Orphan quest

The Quest to Save Children with Rare Genetic Disorders

In Clinical Development by Freya Smale

The Quest to Save Children with Rare Genetic Disorders- By Phillip R. Reilly

Because of a roll of the genetic dice, children can be born with any one of more than several thousand rare genetic disorders.
I have spent much of my life in medicine trying to help people who are afflicted with some of these disorders. Often physicians have no therapies to offer. Care is custodial, and the main goal is to relieve suffering. Although each genetic disorder is rare – often so rare as to be invisible – collectively these disorders touch hundreds of thousands of people…and of course their families.

Orphan questOver the last three decades I have come to know many families burdened with such disorders. Over and over again, I have met mothers and fathers who I am certain are among the great, unsung heroes of our world. Each day they wake to face challenges that most of us cannot even imagine.

I think, for example, of the parents of daughters with Rett Syndrome. Apparently healthy for the first year or so of life, by the age of six or seven many of these girls have lost all speech, cannot walk, have seizures (sometimes on a daily basis), and have abnormal breathing patterns that force some parents into a state of unrelenting fear that the child might die of respiratory arrest. When a child develops Rett syndrome, the family is changed profoundly and forever. So severe is the disorder and so needy is the child that parents often alter the very structure of their homes to provide daily care.

Children born with severe dystrophic epidermolysis bullosa (DEB) do not have the proper form of a protein that holds the outer layer of the skin to its inner layer. The slightest trauma causes the skin to slough off. Sometimes, strangers mistakenly think that these children have been scalded with hot water. Parents often spend two hours each day bandaging the children in a desperate effort to control chronic skin lesions.

During childhood, despite the best medical care, some of these children lose the use of their hands and feet as chronic injuries cause the digits to fuse. The move severely affected live with unremitting pain. Then, sometime in mid-life, most succumb to an unusually aggressive, fatal, cancer of the skin.

Here is one more example. Until recently, children born with the one of the many severe “lysosomal storage disorders” (diseases in which different genetic errors prevent cells from clearing certain metabolites, causing a buildup of toxic material that impairs many organ systems) were doomed to a slow and painful death. Best known among these may be Tay-Sachs disease, a disorder that manifests at about age two, stopping a healthy child in his or her tracks, and leading inexorably to blindness, neurological decline, and death by age four or five. There are about 50 rare genetic disorders like Tay-Sachs-disease. Fortunately there are now some therapies for some of them (but, alas, not yet for children with Tay-Sachs disease).

For more than a century, small groups of physicians and scientists have taken on some of these genetic diseases. In many cases just a few physician-scientists – who I also regard as heroes – have made an immense contribution to blazing a path towards new therapies.
After doing graduate work in human genetics, then qualifying in medicine, I began my real training in clinical genetics in1985 when I joined the Eunice Kennedy Shriver Center for Mental Retardation as a member (and later, director) of the primary care group that cared for about 800 adults with severe neurological disorders who resided at the Walter E. Fernald School, a large state-run institution near Boston.
The physicians at Fernald knew the cause of the disability in only about one quarter of the population for which we cared. But, even then, we suspected that many our patients were burdened with as yet undiagnosed genetic disorders that had harmed brain development. During the course of my time there (1985-2000), new procedures (such as improved cytogenetic testing, DNA testing and MRI scanning) enabled us to diagnose an increasing, but still relatively small, number of patients. For example, we found that several adults had Fragile X syndrome and that several others had severe autism due to deletions or duplications in one of their chromosomes. But, diagnostic success never led to therapeutic benefit.

In medicine, rare genetic diseases are often called “orphan disorders”, largely because (until recently) the progress in biomedical research since World War II had largely bypassed them. When hundreds of thousands of people are dying each year from heart disease and cancer, it is hard to convince NIH or the pharmaceutical industry to allocate millions of dollars to better understand and develop new drugs for diseases that afflict only a few thousand (or even fewer) people. The term, “orphan disease” became firmly set in our lexicon in the mid-1980s after the federal government enacted legislation that offered special tax benefits and market exclusivity to companies that developed drugs for rare disorders. In the United States, to gain the benefits of that law, the drug under development must afflict less than 200,000 persons in the nation. This includes many cancers and almost all single gene disorders.

In 2008, I had the good fortune to start work at the venture capital firm Third Rock Ventures. TRV has so far created, built and launched about 35 innovative biotech companies. One of its areas of focus is in starting companies to develop therapies for rare genetic disorders.

My current work is a determined response to a world in which there is still little to offer children and adults affected with most of these terrible disorders. I often have the privilege of interacting with parents of affected children at many foundations that are dedicated to taking on the immense challenge of developing new therapies. Today, such groups are quintessential partners in the struggle to develop new therapies for rare genetic disorders.

Among other benefits, the study of rare genetic disorders reminds one that – despite the immense discord among peoples on this planet –we are united by our shared membership in the human gene pool. When I think about those who suffer and die from rare genetic disorders, I recall the great English poet, John Dunne who wrote, “No man is an island, entire of itself. Every man is a piece of the continent, 
a part of the main. If a clod be washed away by the sea, Europe is the less, as well as if a promontory were, as well as if a manor of thy friend’s
 or of thine own were. Any man’s death diminishes me, because I am involved in mankind. And therefore never send to know for whom the bell tolls; 
It tolls for thee”.
Phillip R. Reilly MD is the author of Orphan: The Quest to Save Children with Rare Genetic Disorders, to be published by Cold Spring Harbor Laboratory Press in August 2015. More about the book can be found at http://cshlpress.com/link/orphan.htm. This post is adapted from the Preface.

The book includes descriptions of the work of a number of prominent scientists who were pioneers in discovering various treatment methods, as well as the efforts of Henri Termeer, a businessman who oversaw the commercialization of enzyme replacement therapy drugs and became a major figure in the biotech industry as CEO of Genzyme who is joining Total Orphan Drugs via video at World Orphan Drug Congress USA 2015. To see his presentation, book today!