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Gene & Protein in Disease Oral-ERT in PD knockout mice with tobrhGAA

Table 5. Motor activity by RW, forelimb muscle strength by GSM, motor coordination/balance with a rotarod, open‑field
mobility, and spontaneous learning with a T‑maze
RW GSM Rotarod T‑maze Open‑field mobility Complete blood count diff.
Mean±standard deviation rev/12 h lbs at release Time (s) % correct alternation cm/min±standard deviation
Pre-Tx n=7 – 37 M/F 404±128 0.80±59 25±49 32±25 182±79
GAA KO M/F-50 mg, n=4
3 weeks 1800±80* 0.310±133* 158±138* 82±5* 243±46 Nl
6 weeks 2528±60* 0.394±178* 171±70* 65±9* 449±53* Nl
12 weeks 2194±57* 0.304±126* 258±103* 70±2* 436±63* Nl
GAA KO M/F-150 mg, n=3
3 weeks 436±40 0.307±138* 120±73* 86±1* 442±75* Nl
6 weeks 1248±55* 0.452±147* 323±57* 81±3* 432±49* Nl
12 weeks 2549±68* 0.397±180* 355±104* 67±15* 344±54* Nl
WT
M/F n=12 – 15 3200±1423 0.569±296 264±101 60±16 334±96
Note: *P≤0.05 when compared to pretreatment data using the Student’s t-test (1-tail and 2-equal variance).
Abbreviations: GAA: Acid a-glucosidase; KO: Knockout; RW: Running wheel, GSM: Grip-strength meter; WT: Wild-type.

urine peaks showed a significant difference of P ≤ 0.011 (CI-MPR), which is compounded by low blood flow plus
and P ≤ 0.05, respectively, versus the baseline. 97,120,133-136 low affinity of the CHO-produced alglucosidase alfa for
CI-MPR. Alglucosidase alfa is delivered to the lysosome
3.15. Maximum tolerated dose by receptor-mediated endocytosis after binding to the
We determined the lethal dose in GAA KO mice (n = 4) M6P-glycan of the CI-MPR. Alglucosidase alfa has one
starting at 10 mg seeds/mouse, doubling daily to 320 mg M6P per enzyme 137-139 and low affinity with alglucosidase
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seeds/mouse. No weight loss or deaths were observed, and alfa, the high level of infused enzyme is transient, leaving
the CBC remained unchanged (data not shown). the patients with no therapeutic enzyme for the remaining
10 – 13 days between treatments. In August 2021, the
4. Discussion FDA-approved Nexviazyme (avalglucosidase alfa-ngpt)

There is currently no effective treatment or cure for for the biweekly treatment of patients aged 1 year and
people living with PD. Sanofi-Genzyme, Inc. using a older with late-onset PD. Nexviazyme is specifically
rhGAA (alglucosidase alfa) secreted from a CHO cell designed to target M6P to improve cellular enzyme
line has demonstrated moderate success in patients ; uptake and enhance glycogen clearance in the target
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however, annual treatment costs are very high. Although tissues with an approximately 15-fold increase in M6P
alglucosidase alfa has been a wonderful first step in treating content. Nexviazyme has been demonstrated in clinical
PD, it has revealed subtle aspects that must be considered trials to provide late-onset patients with improvements in
for successful treatment. 19,41,43-50 ERT usually starts respiratory function and walking distance. Treated patients
when the patients are already symptomatic; however, all had improved forced vital capacity percent at week 49.
secondary problems are already present, which are further However, the statistical superiority of Nexviazyme over
compounded by the low uptake of alglucosidase alfa in the alglucosidase alfa was not achieved (P = 0.06). A key
muscle (Table 7). Lysosomal enzymes, such as GAA, are secondary endpoint measured the functional endurance
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targeted to the lysosome by a mannose-6-phosphate (M6P) with a 6-min walk test; treated patients walked 32.2 m
recognition sequence that is exposed by post-translational farther at week 49. The most frequently reported adverse
modification in the Golgi apparatus that may be the reactions (>5%) in treated patients were headache, pruritus
mechanism by which extracellular GAA can be recycled (itching sensation), nausea, hives, and fatigue. Infusion-
and targeted back to the lysosomes. This mechanism will associated reactions were reported in 25% of treated
potentially allow rhGAA to be delivered to the cells or patients. 141 Pre-clinical studies in a PD mouse model
tissues and directed to the lysosome. However, some GAA have shown that avalglucosidase alfa has a 1,000-fold
may be taken up or recycled by endocytosis or through a higher binding affinity to M6P receptors 142-144 and greater
M6P-independent mechanism. 23-26 In skeletal muscle, there glycogen clearance from muscle. In GAAKO mice,
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is a low abundance of cation-independent M6P receptors 4 mg/kg was the minimum pharmacologically active dose

Volume 4 Issue 1 (2025) 11 doi: 10.36922/gpd.1760