Abstract does not focus on muscular dystrophy as

Abstract 

The purpose of this research paper
is to answer the question: to what extent has advancements in clinical
treatment for Duchenne muscular dystrophy (DMD) benefited the economic welfare
of U.S households with a diagnosed relative? It should be noted that this paper
does not focus on muscular dystrophy as a whole; rather, the focus is specifically
directed towards the impact DMD has on the economic welfare of the household
caregivers of a diagnosed male relative within the United States. To discuss
this question thoroughly, this paper respectively outlines the scope DMD has
throughout the United States, the causes and development of the disease, the innovative
and advanced treatments recently incepted, and the economic costs associated
with those treatments. This paper shows that these treatments, via therapy, pharmaceutical
drug, clinical testing, and or home modification, are extremely costly for the
average American household caring for a DMD inflicted relative, not only
because of the direct expense associated with that care, but the informal
consequences as well. These costs, however, are qualified with the fact that advanced
treatments have been more effective in benefiting the health of DMD patients,
and consequently, have allowed for caregivers to experience a recovery in the
workforce. Limitations to this paper arise in the lack of comparison to the
effectiveness of treating DMD with more traditional treatment methods. Instead,
the characteristics specific to advanced treatments are described, as well are
the economic impacts those treatments have on a DMD household.

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Duchenne Muscular
Dystrophy Treatment: Effects on American Welfare

With various mutations
resulting in the abnormality of genes that impede the production of crucial
muscle proteins, the Mayo Clinic Staff (2014) defines muscular dystrophy as “a
group of diseases that cause progressive weakness and loss of muscle mass.” Despite
there being over nine types of muscular dystrophy, the most common one, and the
one this paper focuses on, is Duchenne muscular dystrophy (DMD), “an X-linked
inherited neuromuscular disorder due to mutations in the dystrophin gene” that
affects up to one in every thirty-six hundred male births worldwide (Falzarano,
Scotton, Passarelli, & Ferlini, 2015). While there are a few instances of
females being diagnosed with DMD as a result of a random X-inactivation, it is
extremely rare.

Even though the United States
has seen rapid progress in the advancement of medical tools over the course of
this past decade, researchers have yet to discover a definitive cure for DMD. However,
there have been multiple innovations regarding the treatment of the disease
that has contributed to the reduction of DMD’s primary and secondary
pathological effects (Falzarano et al., 2015). Since these newly incepted and
continuously developing methods deviate in both cost and effectiveness from
previously employed treatments for DMD, the essential question needs to be
asked: to what extent has advancements in clinical treatment for DMD benefited
the economic welfare of U.S households with a diagnosed relative? Despite the
initial direct and indirect economic barriers families with a DMD diagnosed
relative experience, through advanced and specific treatments and more in depth
practices brought upon by scientific innovation, family caregivers can once
again gain the ability to fully participate in the workforce.

W. Douglas Biggar (2006), a professor of Paediatrics at the University of Toronto discusses the
pathogenesis behind DMD:

DMD is caused by a mutation of
the X-linked gene that encodes for the protein dystrophin. Dystrophin is a
large, 427-kDa protein that bridges the inner surface of the muscle sarcolemma
to the protein F-actin. The gene, also very large, is located on the short arm
of the X chromosome… Without dystrophin, the glycoprotein structure of the
muscle sarcolemma is less stable. Membrane instability leads to muscle damage,
with the initiation of an inflammatory cascade contributing further to muscle
damage, necrosis, and fibrosis. Proximal muscles are involved first. Skeletal
and cardiac muscle are affected primarily. (p. 83)

The most common mutation
results from the deletion of one or several exons – “a segment of a
DNA or RNA molecule containing information coding for a protein or peptide
sequence” (LaFree, 2011). Mutation
by deletion accounts for sixty five percent of DMD cases while mutation by
duplication accounts for only six percent. The peer-reviewed journal Molecules
(2015) furthers that:

The remaining cases
(approximately 25%) are due to small mutations (missense, nonsense, and splice
site variations) small rearrangements (insertions/deletions, small inversion).
However, a lower rate of cases (approximately less than 2%) is caused by
complex rearrangements and deep intronic changes… These mutations lead to a
loss of dystrophin protein expression resulting in a severe muscle wasting,
respiratory and cardiac failure and death before the age of 30. (p. 18170)

As a
consequence of its gradual nature, the U.S Center for Disease Control and
Prevention (CDC), in coordination with over eighty-four international experts
in DMD diagnosis, performed an extensive clinical study that considered over seventy
thousand different scenarios of DMD in order to identify the symptoms the
disease exhibits (Bushby K, et al., 2010). Through their
observation, the CDC found that symptoms reveal themselves in four stages:
early ambulatory, late ambulatory, early non-ambulatory, and late
non-ambulatory.

