to join them in this exciting venture.

The three of us, and our three wives, became what we called the Neighborhood Drug Company.  This book describes the Neighborhood Drug Company in Chapter Eighteen and what it accomplished.

The book includes other stories that are organized like a collection of short stories, with all the stories being intertwined and interconnected.  It starts with a description of precision medicine, which is the medicine of the future that will provide targeted treatments based on an individual patient’s genetic/genomic profile.  Precision medicine is described in Chapter One and the criticism of precision medicine is near the end of this book in Chapter Twenty-One.

Precision medicine is not just an idea, but it is actually being practiced at The Children’s Hospital of Philadelphia (CHOP), the first pediatric hospital in the United States and one of the premier pediatric hospitals in the world (Chapter Two).  CHOP established a modern genetics and genomics laboratory organized to find the genetic/genomic cause and potential therapy for pediatric diseases called the Center for Applied Genomics (CAG) (Chapter Three and Chapter Nine).

My friend Hakon is the founder and director of CAG and is an eminent physician/scientist (Chapter Eight).  He is one of the leading geneticists in the world.  This book is about one of his most important discoveries—the genetic cause of ADHD, autism and 22q and a potential treatment for these three diseases.

In order to understand how Hakon made this discovery, it is necessary to become familiar with the vocabulary used in the field of genetics, and Chapter Seven is an introduction to this subject matter.  It is very basic, as is the chapter about the procedure for discovery of new drugs (Chapter Ten).

I include a short description of ADHD (Chapter Four) and of autism (Chapter Five).  It is significant that the same genetic malfunction can also be the cause for a virtually unknown serious disease called 22q11.2 disease syndrome.

Chapter Six describes 22q in much greater detail than the discussion of the other two diseases because, even though it is quite common (almost as common as Down syndrome), most of us have never heard of it.  I hope that this book increases the awareness of this terrible disease.

My friend Phil enters the story in Chapter Thirteen because he decided to invest in the company Hakon formed (neuroFix therapeutics inc. described in Chapter Twelve) and this investment enabled the company to conduct a clinical trial.  I briefly describe the clinical-trial process in Chapter Fifteen.

The events leading up to the neuroFix clinical trial (the clinical trial is the subject of Chapter Seventeen) include neuroFix entering into an option agreement with CHOP (Chapter Fourteen) and neuroFix reaching a data-use agreement with a Japanese company that had developed a drug for the treatment of vascular dementia that could be used to treat ADHD, autism and 22q patients (Chapter Sixteen). After the neuroFix clinical trial, neuroFix was sold to an American/Israeli company (Chapters Nineteen and Twenty) that will continue to develop the drug and eventually make it available to patients who need it.   

The heart of the book is the discussion of Hakon’s transformative discovery in Chapter Eleven that ultimately led to the neuroFix clinical trial that I describe in Chapter Seventeen.  The results of this clinical trial create the possibility that millions of people suffering from the three diseases (ADHD, autism and 22q) who have the genetic disorder that Hakon discovered will benefit from the reversal of the effects of the genetic mutation that is the cause of these diseases.

I decided to write this book because I had a ringside seat at the events that are central to this great achievement.  Similar to ADHD being a disease involving multiple genes interacting with other genes and environmental factors, this book involves multiple interconnected stories.  Just as Hakon had many collaborators in making the discovery that is the subject of this book, I had many collaborators who helped me in bringing this book to fruition.  I have included an Acknowledgement in order to recognize and thank those who helped me in writing this book.

I have not included footnotes because I did not want to interrupt the flow of telling the stories.  I have, instead, placed notes at the end of each chapter, which readers may read or disregard.  These notes will have the references and links that will allow the reader to obtain additional information.  There are references in the text to various articles that Hakon wrote.  There is a list of some of Hakon’s articles on ADHD and autism in the Research Notes at the end of the book.

Hakon’s discovery of the genetic cause and potential therapy for these diseases was not a single event, an eureka moment.  It was the culmination of years of research (which research is ongoing).  The reader can follow the gradual development of this discovery by reading Hakon’s articles.  I have presented the discovery in a concise way in an effort to make the description of the discovery more intelligible for the average reader.

Finally, I dedicate this book to my wife Marian who, in more ways than I have time to list, contributes to everything I do, improves my beginnings, makes sure that I arrive at the endings and guides me in all endeavors.  Ours is a great love affair. I will tell the story of our love affair in my next book.

