Gene-depends Neurological Disease Solutions

Gene therapy is designed to deliver genetic material to target cells to introduce copies of dysfunctional genes, trophic factors and modifier genes, or to silence the expression of harmful genes. Commonly used methods of gene therapy include antisense oligonucleotides, RNA interference, gene-editing technology, or adeno-associated virus-mediated gene silencing and delivery. Gene therapy has been a compelling but elusive treatment modality since birth, and it may offer therapeutic opportunities for more challenging and complex diseases.

The emergence of powerful new molecular tools and theories has broadened access to neurological disorders, as a leading company in the field of biology, Creative Biolabs provide our clients around the world with gene delivery, editing, modification, improvement and silencing services through advanced and comprehensive approaches, as well as design, selection and validation of your gene therapy methods.

Fig 1. Gene therapy strategies. (Amado, 2021)

Huntington's Disease (HD)

Therapeutics that target HTT DNA by modulating gene transcription or directly editing the HTT gene are currently being developed. Several promising therapeutic modalities have been proposed, including the use of zinc finger nucleases, transcription activator-like effector nucleases, or other RNA-guided bacterial nucleases. These approaches could develop common agents for all HD mutation carriers and require only one administration to achieve long-term treatment. But these approaches are invasive, the changes targeting brain regions cannot be reversed, and still requires longer and more in-depth design, assembly, selection and validation.

Amyotrophic Lateral Sclerosis (ALS)

ALS has historically presented unique challenges to gene therapy-based approaches, but with the combination and advancement of technology and theory, gene therapy experiments that target SOD1 mutation, C9 or f72 hexanucleotide repeat expansion, ATXN2 trinucleotide expansion and FUS mutation have been proposed and are in progress.

Spinal Muscular Atrophy

Spinal Muscular Atrophy (SMA) is a devastating neurodegenerative disease caused by progressive loss of motor neurons, and with advances in neuro-drug delivery theory, systemic delivery of self-complementary AAV9 has been demonstrated in mouse models to cross the blood-brain barrier and improves neuronal conduction disturbances caused by mutations in the SMN1 gene.

Fig 2. AAV virus and vector. (Hudry, 2019)

Alzheimer's Disease (AD)

Growing insights into AD and related neuropathology have led to the development of multiple virus-mediated gene transfer approaches for AD and promote the survival of cholinergic neurons. At present, therapeutic methods such as AAV2-NGF in the bilateral basal forebrain targeting Aβ, tau, BACE1, BDNF and APOE4 are also being developed.

Fig 3. APOE and other possible AD gene therapy targets. (Serrano-Pozo, 2021)

Parkinson's Disease (PD)

In recent years, AAV2-GAD, which aims to modulate the signaling process of GABAergic neurons, and AAV2-hAADC, which can increase dopamine production, have been validated in early clinical experiments. In addition, more viral-mediated or non-viral-mediated gene therapy methods are also under investigation, and may simultaneously or separately target PD potential therapeutic targets including AADC, TH, GCH, GDNF, ARTM, PSPN, etc.

Canavan Disease

Canavan Disease (CD) is a leukodystrophy caused by pathogenic variants in the aspartate acylase gene (ASPA). AAV2 therapy for ASPA is an evolution of earlier gene transfer studies that have been validated in Phase 1 studies. AAV2-ASPA was effective in reducing NAA concentrations and was well tolerated with minimal systemic inflammation.

Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is an X-linked degenerative muscular dystrophy that is caused by mutations in the DMD gene. There are already some FDA-approved antisense oligonucleotide therapies for this disease, but gene replacement therapy can provide a broader range of treatments. Miniaturized AAV vectors have been developed in recent years, which can achieve more efficient DMD gene-drug delivery efficiency with better pharmacokinetic profiles.

Other Diseases

In addition to some common and well-studied diseases, Creative Biolabs also provides one-stop modalities services for other types of neurological diseases, including,

• Neurodegenerative Disorders
• Neuromuscular Disorders
• Psychiatric Disorders
• Pain
• Rare Diseases
• Brain Tumors
• Ophthalmology

Successful gene therapy depends on the determination of the target, the effective delivery of the target and the effect of disease mitigation intervention. With years of research experience in the field of biotechnology and our advanced and cutting-edge theoretical basis and technology platform, Creative Biolabs now provides services of designing or validating delivery methods, carrier specificity and cargo efficacy for our clients all over the world. Please feel free to contact us with our specialist for further information.

References

1. Amado, D.A.; Davidson, B.L. Gene therapy for ALS: A review. Molecular Therapy, 2021, 29(12): 3345.
2. Hudry, E.; Vandenberghe, L.H. Therapeutic AAV gene transfer to the nervous system: a clinical reality. Neuron, 2019, 101: 839-862.
3. Serrano-Pozo, A.; et al. APOE and Alzheimer’s disease: advances in genetics, pathophysiology, and therapeutic approaches. Lancet Neurol, 2021, 20(1): 68-80.