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February 17, 2022/eMedClub News/--On February 7, 2022, the largest annual conference on lysosomal disorders, WORLDSymposium™, was held in San Diego.
At the conference, many domestic and foreign experts and pharmaceutical companies announced clinical progress, which greatly Accelerates the process of gene therapy entering the market
.
In today's article, the Yimaike team will share with readers the lysosomal storage diseases that received much attention at the 18th WORLDSymposium™ Annual Meeting, as well as the latest development of AAV gene therapy in related disease areas
.
Lysosomal storage disorders (LSDs) are a group of rare inherited metabolic diseases with more than 50 types, of which Gaucher disease and Pompe disease are more common
.
This group of diseases are all caused by gene mutation causing defects in the acid hydrolase in the lysosome, which eventually leads to the dysfunction of cells, tissues and organs
.
The vast majority of lysosomal storage disorders are inherited in an autosomal recessive manner, and although the incidence of each of these disorders is low, it is one of the most common human genetic disorders as a group
.
Mucopolysaccharidosis (MPS) MPS is a distinct inherited lysosomal storage disorder
.
They are all related to the accumulation of glycosaminoglycans (GAGs), also known as mucopolysaccharides
.
MPS is divided into seven subtypes (I, II, III, IV, VI, VII, and IX) based on lysosomal enzyme deficiency
.
REGENXBIO Presents Positive Initial Data from Phase I/II Trial of Its AAV Gene Therapy RGX-111 in Severe Mucopolysaccharidosis Type I (MPS I) in 6 Patients Treated with RGX-111 at WORLDSymposium™ Patients with severe MPS
I.
▲ Phase I/II clinical trial design of RGX-111 in MPS I patients (Image source: REGENXBIO official website) Initial data showed that RGX-111 was well tolerated in patients, showing encouraging CNS Sustained neurodevelopmental and biomarker activity, meeting the trial's primary and secondary endpoints
.
There are currently no drug-related serious adverse events (SAEs)
.
Recommended reading: Penetrating the blood-brain barrier! The latest data on the improved version of AAV gene therapy is releasedYimai Meng broke the news that Lysogene also reported positive biomarker data from the ongoing LYS-SAF302 treatment of MPS IIIA (NCT03612869) in the AAVance clinical trial: 6 months after LYS-SAF302 treatment Analysis of heparan sulfate (HS) concentrations in the cerebrospinal fluid (the primary disease biomarker in MPS IIIA) of all 16 patients analyzed at 12 months and 12 months showed a 23% reduction relative to pre-treatment values
.
In addition, after 12 months of treatment, the patients' brain concentrations of GM2 and GM3 gangliosides, which are thought to be responsible for neuronal damage in lysosomal storage diseases, were reduced by about 30%
.
Pompe disease Pompe disease is a rare autosomal recessive disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA)
.
Dysfunction or lack of functional GAA results in toxic accumulation of glycogen in lysosomes, skeletal and cardiac muscles, the tissues primarily affected by disease
.
On February 9, 2022, Astellas announced positive interim data from a Phase 1/2 clinical trial of its AAV gene replacement therapy AT845, which provides a functional alpha-glucosidase (GAA) gene for the treatment of late-onset Pompe disease (LOPD)
.
Four subjects of AT845 are currently enrolled in FORTIS, with two participants receiving a dose of 3 x 10^13 vg/kg (cohort 1) and two participants receiving a dose of 6 x 10^13 vg/kg (cohort 2)
.
Data reported include an interim safety and tolerability assessment, as well as up to 24 weeks of follow-up for two participants in cohort 1 and preliminary data for two participants in cohort 2
.
The results showed that AT845 demonstrated an encouraging safety profile during the 24-week follow-up period after dosing
.
More importantly, none of the four subjects reported serious adverse events after dosing
.
Astellas Gene Therapies will continue to recruit patients for this clinical trial
.
Recommended reading: Rare diseases usher in a new milestone! Astellas Announces Positive Interim Safety Data for AAV Gene Therapy Neurons die
.
Because juvenile GM1 gangliosidosis is an inherited disorder, children are often inherited from asymptomatic carrier parents
.
LYS-GM101 is a gene therapy candidate for the delivery of GLB1 (responsible for the expression of β-galactosidase) to the CNS using the AAVrh10 vector, aiming to restore the production of the missing enzyme in patients with GM1 gangliosidosis
.
The P1-GM-101 (NCT04273269) adaptively designed gene therapy trial is currently evaluating the safety and efficacy of LYS-GM101
.
