Update on potential future Fabry disease treatments. Update on recent clinical finding in Fabry disease. Update on Newborn Screening in Fabry disease. Update on Quality of Life (QOL) with Fabry disease.

1. Fabry Up date 2018
Robert J. Hopkin
Associate professor of clinical pediatrics
Cincinnati Children’s Hospital Medical Center
Rob.hopkin@cchmc.org

2. WORLD abstracts
• Gene therapy in several abstracts
• Gene therapy requires that you:
– know which gene you wish to express
– Make a vector (piece of DNA that is stable and has
certain markers to show there is a gene there)
that contains the gene of interest
– A delivery mechanism (package for the vector that
will be efficiently taken up by the cells).

3. Gene therapy continued
• The gene has to have all the instructions attached
so it is turned on and off appropriately.
• You may need to use different instructions than
you would in a normal situation
• You can’t get gene therapy into every cell (or
even most cells).
• The product of the gene needs to be
redistributed to get to the places it is most
needed.

4. Gene therapy
• At least 3 approaches
• Ex-vivo Lentivirus
– Stem cells harvested from the body
– Treated to make them express the gene
– Tested for safety
– Bone marrow partial clearance (this is hard on the
patient)
– Infuse the converted cells (GMO but cells from the
patient’s own body)

5. Gene Therapy
• Gene Editing
• Target a vector to a specific place in the genome
so the regulation for that specific part of your
DNA is used to control expression
• Uses viral DNA and proteins to integrate the DNA
into the cells (specifically targeted liver in this
case)
• Goal is to produce enough Alpha-gal enzyme to
supply every cell in the body with active enzyme

6. Gene Therapy
• Target a specific cell type and hope for the
best.
• This is easier than the other 2 and requires
less steps but also gives the people doing the
gene therapy less control of the details of
what happens.

7. Gene Therapy
• LB 50 talked about editing the gene to make
the enzyme effective and active but more
stable and less likely to trigger an immune
response
• CRISPER/CAS9 in vivo gene editing to fix the
copy of the gene in your body or at least in
some cells in your body

8. Fabry Disease Oral Therapies
• Migalastat oral chaperone (chemical that
stabilizes the enzyme produced or infused into
the body) has been approved in Europe
• Abstract reported decreased storage in
podocytes (kidney cells important in Fabry
disease)
• Decreased heart wall thickness and increased
contraction of the affected heart muscle in
some patients

9. Oral Medications
• Substrate inhibition
• 2 companies working on this
– Drugs appear safe and well tolerated
– Decreases production of GL3
– We don’t know how low that production will need
to go
– Could be used either as a stand alone treatment
or with ERT to drain the tub and turn off the tap.

10. Oral Medications
• One of the oral substrate reduction studies is
focusing on pain
• Another on storage clearance
• Both of these are high risk studies because the
methods used to measure on not great.

11. ERT
• Genzyme, Shire, Green Cross, and at least 2
other companies now manufacture ERT
products only Fabrazyme is available in the
USA
• Protalix is working on improved ERT
– Pegylation of the enzyme to decrease immune
response prolong presence in the body and
hopefully increase penetration into the tissues.
– They are studying monthly infusions

12. Dosing of ERT
• Nephrol Dial Transplant 2017 Kramer J et al.
• Patients switched from Agalsidase beta at 1 mg/kg to
Agalsidase alpha at 0.2 mg/kg during the shortage had
increased deterioration in renal function.
• Those who switched back slowed the deterioration.
Those who remained on Agalsidase alpha continued to
deteriorate at an increased rate.
• (note this does not mean one drug works
better than the other it means dose matters)

13. Prognosis
• PLoS One. 2017 Arends M
• Standard risk factors:
– increasing age, male sex, and classical phenotype
• New(ish) risk factors:
– renal function(creatinine), proteinuria and to a
lesser extent cardiac fibrosis and hypertension

14. Death is predominantly Cardiac
• Europace 2017 Baig S et al.
• 75% of reported premature death in people
with Fabry disease was due to heart
• 62% of the deaths in Patients were sudden
cardiac death
• 30% of patients have some evidence of
arrhythmia (palpitations)

17. Vascular disease
• J Inherit Met Dis 2017 Meng XL et al.
• Priapism is increased in the Fabry mouse
• The penis in the affected mice has significant increases
in neuronal nitric oxide synthase and endothelial nitric
oxide synthase
• This increases arterial flow but decreases flow in
smaller vessels
• This may be a common contributor to the systemic
vascular disease in people with Fabry disease.

