Transcript History of the LSDs

The Lysosome and lysosomal
storage disorders (LSD)
Part III B
Clinical profile of the LSDs
Serge Melançon, MD
February 2009
Prevalence of LSDs
Lysosomal Storage Disorders
Sandoff 2%
Gaucher
14%
Gm1 Gangliosidosis 2%
Mucolipidosis II/III 2%
Niemann Pick A/B 3%
MPS I H/S
9%
Maroteaux-Lamy 3%
Niemann Pick C
4%
Sanfilippo B
4%
Metachromatic
Leukodystrophy
8%
Tay-Sachs
4%
Cystinosis
4%
Sanfilippo A
7%
Morquio
5%
Pompe
5%
(For Australia1980-1996; Meikle et al., JAMA 281;249-254
Krabbe
5%
Hunter
6%
Fabry
7%
MPS
34%
Presentation and Progression
Presentation and Progression
• Heterogeneous presentation across the
LSD categories and often even within a
single disease
• Wide clinical variability according to
different types of substrate stored and
locations of storage
• Clinical manifestations tend to be
progressive, as more waste substrate
accumulates over time.
Presentation and Progression
• As a group, LSDs affect nearly every bodily
system
• Symptoms vary in severity from relatively mild to
severe somatic and rapidly progressive
neurologic manifestations.
• Even those without formal sub-types based on
age of onset, affected organs/systems, and
severity generally encompass a spectrum of
clinical manifestations
"Red Flag"
Symptoms
"Red Flag" Symptoms
• While no single symptom is an LSD
hallmark, several frequently present
across enough of the disorders that they
can raise a physician's suspicion and
prompt further investigation.
• LSD symptoms often present in clusters,
so the appearance of more than one of
these is even more suggestive
"Red Flag" Symptoms
Coarse facial features (sometimes with macroglossia)
Corneal clouding or related ocular abnormalities
Angiokeratoma
Umbilical/inguinal hernias
Short stature
Developmental delays
Joint or skeletal deformities
Visceromegaly (especially liver and spleen)
Muscle weakness or lack of control (ataxia, seizures, etc.)
Neurologic failure/decline or loss of gained development
Coarse facial features
Corneal clouding
Umbilical hernia
Skeletal
Abnormalities
Gaucher
MPS I
Angiokeratoma
Visceromegaly
Joint deformities
"Red Flag" Symptoms
Particularly noteworthy are the following signs:
 Loss of motor skills,
 Increasing dementia or behavioural abnormalities,
 Muscular or neurologic deterioration,
That suggest a progressive/degenerative disorder.
Cystine crystal deposits
Kyphosis
Aspartylglycosaminuria
Lymphadenopathy
Farber
Cystinosis
Ataxia
Krabbe
Hypertonia
Disease
Strabismus
Retinitis pigmentosa
Cherry red spot
Infantile Sialic acid SD
Small jaw
Neuronal ceroid lipofuscinosis
GM2 Gangliosidosis
Cardiomegaly
Macroglossia
Picnodysostosis
Pompe
Muscle waisting
Hypotonia
Progression and
outcome
Progression and outcome
• The LSDs with neurologic involvement
can often be the most severe, marked by
rapid decline and high mortality rates
• But generally, predicting LSD progression
and outcome is challenging, especially in
later-onset patients
Progression and outcome
• A single disease is often associated with
several different gene mutations, which may
account in part for the disease's clinical
heterogeneity.
• However, the very same mutations may result
in quite different outcomes in different
patients and genotype-phenotype correlations
are not always consistent;
Progression and outcome
Other factors can also influence outcome:
• residual enzyme activity versus
complete deficiency,
• age of diagnosis and of onset of
treatment or supportive care
• environmental influences;
• unknown genetic and epigenetic factors
Prognosis of LSDs
Prognosis of LSDs
• Early identification and diagnosis is
essential for appropriate management.
