# US 12,109,205 B2 · Methods of treating Fabry patients having renal impairment

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- Number: US 12,109,205 B2
- Document ID: US12109205B2
- Status: Granted
- Kind: B2
- Application number: 17/078,840
- Filed: 2020-10-23
- Published: 2021-02-11
- Granted: 2024-10-08
- Earliest claimed: 2017-05-30
- Assignees: Amicus Therapeutics, Inc.
- Applicants: Amicus Therapeutics, Inc.
- Inventors: Jeff Castelli; Elfrida Benjamin
- Web page: https://patentgrep.com/patent/US12109205B2

## CPC

- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61P 13/12: of the kidneys
- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Provided are methods for treatment of Fabry disease in patients having HEK assay amenable mutations in α-galactosidase A. Certain methods comprise administering migalastat or a salt thereof every other day, such as administering about 150 mg of migalastat hydrochloride every other day.

## Claims

### Claim 1

A method of treating Fabry disease, the method comprising administering migalastat to a patient in need thereof, wherein the patient has an α-galactosidase A protein comprising a HEK assay amenable mutation selected from the group consisting of: R4M/Y207S, A15T, A15G, F18C, W24G, N34D, G35V, M42I, E48Q, N53D, P60S, F69L, M721, G85S, G85N, G104V, L106F, A108T, D109G, R112G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, G271S/D313Y, W277C, D299E, S304T, D313Y/G411D, I319F, F337S, P343L, G361A, P362T, K391T, G395E and p.T400_S401dup.

### Claim 2 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: A15T, F18C, W24G, G35V, M42I, N53D, P60S, F69L, M72I, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 3 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: N53D, P60S, L180W, R196G, P210S, P210L, P214S, R220P, Q221P, I242T, Q250H, p.V254del, G260E, G261S, D299E, S304T and P362T.

### Claim 4 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: R4M/Y207S, A15T, A15G, W24G, G35V, M42I, E48Q, N53D, P60S, F69L, M72I, G85S, G85N, G104V, L106F, A108T, D109G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T, K391T, G395E and p.T400_S401dup.

### Claim 5 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: R4M/Y207S, W24G, G35V, M421, E48Q, N53D, P60S, F69L, G85S, G85N, G104V, L106F, D109G, G144D, L180W, G195V, R196G, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T, K391T, G395E and p.T400_S401dup.

### Claim 6 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: G35V, M421, F69L and L180W.

### Claim 7 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: A15T, W24G, G35V, M42I, N53D, P60S, F69L, M72I, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 8 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: W24G, G35V, M42I, N53D, P60S, F69L, G104V, L106F, G144D, L180W, G195V, R196G, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T and K391T.

### Claim 9 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: R4M/Y207S, A15T, A15G, F18C, W24G, N34D, G35V, M42I, E48Q, N53D, P60S, F69L, M72I, G85S, G85N, G104V, L106F, A108T, D109G, R112G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, G260E, G261S, G271S/D313Y, W277C, D299E, S304T, D313Y/G411D, I319F, F337S, P343L, G361A, P362T, K391T and G395E.

### Claim 10 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: R4M/Y207S, W24G, G35V, M42I, E48Q, N53D, P60S, F69L, G85S, G85N, G104V, L106F, D109G, G144D, L180W, G195V, R196G, E203D, P210S, P210L, P2145, R220P, Q221P, F229L, I242T, Q250H, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T, K391T and G395E.

### Claim 11 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: A15T, F18C, W24G, G35V, M42I, N53D, P60S, F69L, M72I, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 12 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: N53D, P60S, L180W, R196G, P210S, P210L, P214S, R220P, Q221P, I242T, Q250H, G260E, G261S, D299E, S304T and P362T.

### Claim 13 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: W24G, G35V, M42I, N53D, P60S, F69L, G104V, L106F, G144D, L180W, G195V, R196G, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T and K391T.

### Claim 14 (depends on 1)

The method of claim 1, wherein the patient has a Fabry disease-causing mutation.

### Claim 15 (depends on 1)

The method of claim 1, wherein the migalastat or salt thereof is administered to the patient every other day.

### Claim 16 (depends on 1)

The method of claim 1, wherein the patient is administered about 123 to about 300 mg of the migalastat or salt thereof every other day.

### Claim 17 (depends on 1)

The method of claim 1, wherein the patient is administered about 150 mg of the migalastat or salt thereof every other day.

### Claim 18 (depends on 1)

The method of claim 1, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day.

### Claim 19 (depends on 1)

The method of claim 1, wherein the patient is male.

### Claim 20 (depends on 1)

The method of claim 1, wherein the patient is female.