Starting
as early as age two, in the early ambulatory stage, commonly referred to as the
walking stage, boys will begin to show signs of Gowers’ manoeuvre – movements where a young boy has to support
himself with his hands on his thighs in order to rise from the floor. In the
late ambulatory stage, “walking becomes increasingly difficult and there are
more problems with climbing stairs and getting up from the floor” (Bushby K, et al., 2010). At around ages ten to twelve, the disease
begins to take its toll on the body as the late ambulatory stage develops,
often forcing the patient into a wheelchair. Once the boy has entered the final
stage of late non-ambulatory, severe complications in upper limb functions become
apparent and good posture is increasingly difficult to maintain. Aside from
these four main stages, the study concludes that there are other symptoms that diagnoses
can be predicated on. This includes “high
levels of the muscle protein creatine kinase (CK) in a blood test” and “high
levels of the ‘liver enzymes’ AST and ALT in a blood test… DMD patients develop
a severe cardiomyopathy that generally manifests at about 10 years and is
prevalent in most patients by 20 years of age 5” (Falzarano, Scotton,
Passarelli & Ferlini, 2015).

According to the Harvard
Journal of Genetics, diagnosis by a physician can be performed through three main
media: genetic testing, muscle biopsy and multiplex ligation-dependent probe
amplification (MLPA), with the former providing specific information about the
DNA mutation that has occurred (Reddy et al., 2017). While more general in its results,
muscle biopsy, performed from gathering a small muscle sample from the patient
for analysis, can provide data on the levels of dystrophin present in muscle
cells (low levels are indicators of weak muscle movement and, consequently, are
grounds for the diagnosis of DMD). The latter method runs through testing of
all seventy-nine exons of the DMD gene, and identifies “the copy number
variation (CNV) in a multiplex polymerase chain reaction based reaction 16”
(Falzarano, Scotton, Passarelli, & Ferlini, 2015). MLPA is the most widely adopted
method of diagnosis today.

 “Duchenne’s Muscular Dystrophy was initially
described clinically in 1860 by the French neurologist Guillaume Benjamin Amand
Duchenne” (Elangovan, Lepp, & Oh,
2006). During his initial research of the disease, he developed the use
of electrical current to stimulate muscles for diagnostic and therapeutic
purposes. However, despite there being a history of experimental treatments for
DMD that followed Duchenne’s initial diagnosis, only a few have materialized
into mainstream use because of their foundation in more advanced clinical
technologies.

According Simon Guiraud and Kay E. Davies, research associates at the Medical
Research Council Functional Genomics Unit at the University of Oxford (2017),
current “pharmacological intervention for DMD can be categorized into two
groups: (1) strategies targeting the primary defect and (2) approaches to
mitigate secondary and downstream pathological mechanisms” (Guiraud & Davies,
2017). Aartsma Rus explains in a report by the peer-reviewed medical journal Expert
Opinion on Biological Therapy that only one pharmacological approach that
targets the primary defect involving the genetic therapy based application of
the “exon skipping drug, Exondys 51 (Sarepta Therapeutics), has been given conditional
approval by the United States Food and Drug Administration (FDA)” (Rus, 2016). Despite
past obstacles to gene therapy that stemmed from a dearth of inefficient gene
editing enzymes and delivery strategies, Ping Li enunciates in his periodical
included within the Open Journal of Medicinal Chemistry, an internationally
peer-reviewed open-access journal, that “recently, the technological
development of several engineered nucleases” have overcome the aforementioned
inhibitors (Ping et al., 2016). The most useful synthetic nuclease – an enzyme
capable of inducing “cellular DNA repair mechanisms and introduceing
site-specific, predefined genetic modifications in complex genomes” (Ousterout,
2015) – is the Transcription Activator-Like Effector Nuclease (TALEN) because
of its ability to bind to and effectively modify a specific nucleotide in a DNA
sequence. Given that sixty percent to sixty-five percent of disease-causing
mutations related to the DMD gene are caused by the deletion of one or more
exons, by having multiple TALENs work in conjunction to target and correct the size
of a deletion or insertion in the protein-coding region of exons, the
dystrophin coding frame can be modulated for a majority of those diagnosed (Hotta,
2015). Treatments based in this type of genetic testing have materialized in
the form of Exondys 51, a new pharmaceutical drug that specifically targets “a
section of genetic code called exon 51 in the dystrophin gene. It’s estimated
that 13 percent of boys with DMD could benefit from skipping exon 51” because
of the specifics in their genetic mutation (“DMD”, 2017). While genetic therapy
treatments rooted in exon skipping are not a direct cure for DMD, they do have
the ability to lessen the severity of the weaknesses muscles are subject to,
often transforming DMD into its less aggressive sister disease, Becker
muscular dystrophy (BMD).

