Genetic Manipulation for Individuals with Disabilities: Does CRISPR-Cas9 Provide a Magic Bullet?

AMERICAN ACADEMY OF DEVELOPMENTAL MEDICINE & DENTISTRY

BY H. BARRY WALDMAN DDS, MPH, PHD, STEVEN P. PERLMAN DDS, MSCD, DHL (HON), RICK RADER, MD, FAAIDD, DHL (HON) AND MATTHEW COOKE, DDS, MD, MPH

“In 1972, WABC-TV in New York sent rookie reporter Geraldo Rivera to Staten Island to infiltrate the Willowbrook State School. Robert Kennedy had visited the mental institution in 1966 and declared: ‘Willowbrook State School was not fit even for animals to live in.’ Geraldo gained entry using a stolen key and documented the brutal horrific living conditions of its disabled residents, which included several children with mental limitations. The report led to an immediate government inquiry.” 1

More than 45 years have passed since the investigative reporter Geraldo Rivera’s documentary on Willowbrook State School in New York City revealed the gruesome and neglected conditions in which individuals with intellectual and physical disabilities lived under the protection of the state.

In the 1840s, activist Dorothea Dix lobbied for better living conditions for individuals with varied mental conditions after witnessing the dangerous and unhealthy conditions in which individuals with intellectual and physical disabilities were housed in jails. Over a 40-year period, Dix successfully persuaded the U.S. government to fund the building of 32 state hospitals for the care of these patients.

By the mid-1950s, a movement for deinstitutionalization and outpatient treatment for people with disabilities began in many countries, facilitated by the development of a variety of antipsychotic drugs. Deinstitutionalization efforts reflected a largely international movement to reform the “asylumbased” mental health care system and move toward community delivery care. This movement was based on the belief that these patients would have a higher quality of life if assimilated and treated in their communities rather than in large, undifferentiated, and isolated mental hospitals.

SOME PAST DEVELOPMENTS

1. In 1907, Indiana was the first of more than 30 states to enact a compulsory sterilization law, allowing the state to “prevent procreation of confirmed criminals, idiots, imbeciles and rapists.” By 1940, 18,552 people with mental illness were surgically sterilized.

2. In 1936, Dr. Walter Freeman and his colleague James Watt performed the first prefrontal lobotomy. By the late 1950s, an estimated 50,000 lobotomies were performed in the United States.

3. In 1954, Smith-Kline and French marketed Thorazine, chlorpromazine, the first antipsychotic drug approved by the Food and Drug Administration. It quickly becomes a staple in asylums.

4. In 1955, the number of people with mental illness in public psychiatric hospitals peaked at 560,000; reduced to 43,000 in 2010. 2

5. Between 1977 and 2011, the total number of people with intellectual and developmental disabilities receiving residential services grew from almost 247,800 to 460,600 (an increase of 85.9%). There were important differences in the pattern of change, depending on the size of the institution and whether the setting was state or non-state operated. The number of people living in settings of 16 people or more declined from almost 207,400 in 1977 to 55,100 in 2011.3

IS THIS THE FUTURE
“Eager to speed developments of revolutionary treatments, the Food and Drug Administration recently announced that it would expedite approval of experimental gene therapies… The genes intended to fix a defect in the body are carried into each cell by a modified virus, usually a disabled version of an adenovirus or a lentivirus… If a company wanted to deliver a gene therapy to lung or liver, where the organ ‘surface area is huge’ the current price could be as much as $3 million per patient… it might cost a mere $30,000 for the viruses in the future.” 4

WHAT IS CRISPR-CAS9?
It is a unique technology that enables geneticists and researchers to edit part of the genome by removing, adding or altering sections of the DNA sequence. It is faster, cheaper and more accurate than previous techniques of editing DNA and has a wide range of potential applications.

