spinal muscular roz 5

CHAPTER 5
Clinical Trial Strategies for
Spinal Muscular Atrophy
Douglas M. Sproule and Petra Kaufmann, M.D., M.Sc.
Douglas M. Sproule, M.D., Assistant Professor, Division
of Pediatric Neurosciences, Columbia Universitiy,
710 W 168th Street, New York, NY 10032
Petra Kaufmann, M.D., M.Sc., Director, Office of Clinical
Research, National Institute of Neurological Disorders
and Stroke, 6001Executive Boulevard, Bethesda, MD 20895
This work is related to Dr. Kaufmann’s research and clinical
work at Columbia University and does not represent the opinion
of the National Institute of Neurological Disorders and Stroke.
Abstract
Spinal muscular atrophy (SMA) is a disabling disease manifesting
with muscle atrophy and weakness as a consequence of motor neuron loss in the spinal cord. It is a promising disease for therapeutic
intervention, in part because of a modifying gene that can serve as
a treatment target. A mutation in the Survival of Motor Neurons 1
43
Spinal muscular atrophy
(SMN1) gene on chromosome 5q is the most common genetic etiology underlying SMA. In humans, a second gene (SMN2) modifies
the disease severity because it produces some functional SMN protein, and can thus partially compensate for the loss of function. Several interventions are aimed at increasing the amount of functional
SMN protein derived from SMN2. In addition, gene therapy targeting SMN itself, and neuroprotective approaches have been suggested. Several of these approaches have been successful in preclinical
experiments, both in vitro and in animal models of the disease.
Consequently, several clinical trials have been conducted to date.
Although none of those has resulted in the availability of an effective treatment, they have contributed to trial readiness in the field.
Background
Spinal Muscular Atrophy (SMA) is a disabling neuromuscular
disease with a broad phenotypic spectrum ranging from a severe
and often life threatening disease with onset in infancy to a condition of mild proximal muscle weakness with onset in adulthood.
The genetic etiology of SMA has been elucidated, and the presence
of a modifying gene that presents a potential treatment target has
given rise to hope that SMA is a curable disease. Several recent reviews summarize clinical [44, 62, 77, 83, 88, 105], research [23, 50,
96] and molecular aspects [54, 94] of SMA, as do the other contributions in this issues of the symposium proceedings. In this review,
the focus will therefore be on clinical trial strategies for SMA. SMA
is said to be the second most common autosomal recessive disease
(after cystic fibrosis) with an estimated incidence of 1 in 6000-10,000 live births [29, 70, 81, 82]. Most people with the characteristic phenotype of muscle atrophy and proximal weakness harbor
a homozygous deletion of the Survival of Motor Neuron (SMN1)
gene located on chromosome 5q13 [35, 66]. This allows for a genet44
Chapter 5 • Clinical Trial Strategies for Spinal Muscular Atrophy
ic diagnosis by blood testing. The presence of an inverted duplication of the gene in humans, (Survival of Motor Neurons 2, SMN2),
provides a therapeutic target because SMN2 results in some functional protein product so that a higher number of SMN2 copies is
associated with a milder SMA phenotype [30, 57, 109]. A homozygous deletion in SMN1 in the absence of a sufficient copy number
of SMN2 to fully compensate is associated with motor neuron loss
in the spinal cord and brain stem. Clinical phenotypes were described by 19th and 20th century neurologists [55, 107], and a clinical classification based on the highest motor function achieved
is widely in use: Patients with SMA Type 1 (Werdnig-Hoffmann)
have infant onset of the disease and never achieve the ability to sit
independently and need feeding tubes and respiratory support to
survive. [77, 107]. Patients with SMA Type 3 (Kugelberg-Welander)
achieve the ability to walk independently at lease for some time,
and most have childhood onset of symptoms [55]. Life expectancy
is not shortened. Patients with SMA Type 2 have childhood onset,
and achieve the ability to sit, but not to walk independently. [77,
110, 111]. However, within each of these disease phenotypes (SMA
types 1, 2, and 3) there is a range of severity so that the SMA phenotype represents a continuous spectrum. Therefore, in clinical
research investigators often use study entry criteria based on a patient’s current motor function, rather than on the clinical classification of the disease.
The pathogenesis of SMA is incompletely understood. Although
SMN is expressed in all tissues, in all but the most severely affected
SMA Type 1 patients, only motor neurons are affected in a clinically
meaningful way. On the cellular level, SMN is present in the nucleus
where it appears concentrated in so called „gems” [60], and where
its function has been associated with mRNA splicing [79]. While
this points to the soma as cellular localization of the disease, there
45