David R. Cox Prize for Rare Compassion Essay Contest Entry

Dreams of Light

By Calvin Tseng (MD Candidate for Class of 2018 at the University of Alberta)

With support from Global Genes, Student Advocates for Neglected Diseases (STAND) presents the David R. Cox Prize for Rare Compassion, in recognition of the inspiring essays of student doctors who, like Dr. Cox, have most identified with and understood a rare or neglected patient community they have become close to. The winners of this program will be announced at the upcoming 4th annual RARE Patient Advocacy Summit on September 25, 2015. Good luck Calvin!

The hum in the operating room dimmed as the surgery reached a critical point. A computer screen across the room displayed the back of the patient’s eye – and a thin catheter that slowly glided towards it. I craned my neck to get a better view. As the catheter moved closer, I held my breath for this historic moment. The catheter contained 100 million virus particles, each carrying a functional replacement for the patient’s defective choroideremia gene. Although I was only a tiny part of the endeavour, I felt elated to assist in something so momentous – we were trying to find a new cure.

This summer, I had the chance to assist a clinical trial of gene therapy for choroideremia at the University of Alberta. During this experience, I met 6 individuals who would be the first Canadians to test this new therapy. Each had choroideremia, but over the next 3 months, I would learn about them as individuals.

Choroideremia is a rare disease that affects 1 in 50,000 individuals. Since it is inherited in an X-linked fashion, men are most likely to be affected. Choroideremia is caused by a defect in the choroideremia gene, leading to the loss of a protein called REP1. The photoreceptors – the cells responsible for vision – die due to the loss of REP1. This leads to the symptoms of choroideremia: From night blindness during adolescence to diminished peripheral vision later in life, leaving individuals with a tiny cone of central vision. Eventually, legal blindness occurs around the age of 40.

Gene therapy aims to cure choroideremia by delivering a new copy of the defective choroideremia gene. Modified virus particles that contain a healthy copy of the choroideremia gene are injected into the eye, where the virus inserts the healthy copy of the gene to substitute for the defective one. The photoreceptors can then produce REP1, which prevents them from dying. It is hoped that this treatment will preserve the patient’s sight from further deterioration.

Day-to-day in a Clinical Trial

My role was to administer vision tests before and after surgery to see if the treatment was successful. During my job, I learned many lessons on interacting with visually-impaired individuals. Among the most important lessons was to not assume a patient was completely blind. Most of the participants I met were still able to navigate on their own. Thus, it is important to ask before helping, as participants still want to preserve their independence. In addition, participants don’t want to be defined by their disease. Instead of talking about choroideremia, we chatted about the positive aspect of their lives. Their answers revealed their rich experiences – they were still able to raise families, tour countries, and even run marathons. Although these pointers seem simple, they were easy to forget in practice.

I quickly learned that the trial wasn’t an easy task for the participants either. Follow-up appointments are extremely frequent after surgery. Many of the tests involve monotonous tasks that strain even perfectly healthy eyes. Some involve painfully bright lights. Others require stinging eye drops that blur vision for hours. Our experimental data literally comes from six individuals’ blood, sweat, and tears – as we take samples of these for analysis.

Our participants took this difficult regime with flexibility and humour. One of the tests we required was called “microperimetry”, where participants clicked a joystick each time a small, faint light appeared. This test frustrates even people without visual impairment, such as me. However, one participant made light of the test by calling it “the world’s most boring videogame”. “If only there were explosion noises when you correctly clicked for a dot,” he joked, “then things would be more interesting.”

The participant’s families also had a burden to bear, as they took time from their lives to be present during the trial. One family even had to make a 6-hour round trip for each appointment. But they also stayed positive. For example, when one of the participants had to come in for tests on his birthday, his family brought a huge batch of cupcakes. Fittingly, the cupcakes had been decorated to look like eyes. Some of the “eyes” were normal, like an untreated eye. Others were bloodshot, like an eye that had undergone surgery. The whole staff sang “Happy Birthday”, and then shared the cupcakes.

