Clinical overview of targeted gene-related ALS therapy

Last December, 62-year-old ALS patient Philip O'Keefe became the first person to post on social media with his own mind
.

The patient successfully posted a message through a brain-computer interface
.

So can ALS patients really be trapped in their own bodies forever and cannot be completely cured? At least for now
.

Similar to Alzheimer's disease, the exact pathogenesis is unknown, and it is considered to be a multifactorial mediated amyotrophic lateral sclerosis (also known as ALS, including genetic factors) so far there is no cure for it.
Patients often need to experience the ordeal from inability to move their limbs, to the need to cut the trachea to connect to a respirator, and the fatality rate is high.
Some studies have even found that in addition to motor neuron disease, ALS patients may have a higher risk of Less recognized but still significant concomitant psychiatric comorbidities such as psychosis, schizophrenia, and mood disorders
.

At present, the number of ALS patients in China has not been effectively evaluated, and the misdiagnosis rate is high, about 50,000 to 200,000
.

Extended reading: Living to the death, the 43-year-old vice president of Jingdong is in a life-and-death race with ALS.
In the case of SMA, which has similar but different symptoms, there are already effective gene therapy methods (such as Zolgensma), In addition to delaying drug therapy (such as riluzole), targeting defective genes is a new possible option for ALS treatment and will be valuable for other neurodegenerative diseases such as Alzheimer's disease.
reference value
.

The causative genes of ALS In ALS patients, up to 20% of ALS patients show possible genetic and genetic defects, and two-thirds of familial ALS cases can be caused by pathogenic mutations in C9orf72, SOD1, TARDBP, and FUS genes.
, and about 15% of sporadic ALS cases can also be explained by these genetic mutations, with similarities between the two
.

In patients of European ancestry, C9orf72 non-coding hexanucleotide repeat (GGGGCC) expansion is the most common pathogenic mutation, while SOD1 mutation predominates in ALS patients in China, Japan and South Korea, for example: in China Among the patients with familial ALS, the proportion of SOD1 patients exceeds 50%
.

Figure: Familial or sporadic ALS related to different genes Targeted therapy for these gene defects has become the focus of ALS diseases associated with different gene defects
.

SOD1 SOD1 full name Superoxide dismutase 1, superoxide dismutase 1, SOD1 is a metalloprotein that binds copper ions and zinc ions, and plays an important role in converting highly reactive reactive oxygen species superoxide into oxygen molecules and hydrogen peroxide
.

Studies have shown that the highly toxic misfolded SOD1 protein found in both familial and sporadic ALS patients may be involved in the pathogenesis of ALS
.

As China, where SOD1-mutated ALS dominates, the clinical progress of SOD1 target-related drugs deserves attention
.

Tofersen Biogen and Ionis' antisense oligonucleotide (ASO) Tofersen can mediate the degradation of SOD1 messenger RNA through intrathecal injection, thereby reducing the synthesis of SOD1 protein
.

In June 2021, the FDA approved the IND application of Apic-Bio's AAV gene therapy APB-102, which targets SOD1 gene-mutant ALS
.

APB-102 is a recombinant AAVrh10 vector that expresses anti-SOD1 microRNA (miRNA), and then inhibits SOD1 mRNA synthesis through miRNA, thereby reducing the production of SOD1 mutant protein and relieving the symptoms of patients
.

In addition, AveXis, acquired by Novartis, also uses the rAAV9 vector to express anti-SOD1 hairpin RNA (shRNA)
.

It is worth mentioning that both of these two drugs have been granted orphan drug designation by the FDA.
Among them, China Morningside Capital (now renamed Wuyuan Capital) led the Apic-Bio’s Series A financing
.

The GGGGCC (G4C2) hexanucleotide repeat expansion (HRE) in the first intron of the C9orf72C9ORF72 (C9) gene is the most common hereditary factor in ALS and FTD (frontotemporal dementia) and may produce both sense and reverse Sense-expanded RNA and six dipeptide repeat-associated non-ATG (RAN) proteins (sense: GA, GP, GR and antisense: PA, PR, GP) present in a growing number of repeat-expanded diseases (C9orf72 RAN protein was found in related ALS/FTD), and excess RAN showed toxicity in model systems
.

Last December, a team from the Department of Neurology at the University of Massachusetts synthesized and optimized an antisense oligonucleotide (ASO) targeting the GGGGCC repeat of the C9ORF72 gene, and demonstrated that it can safely and effectively reduce disease markers in patients with the genetic mutation.
level of things
.

In addition, an article published in neuron in February 2020 showed that a research team from the University of Florida, Biogen, and Neurimmune of Switzerland developed a high-affinity human antibody targeting GA or GP RAN protein in a C9orf72 mouse model.
, improved behavior, reduced neuroinflammation and neurodegeneration, and improved survival in C9–500 ALS/FTD mice
.

FUS sarcoma fusion protein (FUS) is an RNA-binding protein genetically and pathologically associated with rare and aggressive forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD)
.

Mutations in the FUS gene cause abnormal proteins to be produced and aggregated into clusters, resulting in cumulative toxicity, which in turn causes motor neuron degeneration and death
.

Ionis has shown considerable determination in the field of ALS.
Ionis has developed a FUS RNA-targeting ION363, which is currently in Phase III clinical stage.
In January this year, Ionis published a paper entitled Antisense oligonucleotide silencing of The article on FUS expression as a therapeutic approach in amyotrophic lateral sclerosis discloses clinical data on mouse models
.

The editor concluded that when cell therapy and gene therapy have been used in various rare diseases and cancers, neurodegenerative diseases are still a dark cloud shrouding the medical community.
I believe that more research and the establishment of animal models can help this Disease opens new windows
.

Reference source: https://apic-bio.
com/apic-bio-announces-fda-clearance-of-ind-application-for-lead-gene-therapy-candidate-apb-102-for-the-treatment-of -sod1-als/Zu T, Liu Y, Bañez-Coronel M, Reid T, Pletnikova O, Lewis J, Miller TM, Harms MB, Falchook AE, Subramony SH, Ostrow LW, Rothstein JD, Troncoso JC, Ranum LP.
RAN proteins and RNA foci from antisense transcripts in C9ORF72 ALS and frontotemporal dementia.
Proc Natl Acad Sci US A.
2013 Dec 17;110(51):E4968-77.
doi: 10.
1073/pnas.
1315438110.
Epub 2013 Nov 18.
PMID: 24248382 ; PMCID: PMC3870665.
Zucchi E, Ticozzi N, Mandrioli J.
Psychiatric Symptoms in Amyotrophic Lateral Sclerosis: Beyond a Motor Neuron Disorder.
Front Neurosci.
2019;13:175.
Published 2019 Mar 11.
doi:10.
3389/fnins.
2019.
00175Oxidative misfolding of Cu/Zn-superoxide dismutase triggered by non-canonical intramolecular disulfide formation Suppression of mutant C9orf72 expression by a potent mixed backbone antisense oligonucleotide