Regardless of the hopeful effects Exondys 51 has for a DMD inflicted
patient, the one million dollar cost that comes attached to the drug is dramatic,
especially considering the coincidental fact that most families caring for a
DMD relative are of middle or low income (Thomas, 2017). Moreover, acquiring such
a pharmaceutical has become entrenched in an increasingly restrictive process
that families have to endure due to insurers withdrawing their concession to
cover Exondys 51 or their attempts to impose “severe restrictions that render
patients ineligible” because of the drug’s lack of precedent in proven
effectiveness and its high list price. For example, “insurers, including
UnitedHealth, Aetna and Humana, will cover it only under limited circumstances
— if the boy is under 14, for example, or can walk a certain distance. After
six months, in many cases, the insurers require evidence that the drug appears
to be working” (Thomas, 2017).

While Exondys 51 is the only FDA approved pharmaceutical openly available
to the public at the time this paper was submitted, stem cell transplantation
has also arisen as a promising treatment process for DMD, with the most common
cell of transfer being satellite cells. Also referred to as autologous muscle
stem cells, satellite cells are “unipotent adult stem cells that are activated
in response to severe muscle damage to proliferate and differentiate, thereby
forming myoblasts that can rebuild the muscle through fusion with one another
or with residual myofibers” (Lee et al., 2012). By implanting these cells into inflicted
areas of diseased muscle, Mohammadsharif Tabebordbar of the Division of Medical
Sciences explains in a report from Harvard University that “they presumably
would produce donor-engrafted muscle fibers carrying the normal allele of the
affected gene, and thereby reconstituting the unaffected gene function”
(Tabebordbar, 2016). This method however has its limitations. In its earliest
stages of clinical trials in 1997 especially, transplantation methods were extraordinarily
difficult to perform cleanly. Dr. Roger G. Miller was one of the first to exercise
such trials when he evaluated myoblast
implantations in ten boys diagnosed with DMD. His results showed that a
significant quantity of cells were lost upon transplantation and
resulted in the subsequent death of ninety percent of transferred cells within
five days. With the development of more advanced tools since then, the crux of
the problem today stems not from inaccurate transplantation, but from the cells’
rare population in the muscle, inability to expand in culture and continuously
produce cells for gene correction. Consequently, treatment of this kind is currently
not a viable long-term solution, but is still being developed through the
implantation of other cell types in order to increase the duration the patient
feels the treatments’ benefits.

As an aside, it should be noted that even treatments for muscular
dystrophy that did not bear out still found clinical applications elsewhere. According
to Luc Grobert, head of the Department of Genetics at the University of Liege,
one method that initially received considerable attention from the scientific
community was the inhibition of myostatin – a naturally occurring protein that
limits muscle growth in order to keep the organ at a reasonable and healthy size.
For those patients affected by DMD, this protein only exacerbates their muscular
dysfunction. The MDA For Strength, Independence & Life explains that for
those patients affected by DMD, despite the fact that inhibitors “of myostatin have received much attention from the
neuromuscular disease research community since it was found years ago that
people and animals with a genetic deficiency of myostatin appear to have large
muscles and good strength without apparent ill effects”, such trials were quickly
discontinued due to safety concerns (“DMD”, 2017). However, from the few
tests that did occur, much data was gathered that was later on applied to treatments
for both cancer wasting and deficiencies in
skeletal muscle growth.