CHAPTER  ONE

PRECISION MEDICINE

1.1 Definition

Prior to the term precision medicine being adopted, the general topic of conversation about the future course of medicine revolved around the expression personalized medicine.  This expression was used to describe the practice of designing medical treatment to match the specific characteristics of a particular patient.  Personalized medicine was considered to be the preferred practice in contrast to the concept of one size fits all in deciding upon treatment for individual patients.  Instead of focusing on the average patient, medical treatment would be more specifically related to identifiable situations affecting specific patients; treatment would be more targeted, a rifle being used rather than a shotgun.

Personalized medicine, however, became disfavored as a term to be used for the description of more advanced, individualized medical procedures.  Physicians complained that they had always taken into consideration the specific situation.  They knew their patients, or they learned their history, and, based upon this intimate knowledge, they recommended a treatment regimen for the specific patient.  Physicians regarded personalized medicine as the prevailing methodology, descriptive of how they had always performed in their medical practice.

The preferred term then became precision medicine.  One definition of precision medicine is that it is a methodology, which promotes the customization of healthcare, with medical  decisions, office practices and recommended pharmaceutical products tailored to the individual patient.  This definition, however, does not highlight genetic data.  The definition preferred by the National Institutes of Health (NIH) is that precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. 

To expand upon the distinction between personalized medicine and precision medicine, the National Research Council explains: Precision medicine refers to the tailoring of medical treatment to the individual characteristics of each patient.  It does not necessarily mean the creation of drugs or medical devices that are unique to a patient, but rather the ability to classify individuals into subpopulations that differ in their susceptibility to a particular disease, in the biology and/or prognosis of those diseases they may develop, or in their response to a specific treatment.  Preventive or therapeutic interventions can then be concentrated on those who will benefit, sparing expense and side effects for those who will not.  This term is now widely used, including in advertisements for commercial products, and it is sometimes misinterpreted as implying that unique treatments can be designed for each individual.  For this reason, the Committee thinks that the term ‘Precision Medicine’ is preferred to ‘Personalized Medicine’ to convey the meaning intended in this report.

One hundred years ago, the country doctor dispensed medical treatment.  He was a general practitioner in a small town or neighborhood, who lived in the community in which he had his office.  He knew his neighbors intimately, their family history, the environment in which they lived, and the kinds of lifestyle decisions they had made.  As urbanization developed, this image of the country doctor became blurred.  House calls became rare.  Medical practice lost the personal touch.

Now, in order to improve medical treatment, the precision medicine approach will allow doctors to predict more accurately the treatment and preventative measures that they would recommend for an individual patient coping with a specific disease.  This is an effort to downplay the approach that looks at large groups of people, the average person and the general trend.  Emphasis in the precision-medicine era will be placed on differences between individuals and on subsets of the population.

Many physicians will maintain that medicine has always recognized differences and one obvious example is that, when I was given a blood transfusion to replace blood that I had lost from a bleeding ulcer, I was not given the next bag in the freezer.  Instead, the bag was selected that was compatible with my blood type in order to reduce the risk of complications resulting from the transfusion.

Precision medicine would take the procedure of medical decision-making a few steps further than my example.  When one adds genetic information into the decision-making process, one acquires the ability to design treatments that are much more reflective of the variations between individuals.  This allows for comparison of the gene pathway shared by most people that has evolved over centuries with the genetics of a small subset of individuals who have a gene deletion or gene duplication.  Recognizing this variability allows the physician to concentrate on genetic causes related to specific diseases in order to devise targeted treatments for those diseases.

When I discuss 22q in Chapter Six, I will attempt to explain how the doctors at CHOP (Children’s Hospital of Philadelphia) discovered not only the relationship between the 22q deletion and a single disease, DiGeorge Syndrome, for example, but also the relationship of the 22q deletion to a plethora of other diseases that appeared initially to be unrelated. 

With the genetic information, the focus can be on a subset of patients who share a commonality that differentiates them from the general population.  To carry this one step further, patients may share a genetic anomaly even though they exhibit a variety of different diseases.