In the first two treated patients with advanced infantile GM1 gangliosidosis, no route of administration or study with ICM injection (injection into the cisterna magna at the craniocervical junction) was observed more than 5 months after dosing Adverse events associated with sex gene therapy
.
Recommended reading: Lysogene completes the first patient administration of AAV gene therapy for GM1 gangliosidosisYimai Meng broke the news that another gene therapy using the AAVhu68 capsid, PBGM01, was announced at the 18th WORLDSymposium™.
Clinical evaluation of developmental milestones in cohort 1 (two late-stage infantile GM1 patients receiving low-dose PBGM01) and first published safety and biomarker data in December 2021
.
Passage Bio will follow up further and continue to add more cohorts in the Phase 1/2 clinical study Imagine-1
.
The U.
S.
Food and Drug Administration (FDA) has granted PBGM01 Fast Track, Orphan Drug and Rare Pediatric Disease designations
.
In addition, PBGM01 has been granted orphan designation by the European Commission
.
Recommended reading: An AAV gene therapy IND application of the company founded by AAV Daniel James Wilson has been approved by the US FDAYimai Meng broke the news that CLN7 Barton disease CLN7 disease is a rare, fatal and rapidly progressive neurodegenerative disease, caused by the MFSD8 gene Caused by an autosomal recessive mutation that results in lysosomal dysfunction
.
Researchers from UT Southwestern present clinical safety data for Taysha Gene Therapies' AAV gene therapy at the highest dose of 1.
0x10^15vg in CLN7 Patton disease
.
Safety data for the first-generation construct for the treatment of CLN7 Batten disease in clinical trials conducted after intrathecal injection further demonstrated that the first-generation construct has good efficacy at multiple doses including 1.
0x10^15vg tolerability, which is the highest dose administered in human gene therapy
.
No adverse immune responses were found in the trial, and none of the subjects developed brain inflammation, and stable conduction of the sural nerve showed no inflammation of the dorsal root ganglion
.
GM2 Gangliosidosis It is worth noting that Taysha Gene Therapies also announced earlier that its investigational gene therapy TSHA-101 is in the treatment of Sandhoff and Tay-Sachs disease, two different types of GM2 gangliosidosis.
Positive early clinical results: In Sandhoff disease patients, Hex A enzyme activity reached 190% of normal at 1 month and 288% of normal at 3 months, representing 5 % increased 38-fold and 58-fold; in Tay-Sachs disease patients, Hex A enzyme activity reached 25% of normal levels after 1 month of treatment, a 5-fold increase compared to the usual 5% in asymptomatic patients; safety On the one hand, TSHA-101 was well tolerated and there were no drug-related serious adverse events
.
▲ Early clinical trial data of TSHA-101 (image source: Taysha's official website) Recommended reading: Treatment of rare diseases! The preliminary results of multiple "first" innovative AAV gene therapies are positiveYimai Meng broke the news that Fabry disease affects more than 50,000 people in the United States and the European Union.
Fabry disease is a genetic disease of the GLA gene that causes the body to fail to produce The enzyme α-galactosidase or AGA, which leads to the accumulation of the substrate globulotriglycosylceramide (Gb3) in vital organs such as the heart
.
On February 9, 2022, 4D Molecular Therapeutics presented data from a Phase 1/2 clinical trial of C102 vector gene therapy drug 4D-310 in patients with Fabry disease
.
Following 4D-310 infusion, mean serum AGA enzyme activity was within or significantly above the normal range in all three patients, and updated serum AGA activity data showed AGA activity in patient 1 following discontinuation of enzyme replacement therapy (ERT) Stabilized at 14 times mean normal at week 37 and at 10 times mean normal at week 20 in patient 3
.
At present, about 80% of rare diseases are caused by gene mutations, so they are the most suitable diseases to be overcome by gene therapy
.
At the same time, traditional drug development requires an accurate understanding of the mechanism of action and targets of drug molecules.
This process is sometimes lengthy and costly.
Gene therapy only involves the repair of target genes, and the goals are more specific, so the risks to be taken are much lower
.
It is believed that in the near future, gene therapy will bring a compliant and effective rare disease treatment landscape to rare disease patients
.
References: 1.
https:// -at-2022-worldsymposium/2.
https:// -lys-gm101-presented-at-the-worldsymposium-2022/3.
https:// -of-rgx-111-for-the-treatment-of-severe-mps-i-at-18th-annual-worldsymposium-2022/
At the conference, many domestic and foreign experts and pharmaceutical companies announced clinical progress, which greatly Accelerates the process of gene therapy entering the market
.