The CRISPR-Cas9 system consists of two key molecules that introduce a mutation into the DNA. These are: 1) an enzyme called Cas9. This acts as a pair of molecular scissors that can cut the two strands of DNA at a specific location in the genome so that bits of DNA can then be added or removed; and 2) a piece of RNA which guides the Cas9 to the right part of the genome. This makes sure that the Cas9 enzyme cuts at the right point in the genome. At this stage, the cell recognizes that the DNA is  damaged and tries to repair it. 5

APPLICATIONS AND IMPLICATIONS
CRISPR-Cas9 has unlimited potential as a tool for treating a range of medical conditions that have a genetic component, including cancer, hepatitis B or even high cholesterol. Many of the proposed applications involve editing the genomes of somatic (non-reproductive) cells, but there has been interest in and debate about the potential to edit reproductive cells. However, any changes made in these cells will be passed on from generation to generation and, as such, have important ethical implications. Note: “Carrying out gene editing in germ line cells (e.g. a sperm or egg cells) is currently illegal in the UK and most other countries.” 5 By contrast, the use of CRISPR-Cas9 and other gene editing technologies in somatic cells is uncontroversial. “Indeed they have already been used to treat human disease on a small number of exceptional and/or life threatening cases.” 5

CRISPR-CAS9 AND DISABILITIES
In the future, can CRISPR-Cas9 be a factor in reducing the great number of individuals with disabilities associated with generic aberrations? We already carry out procedures on prenatals in the uterus to correct abnormalities. But once again, CRISPRCas9 procedures on reproductive cells during early stages of pregnancy could be passed on to subsequent generations with unanticipated consequences.

On the other hand, given the technology to improve the life of a child and then as an adult, should such an ability be denied? But, one could image the act of some government office stepping in to deny (or even demand) such an action (in an effort to reduce long term healthcare costs). (Note: Images of Big Brother from George Orwell’s 1984 science fiction novel springs to mind. The reality is that the title of the book is the result of a change instituted by the publisher in an effort to better market the story by setting the events in the future when Big Brother could happen. The initial draft title of the book written in the 1940s was to be 1948. The events had already happened. Who would have believed that?)

The ability to modify genetic factors associated with the disabilities may not totally eliminate the full extent of the encumbrances faced by many individuals. It could, however, help to improve the life of the child and then adult, as well as reducing the lifelong economic burden for the individuals, their families, and even our communities. It might even increase the willingness of health practitioners to provide care for individuals with disabilities.•


ABOUT THE AUTHORS:
H. Barry Waldman, DDS, MPH, PhD – Distinguished Teaching Professor, Department of General Dentistry at Stony Brook University, NY; E-mail: h.waldman@stonybrook.edu
Steven P. Perlman, DDS, MScD, DHL (Hon) is Global Clinical Director, Special Olympics, Special Smiles and Clinical Professor of Pediatric Dentistry, The Boston University Goldman School of Dental Medicine.
Rick Rader, MD, FAAIDD, DHL (hon) is Director of the Morton J. Kent Habilitation Center Orange Grove, Chattanooga, TN and Editor in Chief of Exceptional Parent magazine.
Mathew Cooke, DDS, MD, MPH is Associate Professor, Department of Anesthesiology & Pediatric Dentistry, University of Pittsburgh School of Dental Medicine, Pittsburgh PA.


References
1. NNDB Geraldo Rivera. Available from:
http://www.nndb.com/people/308/000022242 Accessed November 30, 2017.
2. Mother Jones. TIMELINE: Deinstitutionalization and its consequences Available from: http://www.motherjones.com/politics/2013/04/timeline-mental-health-america Accessed November 30, 2017.
3. Larson S, Salmi P, Smith D, et al. Residential services for persons with intellectual and developmental disabilities: status and trends through fiscal year 2011. Available from:
http://rtc.umn.edu/risp/docs/risp2011.pdf Accessed June 28, 2016.
4. Kolata G. Gene therapy hits a peculiar roadblock. NY Times, November 28, 2017, pg D1,D3.
5. Methods and Technology. What is CRISPER-Cas9. Available from: https://www.yourgenome.org/facts/what-is-crispr-cas9 Accessed November 30, 2017.


Source Exceptional Parent Magazine


AMERICAN ACADEMY OF DEVELOPMENTAL MEDICINE AND DENTISTRY
The American Academy of Developmental Medicine and Dentistry (AADMD) was organized in 2002 to provide a forum for healthcare professionals who provide clinical care to people with neurodevelopmental disorders and intellectual disabilities (ND/ID). The mission of the organization is to improve the quality and assure the parity of healthcare for individuals with neurodevelopmental disorders and intellectual disabilities throughout the lifespan.