18. Pulmonology
• PLoS One. 2017 Franzen DP et al.
• bronchial obstruction was 46%,
– with male sex, age and smoking as significant
predictors.
• FEV1 decreased 29 ml per year (95% CI -36, -22
ml, p<0.0001).
• FEV1 decline was significantly higher in males (p =
0.009)
• FEV1 decline also increased in patients on ERT (p
= 0.004) (I have no idea why)

19. Hearing
• Eur J Med Genet 2018 Rodrigues J et al.
• 37% of adults (male and female) with
Fabry disease had measurable hearing loss.
Only 26% recognized that.

20. Neurologic
• Neurobio Dis 2018 Alcalay RN
• Genet Metab Rep 2018 Cocozza et al.
• Several others on this topic too
• Motor neuron hyper-excitability, poor
coordination, parkinsonism, and slow
movements all may be associated with Fabry
disease.

21. Neurology
• Neurology 2017 Godel T
• Abnormal dorsal root ganglia in Fabry disease
• This could be a key factor in causing the nerve pain
• CONCLUSIONS:
• Patients with Fabry disease have severely enlarged dorsal
root ganglia with dysfunctional perfusion. This may be due
to glycolipid accumulation in the dorsal root ganglia
mediating direct neurotoxic effects and decreased neuronal
blood supply. These alterations were less pronounced in
peripheral nerve segments. Thus, the dorsal root ganglion
might play a key pathophysiologic role in the development
of neuropathy and pain in Fabry disease.

22. Neurology
• Front Neurol. 2017 Namer B et al.
• Electrophysiological recordings of Gla-/0 nociceptors revealed
decreased Na+ and Ca2+ currents
• voltage-gated K+ currents was at more depolarized potentials.
• Conclusively, we have observed that reduced sensory perception
due to small-fiber degeneration coincides with altered
electrophysiological properties of sensory neurons.
• This implies a measurable phenomenon that can be tracked with
treatment.
• We should be able to measure and see if we are normalizing. We
can also target medications better if we know the basis of the pain.

23. Neurology
• Audiol Res. 2017 Carmona S
• 75% had cochlear or vestibular abnormalities
• 77.7% had peripheral nerve abnormality
• The degree of involvement of the ears
(hearing and balance) did not correlate with
the amount of abnormality in the peripheral
nerves

24. Vision
Intern Med J. 2017 Kohs et al.

25. Lymph edema
• Med Genet Metab 2018 Okada et al.
• ERT doesn’t successfully treat severe
lymphedema
• Single case report but it is a start

26. New born screen
• Several papers and a talk on this at WORLD
• Most were in favor
• Trends in Cardiovascular Med 2018 Langeveld
– Argued that it is too soon
– Proposed resetting the cut points to only look for
classical Fabry disease because we don’t know
what to do with non-classical patients

27. QOL
• JIMD 2018 Iveva et al
• 40% of adults with Fabry disease have
musculoskeletal complaints that limit activity
• A specific QOL survey is being validated for
QOL
• SF36 plus 77 questions (seems long to me)

28. QOL
• J Inherit Metab Dis. 2018 Arends M et al.
• QOL is decreased as is ability to function for both
men and women.
• Men with classical disease decline in QOL after
age 50
• Pain is a key driver of low QOL
• They did not report what ERT was used but did
report that ERT did not change the scores in this
study

29. Contribution of Fabry disease to
general population health problems
• J Med Genet 2018 Doheny et al.
• Published studies on Fabry disease in stroke, heart failure,
and kidney disease clinics included changes now thought to
be benign variants
• This study looked at all of those and calculated risk
contribution attributable to Fabry disease
• 2/1000 cases of kidney failure
• 1/1000 strokes
• 9/1000 cases of heart failure
• 60% of this risk is from classical Fabry disease
• But for males most of the heart disease is nonclassical