In today's article, the Yimaike team will share with readers the lysosomal storage diseases that received much attention at the 18th WORLDSymposium™ Annual Meeting, as well as the latest development of AAV gene therapy in related disease areas
.
Lysosomal storage disorders (LSDs) are a group of rare inherited metabolic diseases with more than 50 types, of which Gaucher disease and Pompe disease are more common
.
This group of diseases are all caused by gene mutation causing defects in the acid hydrolase in the lysosome, which eventually leads to the dysfunction of cells, tissues and organs
.
The vast majority of lysosomal storage disorders are inherited in an autosomal recessive manner, and although the incidence of each of these disorders is low, it is one of the most common human genetic disorders as a group
.
Mucopolysaccharidosis (MPS) MPS is a distinct inherited lysosomal storage disorder
.
They are all related to the accumulation of glycosaminoglycans (GAGs), also known as mucopolysaccharides
.
MPS is divided into seven subtypes (I, II, III, IV, VI, VII, and IX) based on lysosomal enzyme deficiency
.
REGENXBIO Presents Positive Initial Data from Phase I/II Trial of Its AAV Gene Therapy RGX-111 in Severe Mucopolysaccharidosis Type I (MPS I) in 6 Patients Treated with RGX-111 at WORLDSymposium™ Patients with severe MPS
I.
▲ Phase I/II clinical trial design of RGX-111 in MPS I patients (Image source: REGENXBIO official website) Initial data showed that RGX-111 was well tolerated in patients, showing encouraging CNS Sustained neurodevelopmental and biomarker activity, meeting the trial's primary and secondary endpoints
.
There are currently no drug-related serious adverse events (SAEs)
.
Recommended reading: Penetrating the blood-brain barrier! The latest data on the improved version of AAV gene therapy is releasedYimai Meng broke the news that Lysogene also reported positive biomarker data from the ongoing LYS-SAF302 treatment of MPS IIIA (NCT03612869) in the AAVance clinical trial: 6 months after LYS-SAF302 treatment Analysis of heparan sulfate (HS) concentrations in the cerebrospinal fluid (the primary disease biomarker in MPS IIIA) of all 16 patients analyzed at 12 months and 12 months showed a 23% reduction relative to pre-treatment values
.
In addition, after 12 months of treatment, the patients' brain concentrations of GM2 and GM3 gangliosides, which are thought to be responsible for neuronal damage in lysosomal storage diseases, were reduced by about 30%
.
Pompe disease Pompe disease is a rare autosomal recessive disorder caused by a deficiency of the enzyme acid alpha-glucosidase (GAA)
.
Dysfunction or lack of functional GAA results in toxic accumulation of glycogen in lysosomes, skeletal and cardiac muscles, the tissues primarily affected by disease
.
On February 9, 2022, Astellas announced positive interim data from a Phase 1/2 clinical trial of its AAV gene replacement therapy AT845, which provides a functional alpha-glucosidase (GAA) gene for the treatment of late-onset Pompe disease (LOPD)
.
Four subjects of AT845 are currently enrolled in FORTIS, with two participants receiving a dose of 3 x 10^13 vg/kg (cohort 1) and two participants receiving a dose of 6 x 10^13 vg/kg (cohort 2)
.
Data reported include an interim safety and tolerability assessment, as well as up to 24 weeks of follow-up for two participants in cohort 1 and preliminary data for two participants in cohort 2
.
The results showed that AT845 demonstrated an encouraging safety profile during the 24-week follow-up period after dosing
.
More importantly, none of the four subjects reported serious adverse events after dosing
.
Astellas Gene Therapies will continue to recruit patients for this clinical trial
.
Recommended reading: Rare diseases usher in a new milestone! Astellas Announces Positive Interim Safety Data for AAV Gene Therapy Neurons die
.
Because juvenile GM1 gangliosidosis is an inherited disorder, children are often inherited from asymptomatic carrier parents
.
LYS-GM101 is a gene therapy candidate for the delivery of GLB1 (responsible for the expression of β-galactosidase) to the CNS using the AAVrh10 vector, aiming to restore the production of the missing enzyme in patients with GM1 gangliosidosis
.
The P1-GM-101 (NCT04273269) adaptively designed gene therapy trial is currently evaluating the safety and efficacy of LYS-GM101
.