Contrary to the benefits various clinical
treatments can bring, when applied in a vacuum, they are not enough to adequately
improve a DMD diagnosed patient’s health concerns. Doris G.
Leung, an associate professor of the Center for Genetic Muscle
Disorders, explains that for almost all DMD patients, physical therapy is a necessary
contributive in order to retard the disease’s abasement of muscle (Leung, 2013).
Moreover, in order to be effective, most therapies need to be specialized and
custom fit to match the patient’s needs. Wendey M. King, an assistant professor
of neurology of the FHS society, states that when abdominal muscles begin to
break down, depending on which stage the patient is in, their muscles might be
weakened to such an extent that generic therapy exercises are not a viable option
as the body cannot overcome the force of gravity. Consequently, other custom
specific therapies, like when a trainer recommends a certain abdominal binder
brace, are an alternative (King, 2007). However, according to a report from the
peer-reviewed journal, Neuromuscular Disorders (2002), methods such as these
have been controversial:

Efforts to increase muscle strength
through exercise may be countered by the risk of overuse and excessive
breakdown of muscle that has limited regenerative capacity. Numerous studies have examined a variety of exercise programs in small
numbers of patients with various types of muscular dystrophy, and there is
evidence that some of these programs can be performed safely and at least temporarily
improve muscle function. However,
the lack of uniformity in exercise protocols and outcome measures has been a
limiting factor in the development of widely applicable exercise guidelines. (p.
975)

These aforementioned advanced treatments
and the technologies developed to help DMD diagnosed patients cope with daily
life have subject families who assume the role of caregiver to a looming cloud
of debt and expenses. Neurology Journals performed a survey of seven-hundred
and seventy patients diagnosed with DMD and found that the mean “per-patient
annual direct cost of illness was estimated at between $23,920 and $54,270… 7
to 16 times higher than the mean per-capita health expenditure,” with the
corresponding mean household cost set between 58,440 dollars and 71,900 dollars
(Landfeldt et al., 2014).

One of the preeminent economic concerns
families bear are endowed in the process of obtaining and maintaining new medical
modifications and other assistive technologies in their homes in order to ensure
that their diagnosed son or relative is able to maintain a comfortable level of
mobility and accessibility. This is particularly important as the disease
evolves and more assistance to the patient is required. Often with the specific
design of and assisted implantation by a physical therapist, assistive
technologies such as harnesses to get a patient into bed are part of a DMD
patient’s daily life (Stuberg, 2001). Ventilation pumps are one of the most
expansive but necessary devices used by DMD inflicted individuals. This is
because as the musculoskeletal framework for the pulmonary system continues to
break down and deteriorate, the device itself needs to be either added onto or
replaced with a newer and more aggressive working part as the condition
exacerbates (Amin et al., 2002). As a result of such expenses, a study from the
American Medical Association explains that the “willingness-to-pay for a
quality-adjusted life-year for DMD patients is $75,000” (Ubel, 2013).

Another large contributor to these accumulating
costs stem not just from medical expenses or adaptive equipment modifications
employed in the household, but also from the indirect and informal costs –
money lost from a breadwinner’s inability to meet societal production
requirements – of the care. The bright line to such expenses attached to
innovative technologies, however, is that the deteriorating condition of
Duchenne muscular dystrophy can be temporarily halted. Dr. Craig Mc. Donald of
UC Davis Health explains that as a result of consistently innovative treatments
employed for patients with DMD – with steroids such as glucocorticoid included
in his analysis – young boys experienced up to a four-year delay in their
inability to climb stairs or run for more than ten meters, and more
impressively, “an overall reduction in risk of adolescent death by more than
50 percent” (Mc. Donald, 2017). This is a worthy milestone because, according
to a Duke University study, even a four percent revival in dystrophin protein
levels could leave a patient diagnosed with DMD enough muscular function to be
independently mobile (Radford, 2016).

In consequence, this improved condition can
result in an alleviation of the economic barriers families face. When DMD is
left untreated, many families witness these aforementioned societal production drawbacks
come to fruition in the form of decreased efficiency, increased absenteeism, or
even a complete separation with their job. Erik Landfeldt, Associate
Scientific Director of Mapi Group, furthers that “49%
of caregivers have to reduce their working hours or stop working completely
because of their son’s DMD”, explaining why “Labor-force participation among
patients is very low (