### Claim 21 (depends on 1)

The method of claim 1, wherein the patient has renal impairment.

### Claim 22 (depends on 21)

The method of claim 21, wherein the patient has mild or moderate renal impairment.

### Claim 23 (depends on 1)

The method of claim 1, wherein the patient is an enzyme replacement therapy (ERT)-experienced patient.

### Claim 24 (depends on 1)

The method of claim 1, wherein the patient is an enzyme replacement therapy (ERT)-experienced patient with renal impairment.

### Claim 25 (depends on 1)

The method of claim 1, wherein the patient is an enzyme replacement therapy (ERT)-naïve patient.

### Claim 26 (depends on 1)

The method of claim 1, wherein the patient has a proteinuria level of less than 100 mg/24 hr prior to initiating the administration of the migalastat or salt thereof.

### Claim 27 (depends on 1)

The method of claim 1, wherein the patient has a proteinuria level of 100 to 1,000 mg/24 hr prior to initiating the administration of the migalastat or salt thereof.

### Claim 28 (depends on 1)

The method of claim 1, wherein the patient has a proteinuria level of greater than 1,000 mg/24 hr prior to initiating the administration of the migalastat or salt thereof.

### Claim 29 (depends on 1)

The method of claim 1, wherein the migalastat or salt thereof is administered orally.

### Claim 30 (depends on 29)

The method of claim 29, wherein the migalastat or salt thereof is in a solid dosage form.

### Claim 31 (depends on 30)

The method of claim 30, wherein the solid dosage form comprises a capsule.

### Claim 32 (depends on 1)

The method of claim 1, wherein the migalastat is administered as a pharmaceutically acceptable salt.

### Claim 33 (depends on 1)

The method of claim 1, wherein the patient is orally administered a capsule comprising about 150 mg of migalastat hydrochloride every other day.

### Claim 34 (depends on 8)

The method of claim 8, wherein the patient has a Fabry disease-causing mutation.

### Claim 35 (depends on 8)

The method of claim 8, wherein the migalastat or salt thereof is administered to the patient every other day.

### Claim 36 (depends on 8)

The method of claim 8, wherein the patient is administered about 123 to about 300 mg of the migalastat or salt thereof every other day.

### Claim 37 (depends on 8)

The method of claim 8, wherein the patient is administered about 150 mg of the migalastat or salt thereof every other day.

### Claim 38 (depends on 8)

The method of claim 8, wherein the patient is administered about 150 mg of migalastat hydrochloride every other day.

### Claim 39 (depends on 8)

The method of claim 8, wherein the patient is male.

### Claim 40 (depends on 8)

The method of claim 8, wherein the patient is female.

### Claim 41 (depends on 8)

The method of claim 8, wherein the patient has renal impairment.

### Claim 42 (depends on 41)

The method of claim 41, wherein the patient has mild or moderate renal impairment.

### Claim 43 (depends on 8)

The method of claim 8, wherein the patient is an enzyme replacement therapy (ERT)-experienced patient.

### Claim 44 (depends on 8)

The method of claim 8, wherein the patient is an enzyme replacement therapy (ERT)-experienced patient with renal impairment.

### Claim 45 (depends on 8)

The method of claim 8, wherein the patient is an enzyme replacement therapy (ERT)-naïve patient.

### Claim 46 (depends on 8)

The method of claim 8, wherein the patient has a proteinuria level of less than 100 mg/24 hr prior to initiating the administration of the migalastat or salt thereof.

### Claim 47 (depends on 8)

The method of claim 8, wherein the patient has a proteinuria level of 100 to 1,000 mg/24 hr prior to initiating the administration of the migalastat or salt thereof.

### Claim 48 (depends on 8)

The method of claim 8, wherein the patient has a proteinuria level of greater than 1,000 mg/24 hr prior to initiating the administration of the migalastat or salt thereof.

### Claim 49 (depends on 8)

The method of claim 8, wherein the migalastat or salt thereof is administered orally.

### Claim 50 (depends on 49)

The method of claim 49, wherein the migalastat or salt thereof is in a solid dosage form.

### Claim 51 (depends on 50)

The method of claim 50, wherein the solid dosage form comprises a capsule.

### Claim 52 (depends on 8)

The method of claim 8, wherein the migalastat is administered as a pharmaceutically acceptable salt.

### Claim 53 (depends on 8)

The method of claim 8, wherein the patient is orally administered a capsule comprising about 150 mg of migalastat hydrochloride every other day.

### Claim 54 (depends on 1)

The method of claim 1, wherein the administration is effective to reduce globotriaosylceramide (GL-3) accumulated in an organ of the patient.