The neuroFix clinical trial (in 2015) that I will describe in Chapter Seventeen is a prime example of the possible benefits that can be derived from the precision medicine approach.  Doctors treating patients who are diagnosed with attention deficit hyperactivity disorder (ADHD) struggle with finding the appropriate treatment.  There are several potential medicines that can be prescribed.  These medicines, however, often have undesirable side effects.  There appears to be no way to determine which medicine will provide acceptable results except by trial and error. 

If one could find the genetic cause for ADHD, then the appropriate drug could be selected for the individual patient based upon his genetic profile.  The undesirable side effects could be avoided.  The doctor might even be able to determine the right dosage for a specific patient based upon his genetic profile.

As I will explain, this neuroFix clinical trial demonstrated that genes belonging to a specific gene network (called the mGluR  family of genes) appear to be significantly different in some ADHD patients from the norm and even from the genetic profile of other ADHD patients.  This variation in genetic activity could have a causal relationship with ADHD in an identifiable group of children. 

There are 279 genes that belong to this gene network.  It is estimated that 79 of the 279 genes are involved in causing ADHD in some patients.  In the neuroFix clinical trial, the ADHD patients who participated were positive for one or more of the 79-targeted genes.  These patients responded favorably to the drug that was being tested to correct the functional aberrations in those genes.

I will discuss in Chapter Twenty the follow-up clinical trials that are being conducted in 2016 that I believe will confirm the findings in the neuroFix clinical trial.  The drug that is the central focus of this book may prove to be beneficial for managing other diseases besides ADHD, such as, for example, autism and 22q.

While I hope and expect to provide a happy ending to this story, I should acknowledge that genetics research has not yet fulfilled the initial expectations.  I will discuss this disappointment in Chapter Twenty-One because it is germane to the criticism of precision medicine.  An example of this failure to satisfy expectations is the research efforts to find a cure for sickle cell disease. 

Sickle cell disease affects the hemoglobin in a person’s red blood cells.  These red blood cells are usually round.  When they are shaped like a crescent, they look like a sickle (hence, the name of the disease).  In the crescent shape, the cells are unable to deliver an adequate amount of oxygen to all of the person’s tissues.

Without sufficient oxygen, the individual with sickle cell disease will not only feel weak, but he may also have more severe symptoms.  These could include severe pain, anemia, infection, kidney failure and strokes.  Sickle cell disease is a rare disease. Approximately 100,000 people in the U.S. have the disease.  It could be fatal, thereby reducing the number of children who inherit the disease.

Sickle cell disease is a single-gene disorder (humans can suffer from approximately 10,000 single-gene disorders).  Consequently, unlike the multiple-gene disorders such as ADHD, one might expect that genetic therapy would be available for sickle cell patients.

The genetic abnormality was discovered in 1956.  To this date, the Federal Drug Administration (FDA) has approved only one drug for treatment of this condition. and this drug is effective for only one-half of the sickle cell patients.  The drug also has serious side effects. 

While there have been many efforts by scientists to discover a cure for this genetic problem, they have been unable to find what triggers the gene to fail to do the work that it does in people who do not have the disease. In this instance, scientists have been unable to close the gap between the discovery of the genetic problem and the development of an effective therapy to manage the situation. 

The bottom line is that it is very difficult to find a compound that will correct, reverse, or modify a genetic failure.  Researchers have been unable to find an effective treatment for sickle cell disease, even though it is a single-gene malady.  Just imagine, then, how difficult it is to close the gap between finding a genetic cause and discovering how to reverse the genetic malfunction for multi-gene, complex diseases.

But, I am getting ahead of myself.  Let me return to precision medicine because one of its goals is to make available the data developed by genetic tests to a wide community of scientists so that they can move the ball forward in developing effective medical solutions to crippling diseases.

1.2 Proposal for the Precision Medicine Initiative

During the 2015 State of the Union address, delivered on January 20, 2015, President Barack Obama announced that he was promoting the Precision Medicine Initiative—a large, new research effort designed to improve healthcare.  The basic idea was to shift the focus from the average patient in order to concentrate, instead, on the differences in people’s genes, environments and lifestyles. 

President Obama observed that precision medicine has already started to be effective in cancer treatment.  Doctors are looking at the genetic profile of individual cancer patients as related to the specific type of tumor the patient has.  By doing so, doctors could tailor the treatment to the patient’s particular characteristics. 