Throughout this experience, I was astounded by each participant’s good humour in face of a rigorous schedule and uncomfortable tests. Gradually, I learned about what motivated each one to persevere. One wanted to keep playing catch with his kids. One hoped there would be a cure for his siblings. One participant thought about the generations to follow: “I just hope other kids won’t have to grow up with choroideremia.” These individuals were here because even after learning of choroideremia’s outcome, they kept dreaming of a brighter future.

Daily Life with Choroideremia

Even though their lives were already being turned upside down by the trial, the participants were kindly willing to take extra time to tell me about their daily lives with choroideremia. Here is the story of one such patient, “John”.

In terms of John’s daily life, choroideremia’s largest effect has been on driving. He misses driving not only for the ability to travel, but also for the relaxation it offers. “I love being alone in my truck, listening to my music,” he says. But now, he feels he has much less time to himself. Furthermore, John feels being able to drive was a large part of his ability to support his family. Now, he feels “less like a man – less helpful and less useful.”

Sports are another chunk of John’s life choroideremia has taken. He can no longer play hockey, baseball, or basketball, as the lack of peripheral vision makes tracking the ball impossible. Thinking a larger ball would make things easier, he tried indoor soccer last winter, but he even lost sight of the ball while dribbling it. Not wanting to let his teammates down, he no longer plays team sports.

As John reflects back further, he recalls even more ways in which choroideremia has affected his life. In terms of careers, John once considered becoming a police officer or a firefighter, but his vision ruled out these options. Currently, he finds his career as safety inspector ironic, given it’s dangerous for him to walk around.

Despite his struggles, he has found ways to move forward. When it comes to outings, his friends and family accompany him to be sure that doesn’t get lost or bump into anything. Unable to play sports that rely on vision, he recently picked up competitive arm-wrestling. But he misses playing with his family and kids tremendously: His biggest hope for the trial is to be able to play sports with his kids. “Who knows how many more years I can play catch with them?” he wonders.

Ultimately, it is for his family that he took the risk of the trial. “I will risk … the trial if there is a chance I can play catch with my boys for years to come. Or  walk my daughter down the aisle without a [guide] dog … Or  dance with her at her wedding without tripping all over. Being the man of the family I want to be able to take care of my family and I don’t want them to have to take care of me.”

John’s story opened my eyes to the full consequences of choroideremia. Over the course of the trial, I had measured choroideremia’s effects in objective, scientific ways – but listening to John told me more than any of those tests ever could. What I learned was that visual impairment does more than compromise independence. It also changes an individual’s self-worth. While the inability to drive and exercise had great effects on John’s life, what he feared the most was being unable to support his family. We can measure John’s vision all we want, but the best indicator of success will be when he feels like a father again.

The Myth of “Incurability”

When I think of the dreams John still holds onto, I am ashamed to think of how many times I had accepted a disease as “incurable” simply because that was what I was told in medical school. I had learned little about rare diseases beyond how to identify them, as the majority of our time was dedicated to common diseases. But from this experience, it is clear that the diagnosis of a rare disease is but the beginning for these individuals.

After being diagnosed, these individuals often begin a journey from clinical trial to another, seeking to be accepted as a candidate. When no trials are available, patients and their families sometimes take things into their own hands, spearheading fundraising to research a cure. All the while, these individuals must also cope with the disease’s effects on their careers, hobbies, and finances. Evidently, the diagnosis is but the beginning of a longer struggle.

As future physicians, our role needs to go beyond merely identifying the disease. As I learned from John, the essential step is to learn about our patients as humans, not case studies. When we know what goals patients want to accomplish in spite of their disease, we can begin making a plan. For John, our plan would revolve on how he can still be a valuable part of his family. For another patient, the plan would differ depending on their goals. When we connect with our patients in this manner, we realize that though two people may have the same disease, their goals – and thus their treatment – can still be different.

