By William R. Wilcox, M.D., Ph.D.
General Principles
Treating genetic diseases is neither new nor unfamiliar: physicians treat common diseases with a heritable genetic component every day – including diabetes, hypertension, atherosclerosis, some forms of cancer, etc.
Specialists in medical genetics focus on the diagnosis and treatment of disorders that are predominantly due to the effects of a single dysfunctional gene (i.e. Mendelian with autosomal dominant, autosomal recessive or X-linked inheritance), mitochondrial DNA mutations (maternal inheritance) or are chromosomal in nature (such as Down syndrome).
The goals of treatment are to prevent morbidity and mortality and ensure better developmental outcomes through disease-specific therapies, symptomatic treatment and anticipatory guidance and surveillance. Our success in achieving these goals varies greatly depending on the given disorder.
In general, treatment outcomes are better the earlier a diagnosis can be made and require coordinated, multidisciplinary care and compliance with recommendations by the patient and family. Unfortunately, except for some disorders detected by newborn screening, a correct diagnosis is often delayed for many years or made post-mortem.
Current treatment for genetic disorders is usually lifelong. With few exceptions, treatments are not curative but only modify the course of the disease. For disorders with a pediatric onset, the lack of medical coverage for many adults often leads to a cessation of proper treatments, with disastrous and expensive consequences.
The number of specific therapies for genetic disorders is increasing, but there is a substantial lag between advances in the laboratory, clinical trials and approval by the FDA. In part, this is due to the relative rarity of the disorders, the lack of good natural history data, a paucity of surrogate markers for the efficacy of treatment, the expense of clinical trials for rare disorders and a regulatory structure that, in spite of the orphan drug pathway, is really designed for common diseases.
Fortunately, pharmaceutical companies are showing more interest in orphan diseases, and the regulatory framework is evolving due to the advocacy of patient organizations. A major problem in the future will be affordability of these treatments for any health system. In the absence of any pricing regulation, most treatments are extremely costly.
For best outcomes and quality of life, the healthcare team cannot forget the importance of symptomatic therapies (e.g. occupational, physical and speech therapies, pain control, gastrostomy tubes for feeding, etc.), anticipatory guidance and surveillance for complications of the disorder (e.g. hypothyroidism, strabismus and hearing loss in Down syndrome; hepatic tumors in tyrosinemia), and treatment of diseases unrelated to the primary genetic diagnosis (e.g. obesity and hypertension in a dwarf).
The specific ways we treat genetic disorders include decreasing the amount of toxins; increasing the amount of functional protein; providing what is lacking; and modifying the disease pathogenesis. Gene therapy can theoretically result in a permanent cure, but that has been difficult to successfully accomplish. While there have been some promising clinical trials and a few regulatory approvals in other countries, no gene therapy is currently approved by the FDA.
Specific Treatments
1. Decrease the amount of toxins: Many disorders of intermediary metabolism cause an increase in toxic metabolites that can increase further during intercurrent illnesses with concomitant catabolism. A variety of strategies exist for decreasing the amount of toxins.
a. Limit intake of the toxin or its precursors: Phenylketonuria (PKU) is a classic example wherein a deficiency of phenylalanine hydroxylase leads to increased phenylalanine in the brain disrupting normal function at all ages and brain development in young children. Restriction of dietary phenylalanine can successfully reduce phenylalanine to levels that are not harmful. Supplementation with special formula and other medical foods containing the other amino acids and calories are essential for treatment to be successful.
Pregnancies in women with PKU present a particular challenge because phenylalanine is teratogenic to the developing fetus. Failure to adequately treat women during pregnancy leads to microcephalic, intellectually disabled children. However, when properly treated, PKU patients and their children can be normal. In that sense, PKU has been a great success story for newborn screening, but adherence to diet can be difficult, especially for older patients.
A preventable source of difficulty for patients is that of access to treatment. In many states, there are laws mandating insurance coverage for medical foods and insurance coverage for adults with PKU, but not in Georgia in spite of advocacy by genetics and the families. Consequently, many cannot afford the formula with tragic and permanent consequences for themselves and their offspring.
b. Use alternate pathways to eliminate the toxic metabolites: Ornithine transcarbamylase (OTC) deficiency is a disorder of the urea cycle leading to elevations in ammonia. In addition to limiting protein in the diet, the amount of toxic ammonia the patient has to contend with can be decreased by giving phenylbutyrate, which is conjugated with the amino acid glutamine in the liver and excreted in the urine, eliminating the two ammonia molecules contained within glutamine.
c. Block production of toxic metabolites: Deficiency of the last step of tyrosine degradation, fumarylacetoacetate hydrolase, causes hepatorenal tyrosinemia. Much of the pathogenesis of the disease is to the formation of a toxin formed by alternate pathways, succinylacetone. Inhibition of a proximal step in the pathway with nitisisone markedly decreases the production of succinylacetone thus decreasing hepatocellular damage and malignant transformation, neurologic crises and renal tubular dysfunction.