In the Precision Medicine Initiative, the President proposed a $215 million plan for subsidization of research in genomic mapping in order to advance precision medicine.  Of the total proposed budget, $130 million is earmarked for NIH to build a national large-scale research participant group, called a cohort.  The cohort would include over one million or more U.S. participants from various locations, covering all ages, backgrounds, economic conditions and varieties of health histories. 

This major step in the initiative is designed to track the health of a minimum of one million volunteers by 2019 using state-of-the-art techniques going beyond standard medical examinations.  The data, including gene sequencing (Chapter Nine) and other biological information from diverse groups of people, would be compiled to allow researchers to discover patterns by which diseases can be identified. 

Part of the initiative is to collect more data, compile that data and make it available to all researchers.  Genetic data is now much more available. When the genetic data is available, however, it is often not combined with the patient’s electronic medical records.

The missing element in the present general practice, the connection that is lacking, is to marry that genetic data with the medical records of subsets of patients.  What is needed to implement the Precision Medicine Initiative is to leverage advances in genomics, informatics (the science of computer information systems) and medical health information technology to enable precision medicine to improve healthcare.

The members of the cohort who are selected will be required to consent to providing the blood and saliva samples used to generate detailed genetic data as well as the electronic medical records to all researchers.  The ultimate goal will be to use this information to provide the understanding of the origins and characteristics of diseases.

The medical history and genetic data of the one million volunteers to be gathered as part of the Precision Medicine Initiative will be available to all researchers in order to provide a knowledge base for multiple diseases that can be identified by reference to their specific genetic causative features.  The goal is to develop a cutting-edge medical approach that would lead to the recommendation of treatments that are related to individual conditions.

With better data, it should be possible to reduce undesirable side effects, to be more precise in determining dosage for individual patients, to design clinical trials that are more directed toward individual conditions based upon genetic data, to avoid some of the waste in the medical decision-making process and to achieve greater efficiency in finding cures for diseases.

The Children’s Hospital of Philadelphia (CHOP) and the genomics institution it established ten years ago, the Center for Applied Genomics (CAG) have already been implementing the research goals of the Precision Medicine Initiative for the past ten years.  The program at CHOP and CAG is designed to accelerate the process of the discovery of the genetic causes of diseases such as ADHD, autism and 22q and to find therapies to reverse, eliminate or manage the genetic defects that cause these diseases.

NOTES FOR CHAPTER ONE  PRECISION MEDICINE

1.  Definition preferred by NIH (Section 1.1): 

https://ghr.nlm.nih.gov/primer/precisionmedicine/definition.

2.  Definition by National Research Council (Section 1.1): quoted in an article by Luke Timmerman, What’s in a Name?  A Lot, When it Comes to ‘Precision Medicine,’ Exome:

http://www.xconomy.com/national/2013/02/04/whats-in-a-name-a-lot-when-it-comes-to-precision-medicine/2/2.

3. Sickle cell disease (Section 1.1)—for more information, see:

https://www.statnews.com/2016/05/19/sickle-cell-disease-cure. 

In this article, it is pointed out that 100,000 people in the U.S. have this disease.  The mutation was discovered in 1956.  The discovery of the mutation has not led to an effective treatment for over 60 years.

4. State of the Union Address (Section 1.2):

http://www.mediaite.com/online/president-obamas-2015-state-of-the-union-address-full-transcript./.

5. For more information about the Precision Medicine Initiative (Section 1.2)—see the article by Francis S. Collins and Harold Varmus, A new Initiative on Precision Medicine, N Engl J Med, 793-795, February 26, 2015:

http://www.nejm.org/doi/full/10.1056/NEJMp1500523#t=article.

6.  It is too early to determine whether the timetable set forth in the Precision Medicine Initiative for the collection of the samples for the biobank will be met.  If the institutions that are utilized for sample collection, analysis, storage and retrieval have already established facilities for the process, such as CAG (Chapter Three), one can be optimistic about the timely implementation of the PMI.

CHAPTER TWO

CHIDREN’S HOSPITAL OF PHILADELPHIA

(CHOP)

The Children’s Hospital of Philadelphia (CHOP) is a charitable nonprofit hospital that was founded in 1855 as the first hospital in the United States to concentrate on pediatric treatment.  Over the years since then, it has moved several times in the Philadelphia area, and has expanded and grown to become one of the premier pediatric hospitals in the world.