• Early intervention is mandatory for the
most serious and debilitating symptoms
(particularly neurologic and skeletal)
• Once established these often will not
respond to even disease-specific
therapies
Disease Management
• Requires a multidisciplinary team
approach, with a lead physician (usually
a geneticist) directing care and referring
to other specialists as necessary
• Treatment options vary across the LSDs
• Often various therapies and/or care will
be offered
Therapies for lysosomal storage disorders
Disease Management
• For most LSDs, no disease-specific therapy is
available
• Clinical manifestations can only be addressed
through palliative measures such as physical
therapy, dialysis or surgery
• These methods can be effective in managing
symptoms, but they do not affect the
biochemical cause of the disease
Disease-Specific Treatment Options
• Hematopoietic stem cell transplant
(HSCT)
Healthy stem cells (from bone marrow or
cord blood) are transplanted i.v. to the
patient to provide new healthy cells that
produce the missing enzyme.
• Enzyme replacement therapy (ERT)
A recombinant form of the deficient enzyme
is infused i.v. at definite intervals.
Disease-Specific Treatment Options
• Enzyme enhancement therapy (EET)
Misfolded enzyme is stabilized during its
synthesis by the use of small chemical
chaperones
• Substrate reduction therapy (SRT)
The rate of production of the substrate is
slowed by drug therapy.
Bone marrow transplant
• First attempted in the 1980s and has been most
used for MPS I
• Positive results when performed early in a
disease's course, despite its challenges and
risks
 transplant failure or rejection
 toxicity of the conditioning regimen
 difficulty finding a good donor match
• Improved chance for success in newborns with
naturally suppressed immune systems
Enzyme Replacement Therapy
Enzyme Replacement Therapy
• R&D began in the mid-1960s, and
by the 1980s clinical trials were
underway.
• In the early 1990s, advances in
recombinant DNA manufacturing
enabled enzyme production in
quantities large enough for
commercial development
Enzyme Replacement Therapy
• The first ERT for Gaucher type I went
on the market in 1991
• ERT is a treatment option for 4 LSDs
Gaucher Type I, Fabry, MPS I
(Hurler/Scheie) and MPS II (Hunter)
• And will soon be for 3 more LSDs
Pompe (GSD type II) and MPS VI
(Maroteaux-Lamy)
Current cost of ERT (US$)
Substrate Reduction Therapy
• SRT was introduced in 2002 for Gaucher
Type I patients where ERT is not an option
• Further clinical studies are in progress for
 Fabry disease
 GM2-gangliosidoses (Tay-Sachs, Sandhoff,
GM2 activator disease)
 Niemann-Pick type C
Before SRT
After SRT
Glucosylceramide exceeds
capacity of residual
glucocerebrosidase activity.
Reduced level of glucosylceramide
helps relieve the burden on the
residual glucocerebrosidase.
Zavesca inhibits glucosylceramide synthase, the first enzyme
responsible for glycosphingolipid (GSL) synthesis.
Research Efforts for LSD
Research Efforts for LSD
Treatment Options
• Both ERT and HSCT have limited
efficacy on neurologic symptoms, since
the large enzyme molecules introduced
intravenously cannot penetrate the
blood-brain barrier
• ERT development continues to face
challenges, such as difficulties targeting
the affected cell
Research Efforts for LSD
Treatment Options
• Small molecule drugs can generally be
administered orally and cross the blood-brain
barrier where they act as pharmacologic
"chaperones” to enable:
• Enzyme enhancement therapy which
attempts to stabilize faulty enzymes in LSDs
caused by enzyme malfunctions (rather than
total deficiency)
Research Efforts for LSD
Treatment Options
• Substrate synthesis inhibition therapy
 attempts to block a step in the production
of waste to minimize the accumulation
 may be most effective in patients with
some residual enzyme presence (rather
than total deficiency) and as an adjunct to
other treatments (such as ERT).
Research Efforts for LSD
Treatment Options
• Gene therapy
 involves replacing the patient's mutated
gene with a normal copy so proper enzyme
production can occur.
 still only in preclinical (animal) studies, and
much research is needed, especially in
identifying appropriate vectors for gene
delivery.
GENE THERAPY
THANK YOU
AND
HAVE A NICE DAY