2. Increase functional protein: Increasing the amount of functioning protein to a sufficient level to ameliorate or prevent disease progression can be accomplished by the use of chemical chaperones, which help mutant protein fold correctly. We have done this for many years with increased doses of vitamin cofactors. Tetrahydrobiopterin administration, for example, can increase phenylalanine hydroxylase activity in some patients with PKU, increasing the amount of phenylalanine they can tolerate. Non-vitamin chaperones are currently in clinical trials for other disorders.
Another way of increasing the amount of functional protein is enzyme replacement therapy. Gaucher disease type I, due to a deficiency of the lysosomal enzyme glucocerebrosidase, causes accumulation of glucocerebroside in macrophages with resultant hepatosplenomegaly, hypersplenism, and bone disease. Gaucher can be effectively treated with biweekly infusions of recombinant enzyme. Enzyme replacement therapy is currently approved for several other diseases.
Transplantation is used for a few disorders, albeit with the mortality and morbidity associated with transplantation for any condition. For example, males with OTC deficiency who survive the neonatal period without severe brain injury can receive a liver transplant, which provides functioning OTC enzyme thereby preventing future hyperammonemic crises. Hematopoietic stem cell transplantation is used not just for hematologic genetic disorders but also as a means for delivery of enzyme into the brain. In severe mucopolysaccharidosis type I, transplantation before 2 years of age can allow transplanted cells to migrate to the CNS, becoming microglial cells that can release enough enzyme to correct the storage found in other cells, preserving cognitive abilities. New means of delivery of enzyme to the CNS may eliminate the need for transplantation in the future.
3. Provide what is missing: The pathogenesis of some disorders is due to the lack of production or recycling of something essential. Biotinidase deficiency, for example, is due to a defective ability to recycle the essential vitamin biotin, leading to progressive deficiency after birth and damage to the CNS. We now detect this condition by newborn screening. Supplementation with biotin completely prevents the manifestations of the disease and is as close to a cure as we have in genetics.
4. Modify the disease pathogenesis: The pathogenesis of genetic disorders is complex and generally imperfectly understood. Marfan syndrome’s most serious manifestation is aortic aneursyms leading to fatal dissection and rupture. For many years, beta-blockers were used to decrease the stress on the aorta, slowing down the rate of progression, but a more effective medication is used now. Marfan is caused by mutations in the gene for fibrillin, leading to decreased fibrillin microfibrils in the extracellular matrix. The damaging effect on the aorta is not predominantly due to some mechanical property of microfibrils, however. Instead, one of fibrillin’s functions is to sequester transforming growth factor beta (TGFβ). Excess action of TGFβ leads to damage to the aorta. Losartan, an angiotensin receptor blocker, is also able to inhibit the intracellular actions of TGFβ, more effectively slowing the progression of the disease.
The Future
This is a hopeful time for patients with genetic disease and their families. An astonishing array of treatments for genetic disorders is currently being developed in the laboratory and tested in the clinic.
The genetic clinical trials unit in the Department of Human Genetics at Emory University is one of the most capable in the world. We are currently conducting clinical trials for Down syndrome, Fragile X, PKU, mucopolysaccharidoses types I and II, and Fabry disease; we will soon begin enrolling patients in trials of treatments for osteogenesis imperfecta, achondroplasia, and Niemann-Pick Disease type B and pre-FDA approval expanded-access studies for hypophosphatasia and cholesterol ester storage disease. In addition to these clinical trials, we participate in many disease registries that yield new insights into specific genetic diseases.
The trials are directed by the physicians Joseph Cubells, Michael Gambello, Hong Li, Suma Shankar, Amy Talboy, Jaime Vengoechea-Barrios, and the author along with a team of experienced coordinators led by Dawn Laney, metabolic dieticians directed by Rani Singh and adult and pediatric psychologists Nadia Ali, Debra Hamilton and Sarah McMurty.