In addition, finding clinical trials and assessing participation risk can be difficult for patients. Thus, basic training on navigating clinical trial databases could greatly increase our ability to help patients, and would be applicable to many rare diseases. Unfortunately, such training is often lacking during medical school. To help to patients with rare disease, the medical school curriculum must be reconsidered.

The Path to Hope – “Lucas’s Story”

Having said that, not all individuals with rare diseases start off interested in clinical trials. As I learned more about the participants, I realized that many had given up hope at some point in their lives. This is the story of “Lucas”, another participant in the trial.

Lucas first realized something was off during high school, when his friend vanished ahead of him in a dark movie theatre. Until then, he just thought he had poor night vision. When he mentioned his night blindness to his doctor, this started a chain of inconclusive referrals. Gradually, it became clear that whatever he had, it wasn’t common. When a retina specialist diagnosed choroideremia, it was a relief to finally know what he had. But then he heard there was no cure. Disappointed because there was no treatment, Lucas declined the chance to participate in clinical trials or to connect with specialists.

Later on, Lucas noticed his peripheral vision worsening. It was harder to locate people in crowds or to find things he dropped. Because the progression of choroideremia varies from person-to-person, Lucas started worrying about whether he would be able to care for himself. Even more worrying was whether he would pass choroideremia to his kids, because Lucas had begun planning to start a family. It was then that he had a change of heart – a chance for a cure was worth a shot after all. It was due to this fateful decision that he took part in the current trial.

Currently, Lucas has undergone surgery and started his follow-up appointments. He has an optimistic outlook: “Since none of us can predict the future, I think we make the best of each day and I think we approach the future with an attitude along the lines of ‘we’ll deal with things as they arise.’” With regards to children, Lucas hopes he won’t pass on the choroideremia gene, but believes his kids would receive greater help due to advances in choroideremia research. As we see with Lucas, some patients initially reluctant to participate in a trial, but we should leave the invitation open. Many end up changing their mind.

Why Research Rare Diseases?

As I write this essay, my time with the clinical trial is ending. Having come to know the 6 participants, I truly hope that this treatment can preserve their vision – and that of individuals with choroideremia around the world. But for that to happen, the treatment will have to receive drug approval, an arduous process that will likely take years. In an age where healthcare finances are increasingly strained, one must ponder the question: Why spend vital resources researching rare diseases when cures for common ones are also lacking?

My personal conviction is that John and Lucas are no less deserving of a cure than patients with common diseases. However, another argument is that research on rare disease can benefit not only that specific population, but also lead to cures for other diseases. The current gene therapy technique for choroideremia was inspired by the success of another gene therapy trial, that for Leber Congenital Amaurosis (LCA2). In the LCA2 trial, sight was restored to children who were about to become legally blind, proving gene therapy worked. It is my hope that this trial will be equally successful.

But this treatment is not the only one inspired by LCA2’s success. Similar approaches are being tried for other rare diseases, such as Leber Hereditary Optic Neuropathy, X-linked Retinoschisis, and Hemophilia B. And the benefits have not stopped with rare diseases. There is also a gene therapy trial for Age-Related Macular Degeneration, a disease that is among the leading causes of visual impairment. Clearly, the findings from rare diseases research can have many benefits.

Takeaways

During my time with the clinical trial team, I learned lessons that will stay with me for the rest of my career. I learned that only by knowing the patient as a person can you truly grasp the effects of disease. I learned to look beyond the superficial effects of disease and to ask about the patient’s life goals. I learned that I must learn beyond the medical school curriculum to help patients in a holistic manner. Finally, I learned that rare diseases can be difficult for patients to accept, but we cannot give up on them.

But most importantly, I will never forget what I learned in that operating room. As I watched the virus particles flow into the eye, I realized with certainty that rare diseases are curable. I will no longer thoughtlessly accept rare diseases as hopeless, but always imagine a future with a cure. For if we can’t imagine a future where a cure is reality, then we will fail to help not only the patients of today, but also the patients of tomorrow. So let us keep dreaming of a brighter future – a dream that is filled with light.