### Claim 55 (depends on 1)

The method of claim 1, wherein the administration is effective to reduce plasma globotriaosylsphingosine (lyso-Gb3) in the patient.

### Claim 56 (depends on 1)

The method of claim 1, wherein the administration is effective to increase white blood cell (WBC) α-galactosidase A activity in the patient.

### Claim 57 (depends on 1)

The method of claim 1, wherein the administration is effective to reduce left ventricular mass index (LVMi) in the patient.

### Claim 58 (depends on 1)

The method of claim 1, wherein the administration is effective to stabilize renal function in the patient.

### Claim 59 (depends on 1)

The method of claim 1, wherein the administration is effective to (i) reduce globotriaosylceramide (GL-3) accumulated in an organ of the patient, (ii) reduce plasma globotriaosylsphingosine (lyso-Gb3) in the patient, (iii) increase white blood cell (WBC) α-galactosidase A activity in the patient, (iv) reduce left ventricular mass index (LVMi) in the patient, or (v) stabilize renal function in the patient.

### Claim 60

A molecule comprising migalastat bound to an a-galactosidase A protein comprising a HEK assay amenable mutation selected from the group consisting of: R4M/Y207S, A15T, A15G, F18C, W24G, N34D, G35V, M42I, E48Q, N53D, P60S, F69L, M721, G85S, G85N, G104V, L106F, A108T, D109G, R112G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, G271S/D313Y, W277C, D299E, S304T, D313Y/G411D, I319F, F337S, P343L, G361A, P362T, K391T, G395E and p.T400_S401dup.

### Claim 61 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: A15T, F18C, W24G, G35V, M42I, N53D, P60S, F69L, M72I, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 62 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: N53D, P60S, L180W, R196G, P210S, P210L, P214S, R220P, Q221P, I242T, Q250H, p.V254del, G260E, G261S, D299E, S304T and P362T.

### Claim 63 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: R4M/Y207S, A15T, A15G, W24G, G35V, M42I, E48Q, N53D, P60S, F69L, M72I, G85S, G85N, G104V, L106F, A108T, D109G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T, K391T, G395E and p.T400_S401dup.

### Claim 64 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: R4M/Y207S, W24G, G35V, M421, E48Q, N53D, P60S, F69L, G85S, G85N, G104V, L106F, D109G, G144D, L180W, G195V, R196G, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T, K391T, G395E and p.T400_S401dup.

### Claim 65 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: G35V, M421, F69L and L180W.

### Claim 66 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: A15T, W24G, G35V, M421, N53D, P60S, F69L, M721, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 67 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: W24G, G35V, M421, N53D, P60S, F69L, G104V, L106F, G144D, L180W, G195V, R196G, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T and K391T.

### Claim 68 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: R4M/Y207S, A15T, A15G, F18C, W24G, N34D, G35V, M421, E48Q, N53D, P60S, F69L, M721, G85S, G85N, G104V, L106F, A108T, D109G, R112G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, G260E, G261S, G271S/D313Y, W277C, D299E, S304T, D313Y/G411D, I319F, F337S, P343L, G361A, P362T, K391T and G395E.

### Claim 69 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: R4M/Y207S, W24G, G35V, M421, E48Q, N53D, P60S, F69L, G85S, G85N, G104V, L106F, D109G, G144D, L180W, G195V, R196G, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T, K391T and G395E.

### Claim 70 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: A15T, F18C, W24G, G35V, M42I, N53D, P60S, F69L, M72I, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 71 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: N53D, P60S, L180W, R196G, P210S, P210L, P214S, R220P, Q221P, I242T, Q250H, G260E, G261S, D299E, S304T and P362T.

### Claim 72 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: W24G, G35V, M42I, N53D, P60S, F69L, G104V, L106F, G144D, L180W, G195V, R196G, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T and K391T.

### Claim 73

An α-galactosidase A protein having a HEK amenable mutation selected from the group consisting of: R4M/Y207S, A15T, A15G, F18C, W24G, N34D, G35V, M42I, E48Q, N53D, P60S, F69L, M72I, G85S, G85N, G104V, L106F, A108T, D109G, R112G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, G271S/D313Y, W277C, D299E, S304T, D313Y/G411D, I319F, F337S, P343L, G361A, P362T, K391T, G395E and p.T400_S401dup,
wherein the protein is bound to migalastat and the protein has increased stability as compared to a naturally-occurring a-galactosidase A protein having the same mutation.

