Novel Gene Therapy for Acute Intermittent Porphyria
Gonzalez-Aseguinolasa G1,D’Avola D2, Paneda A3, Petry H4, Lopez-Franco F1, Olague C1, Fontanellas A1,Unzu C1, Sampedro A1, Mauleon I1, Prieto J2,
Sangro B2, Troconiz I5, Ruiz J3, Urdaneta M3, Cornet M3, Municio M3, Salamanca R6, Abecias S6, SWchmidt M7, Kappel Ch7, Salmon F4, Camozzi C4,
Nijmeijer B4, Twisk J4, Harper P8, Henrichson A8. 1-CIMA, Gene Therapy and Hepatology, Pamplona; 2-Clinical Universidad de Navarra, Pamplona;
3-Digna Biotech, Madrid; 4-uniQure B.V. (ex-AMT), Amsterdam; 5-Universidad de Navarra, Pamplona; 6-Hospital 12 de Octubre, Madrid; 7-DKFZNCT, Heidelberg; 8-Karolinska University Hospital, Stockholm.
Summary
Acute intermittent porphyria (AIP), a rare genetic disease (1/10 000 people in the EU) in which porphobilinogen-deaminase
(PBGD) gene produces insufficient enzyme activity for heme synthesis, leading to accumulation of toxic ALA, PBG, resulting in life
threatening acute abdominal pain attacks, psychiatric and neurological disorders, muscular weakness, irreversible nerve damage,
liver cancer and kidney failure. Curative therapy is liver transplantation. Current therapies do not prevent symptoms or long term
consequences. Gene therapy AMT-021 (rAAV5-PBGD) delivers the PBGD expression cassette into hepatocytes. 50% of the normal
PBGD activity will be sufficient to prevent from porphyria attacks. The project targets: I- to develop GMP for AMT-021 and define
the accurate selection/evaluation clinical criteria; II- safety and efficacy of AMT-021 in a dose escalation Phase I clinical trial.
Recombinant Adeno-Associated Vector (rAAV5) + Therapeutic Genome (hPBGD)
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



NON PATHOGENIC
NATURALLY REPLICATION DEFECTIVE
LONG TERM TRANSDUCTION
SEROTYPES TARGET DIFFERENT TISSUES.
CLINICAL TRIALS (Hemophilia B)
pA
EalbAATp
3’ UTR
5’ ITR
3’ ITR
codon optimized
PBGD
Efficacy and toxicology evaluation of rAAV5-AAT-PBGD in Non Human Primates
180
Males
B C 012
140
120
High dose: 5x1013 GC/kg
150
100
B D359
80
60
40
20
Low dose: 1x1013
GC/kg
50
AST / CPK
100
B D355
0
Día 0
8 horas
24 horas
180
48 horas
72 horas
Día 7
Día 30
Females
A W 734
160
140
A W 073
120
A X593
100
A Z265
80
60
0
A Z224
A Z126
Z2
2
4
20
0
A
35
9
5
D
B
Z2
6
A
A
X5
93
01
2
3
B
C
07
W
A
W
73
4
40
A
(Viral PBGD mRNA /endogenous PBGD mRNA copies) x 100
160
A Z356
Día 0
Transgene Expression
8 horas
24 horas
48 horas
72 horas
Día 7
Día 30
Only a transient elevation (8-72 h)
AST and CPK
CONCLUSIONS
 The selected AAV5 vector doses are able to provide an efficient liver transduction. to significantly increase DNA copies
 50% endogenous levels with 5x1013 GC/kg
 10% endogenous levels with 1x1013 GC/kg
 The selected AAV5 vector doses are able to increase PBGD activity:
 2-5 times with 5x1013 GC/kg
 No morbidity, no changes in body weight or food intake.
 No changes in biochemistry, haematology, coagulation and urinalysis associated with AAV5.
 Negative viremia 30 days after viral administration in serum, saliva, nasal secretions, urine, faeces and semen.
 Tissue biodistribution mainly limited to liver although some significant transduction was detected in spleen, lymph nods, heart
and adrenal gland.
 Specific hepatic PBGD expression except for the adrenal glands.