In the first two treated patients with advanced infantile GM1 gangliosidosis, no route of administration or study with ICM injection (injection into the cisterna magna at the craniocervical junction) was observed more than 5 months after dosing Adverse events associated with sex gene therapy
.
Recommended reading: Lysogene completes the first patient administration of AAV gene therapy for GM1 gangliosidosisYimai Meng broke the news that another gene therapy using the AAVhu68 capsid, PBGM01, was announced at the 18th WORLDSymposium™.
Clinical evaluation of developmental milestones in cohort 1 (two late-stage infantile GM1 patients receiving low-dose PBGM01) and first published safety and biomarker data in December 2021
.
Passage Bio will follow up further and continue to add more cohorts in the Phase 1/2 clinical study Imagine-1
.
The U.
S.
Food and Drug Administration (FDA) has granted PBGM01 Fast Track, Orphan Drug and Rare Pediatric Disease designations
.
In addition, PBGM01 has been granted orphan designation by the European Commission
.
Recommended reading: An AAV gene therapy IND application of the company founded by AAV Daniel James Wilson has been approved by the US FDAYimai Meng broke the news that CLN7 Barton disease CLN7 disease is a rare, fatal and rapidly progressive neurodegenerative disease, caused by the MFSD8 gene Caused by an autosomal recessive mutation that results in lysosomal dysfunction
.
Researchers from UT Southwestern present clinical safety data for Taysha Gene Therapies' AAV gene therapy at the highest dose of 1.
0x10^15vg in CLN7 Patton disease
.
Safety data for the first-generation construct for the treatment of CLN7 Batten disease in clinical trials conducted after intrathecal injection further demonstrated that the first-generation construct has good efficacy at multiple doses including 1.
0x10^15vg tolerability, which is the highest dose administered in human gene therapy
.
No adverse immune responses were found in the trial, and none of the subjects developed brain inflammation, and stable conduction of the sural nerve showed no inflammation of the dorsal root ganglion
.
GM2 Gangliosidosis It is worth noting that Taysha Gene Therapies also announced earlier that its investigational gene therapy TSHA-101 is in the treatment of Sandhoff and Tay-Sachs disease, two different types of GM2 gangliosidosis.
Positive early clinical results: In Sandhoff disease patients, Hex A enzyme activity reached 190% of normal at 1 month and 288% of normal at 3 months, representing 5 % increased 38-fold and 58-fold; in Tay-Sachs disease patients, Hex A enzyme activity reached 25% of normal levels after 1 month of treatment, a 5-fold increase compared to the usual 5% in asymptomatic patients; safety On the one hand, TSHA-101 was well tolerated and there were no drug-related serious adverse events
.
▲ Early clinical trial data of TSHA-101 (image source: Taysha's official website) Recommended reading: Treatment of rare diseases! The preliminary results of multiple "first" innovative AAV gene therapies are positiveYimai Meng broke the news that Fabry disease affects more than 50,000 people in the United States and the European Union.
Fabry disease is a genetic disease of the GLA gene that causes the body to fail to produce The enzyme α-galactosidase or AGA, which leads to the accumulation of the substrate globulotriglycosylceramide (Gb3) in vital organs such as the heart
.
On February 9, 2022, 4D Molecular Therapeutics presented data from a Phase 1/2 clinical trial of C102 vector gene therapy drug 4D-310 in patients with Fabry disease
.
Following 4D-310 infusion, mean serum AGA enzyme activity was within or significantly above the normal range in all three patients, and updated serum AGA activity data showed AGA activity in patient 1 following discontinuation of enzyme replacement therapy (ERT) Stabilized at 14 times mean normal at week 37 and at 10 times mean normal at week 20 in patient 3
.
At present, about 80% of rare diseases are caused by gene mutations, so they are the most suitable diseases to be overcome by gene therapy
.
At the same time, traditional drug development requires an accurate understanding of the mechanism of action and targets of drug molecules.
This process is sometimes lengthy and costly.
Gene therapy only involves the repair of target genes, and the goals are more specific, so the risks to be taken are much lower
.
It is believed that in the near future, gene therapy will bring a compliant and effective rare disease treatment landscape to rare disease patients
.
References: 1.
https:// -at-2022-worldsymposium/2.
https:// -lys-gm101-presented-at-the-worldsymposium-2022/3.
https:// -of-rgx-111-for-the-treatment-of-severe-mps-i-at-18th-annual-worldsymposium-2022/