U.S. News & World Report’s survey of U.S. medical schools and pediatric hospitals has listed CHOP in its 2016-17 ranking as the number two facility in the United States.  CHOP is consistently ranked as one of the best pediatric hospitals in the U.S.

CHOP now has 529 beds and provides for more than one million patient visits each year (both outpatient and inpatient) in more than 50 facilities.  During 2015, CHOP had 1.24 million outpatient visits and 29,062 hospital admissions.  CHOP’s revenues in 2015 were $2.5 billion.  It had 11,522 employees. 

Patients come to CHOP from all over the United States and from other countries.  CHOP treats 10 percent of all the rare/orphan disease patients in North America.

CHOP’s website has an impressive list of its firsts:

"First formal medical training for pediatric doctors.

"First pediatric day surgery unit in the U.S.

"First neonatal surgical and pediatric intensive care units in the U.S.

"First clinic in the nation for the treatment of children’s speech defects.

"First closed incubator for newborns.

"First balloon catheter for treatment of heart defects.

"First to discover the cause of infectious mononucleosis.

"First test to diagnose a form of congenital hyperinsulinism [above normal level of insulin in the blood].

First specialized training in pediatric emergency medicine.

CHOP has also become a major pediatric research institution. Its research spending in 2015 was $325 million.  In 2014, it received 506 new grant/contract awards in the amount of $116,284,187.

In CHOP’s Research Institute’s Annual Report for 2014, it lists 13 research centers and programs and 81 different research projects.  These research projects generated 93 Invention Disclosures received, 23 U.S. Patent Applications filed, (Utility and Nationalized PCT), 27 U.S. Patent Applications filed (Provisional), 9 U.S. Patents issued and 50 International Patents received. 

One of the research projects mentioned in this 2014 report is the discovery of a risk susceptibility gene associated with severe asthma.  The discovery of this gene may lead to more effective targeted treatments for this disease.  The concept of targeted treatments is primarily based upon increased emphasis on genetics at CHOP, which is consistent with the Precision Medicine Initiative.

This discovery was the result of efforts by many scientists in five different countries.  One of the co-lead authors of the asthma study was Hakon Hakonarson MD, PhD, who is the director of CHOP’s Center for Applied Genomics (CAG) (I will profile him in Chapter Eight).  Both CAG and Dr. Hakonarson figure prominently in the discussion about finding the genetic cause for ADHD, autism and 22q (Chapter Eleven)

In an article in the Philadelphia Inquirer on February 28, 2016 in which the President and CEO of CHOP, Madeline Bell, was interviewed, she was asked: "What do you think is the most exciting medical development since you have been at CHOP?" Ms. Bell responded: What we’re doing in the area of gene therapy.  Some day we will find the cure for our children’s disease by finding the defective gene and being able to replace it with a good gene.  It’s really exciting to think that we will be preventing childhood disease versus just treating them.

The heart of the gene discovery and therapy research being conducted at CHOP is in the Center for Applied Genomics. (CAG). CAG has the largest data bank of pediatric genetic data in the world.  CHOP and CAG, almost ten years before the Precision Medicine Initiative (PMI) was announced, implemented procedures designed to accomplish the goals of the PMI.  Their success represents a prime example of what the PMI may accomplish.

NOTES FOR CHAPTER TWO CHILDREN’S HOSPITAL OF PHILADELPHIA (CHOP)

7.  CHOP’s web page:

http://www.chop.edu/about-us/about

8.  CHOP’s 2014 Research Institute Annual Report:

http://annualreport2014.research.chop.edu/.

9.  CHOP has also discovered a new disease called CHOP’S Syndrome:

http://annualreport2015.research.chop.edu/facts-and-figures.

10.  For more information about CHOP, see The CHOP You Tube Channel:

https://www.youtube.com/user/ChildrensHospPhila.

11.  For more information about research at CHOP, see The CHOP Research Institute Website:

http://www.research.chop.edu/.

12.  For CHOP’s ranking as a pediatric hospital, see: 

http://www.chop.edu/about-us/us-news-world-report#.V8Cj5iMrJFw

13. Philadelphia Inquirer article:

http://articles.philly.com/2016-02-28/business/71035079_1_gene-therapy-front-lines-chief-operating-officer.