### Claim 74 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: A15T, F18C, W24G, G35V, M421, N53D, P60S, F69L, M721, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 75 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: N53D, P60S, L180W, R196G, P210S, P210L, P214S, R220P, Q221P, I242T, Q250H, p.V254del, G260E, G261S, D299E, S304T and P362T.

### Claim 76 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: R4M/Y207S, A15T, A15G, W24G, G35V, M421, E48Q, N53D, P60S, F69L, M721, G85S, G85N, G104V, L106F, A108T, D109G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T, K391T, G395E and p.T400_S401dup.

### Claim 77 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: R4M/Y207S, W24G, G35V, M421, E48Q, N53D, P60S, F69L, G85S, G85N, G104V, L106F, D109G, G144D, L180W, G195V, R196G, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T, K391T, G395E and p.T400_S401dup.

### Claim 78 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: G35V, M421, F69L and L180W.

### Claim 79 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: A15T, W24G, G35V, M42I, N53D, P60S, F69L, M72I, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 80 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: W24G, G35V, M42I, N53D, P60S, F69L, G104V, L106F, G144D, L180W, G195V, R196G, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, p.V254del, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T and K391T.

### Claim 81 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: R4M/Y207S, A15T, A15G, F18C, W24G, N34D, G35V, M42I, E48Q, N53D, P60S, F69L, M72I, G85S, G85N, G104V, L106F, A108T, D109G, R112G, G144D, L167V, L180W, G195V, R196G, V199A, E203D, P210S, P210L, P214S, R220P Q221P, F229L, I242T, W245G, Q250H, G260E, G261S, G271S/D313Y, W277C, D299E, S304T, D313Y/G411D, I319F, F337S, P343L, G361A, P362T, K391T and G395E.

### Claim 82 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: R4M/Y207S, W24G, G35V, M42I, E48Q, N53D, P60S, F69L, G85S, G85N, G104V, L106F, D109G, G144D, L180W, G195V, R196G, E203D, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, G260E, G261S, W277C, D299E, S304T, I319F, F337S, G361A, P362T, K391T and G395E.

### Claim 83 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: A15T, F18C, W24G, G35V, M42I, N53D, P60S, F69L, M72I, G104V, L106F, A108T, G144D, L167V, L180W, G195V, R196G, V199A, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, W245G, Q250H, G260E, G261S, W277C, D299E, S304T, I319F, F337S, P343L, G361A, P362T and K391T.

### Claim 84 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: N53D, P60S, L180W, R196G, P210S, P210L, P214S, R220P, Q221P, I242T, Q250H, G260E, G261S, D299E, S304T and P362T.

### Claim 85 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: W24G, G35V, M42I, N53D, P60S, F69L, G104V, L106F, G144D, L180W, G195V, R196G, P210S, P210L, P214S, R220P, Q221P, F229L, I242T, Q250H, G260E, G261S, W277C, D299E, S304T, 1319F, F337S, G361A, P362T and K391T.

### Claim 86 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: A15T, A15G, F18C, E48Q, F69L, G104V, L106F, A108T, D109G, L167V, G195V, R196G, P210S, P210L, Q221P, F229L, W245G, D299E, F337S, P343L and K391T.

### Claim 87 (depends on 60)

The molecule of claim 60, wherein the mutation is selected from the group consisting of: A15T, A15G, F18C, E48Q, F69L, G104V, L106F, A108T, D109G, L167V, G195V, R196G, P210S, P210L, Q221P, F229L, W245G, D299E, F337S, P343L and K391T.

### Claim 88 (depends on 73)

The α-galactosidase A protein of claim 73, wherein the mutation is selected from the group consisting of: A15T, A15G, F18C, E48Q, F69L, G104V, L106F, A108T, D109G, L167V, G195V, R196G, P210S, P210L, Q221P, F229L, W245G, D299E, F337S, P343L and K391T.

### Claim 89 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: N34D, M42I, R196G, V199A, E203D, p. V254del and G260E.

### Claim 90 (depends on 1)

The method of claim 1, wherein the mutation is N34D.

### Claim 91 (depends on 1)

The method of claim 1 wherein the mutation is M42I.

### Claim 92 (depends on 1)

The method of claim 1 wherein the mutation is R196G.

### Claim 93 (depends on 1)

The method of claim 1 wherein the mutation is V199A.

### Claim 94 (depends on 1)

The method of claim 1 wherein the mutation is E203D.

### Claim 95 (depends on 1)

The method of claim 1 wherein the mutation is V254del.

### Claim 96 (depends on 1)

The method of claim 1 wherein the mutation is G260E.

### Claim 97 (depends on 1)

The method of claim 1, wherein the mutation is selected from the group consisting of: R196G, p. V254del and G260E.