What side effects are associated with this type of intervention?

Gene therapy for Charcot-Marie-Tooth Disease, such as the AAV9 vector carrying the IGHMBP2 gene, aims to correct the genetic defect by delivering a functional gene. Known side effects of gene therapy can include immune responses to the viral vector, which may cause inflammation or other immune-mediated reactions. Additionally, there is a risk of insertional mutagenesis, where the integration of the gene into the host genome could potentially disrupt other genes and lead to unintended effects. Other common treatments for CMT, such as physical therapy and orthopedic devices, generally have fewer side effects but may include discomfort or skin irritation from braces and orthotics.

What prior FDA approvals exist?

As of now, there are no FDA-approved gene therapies specifically for Charcot-Marie-Tooth Disease (CMT). Traditional treatments for CMT focus on managing symptoms and improving quality of life, including physical therapy, occupational therapy, and orthopedic devices. The investigational AAV9 vector carrying the IGHMBP2 gene represents a novel approach aimed at correcting the genetic defect underlying certain forms of CMT. This type of gene therapy is still in the experimental stages and has not yet received FDA approval.

What other types of research exist?

Promising novel alternatives to AAV9 vector for Charcot-Marie-Tooth Disease treatment include CRISPR-Cas9 gene editing, which allows precise correction of genetic mutations, and lentiviral vectors, which can integrate into the host genome for long-term expression. Additionally, antisense oligonucleotides (ASOs) are being explored to modulate gene expression and correct splicing defects. These approaches are in various stages of research and clinical trials, showing potential for effective and safe treatment options.

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Virus Therapy

Gene Therapy for Spinal Muscular Atrophy

Phase 1 & 2

Waitlist Available

Led By Megan Waldrop, MD

Research Sponsored by Megan Waldrop

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Confirmation of two pathogenic variants in the IGHMBP2 gene from a CLIA-certified lab

Pre-ambulant (not yet walking and less than 18 months) or ambulant (as defined by the ability to walk 10 meters without assistance) or non-ambulant (inability to walk more than 10 meters unassisted)

Must not have

Abnormal liver function as indicated by an elevated GGT (>2X normal if no other laboratory abnormalities), bilirubin and/or abnormal PT/INR

A positive JCV antibody test of >0.40

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 3 years

Awards & highlights

Summary

This trial uses a harmless virus to deliver a healthy gene directly into the spinal fluid of patients with diseases caused by IGHMBP2 gene defects. The virus helps correct the genetic issues by bringing the healthy gene to the affected cells. This approach has been shown to improve conditions in similar diseases in animals.

Who is the study for?

This trial is for individuals with genetic confirmation of IGHMBP2-related diseases, such as Spinal Muscular Atrophy or Charcot-Marie-Tooth Disease. Participants can be pre-ambulant, ambulant, or non-ambulant and must be able to perform functional assessments. They cannot have had recent immunizations, infections like HIV/Hepatitis B/C, abnormal blood counts or liver function tests, high AAV9 antibody levels, other systemic illnesses that increase gene transfer risks or require chronic drug treatment.

What is being tested?

The study involves a one-time intrathecal injection (into the spinal canal) of an AAV9 vector carrying the IGHMBP2 gene. It's an open-label trial meaning everyone knows what treatment is being given. The goal is to see if this gene therapy can help with conditions related to IGHMBP2 mutations.

What are the potential side effects?

Potential side effects may include immune reactions to the AAV9 vector used in gene therapy which could lead to inflammation in various organs. There might also be complications from the intrathecal injection procedure itself.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I have two confirmed genetic mutations in the IGHMBP2 gene.

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I can walk more than, less than, or exactly 10 meters without help.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My liver isn't working properly, shown by high GGT or bilirubin levels, or abnormal PT/INR.

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I have tested positive for the JC virus with a level above 0.40.

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I currently have an infection.

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I am being treated for an autoimmune disease.

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I cannot have treatments injected into my spinal canal.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 3 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~3 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 3 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Monitoring for the development of unacceptable toxicity.

Side effects data

From 2019 Phase 2 trial • 12 Patients • NCT00598481

67%

Rhinitis

42%

Device related infection

42%

Upper respiratory tract infection

42%

Hepatic enzyme increased

33%

Neutropenia

33%

Oral candidiasis

33%

Cough

33%

Anaemia

33%

Diarrhoea

33%

Pyrexia

25%

Bronchitis

25%

Upper respiratory tract infection bacterial

25%

Urinary traction infection pseudomonal

25%

Skin lesion

25%

Hypertension

25%

Rash

25%

Escherichia urinary tract infection

25%

Computerized tomogram thorax abnormal

17%

Eosinophilia

17%

Decreased appetite

17%

Blood immunoglobulin E increased

17%

Weight decreased

17%

Febrile neutropenia

17%

Tympanometry abnormal

17%

Gastroenteritis

17%

Varicella

17%

Hemophilus infection

17%

Otitis media

17%

Dermatitis

17%

Dermatitis atopic

17%

Acquired phimosis

17%

Candida infection

17%

Ear infection

17%

Iron deficiency anaemia

17%

Urinary Tract Infection (bacterial)

17%

Nasopharyngitis

17%

Phimosis

17%

Electrophoresis protein abnormal

17%

Blood alkaline phosphatase increased

17%

Bone development abnormal

17%

Hypothyroidism

17%

Deafness bilateral

17%

Enteritis

Staphylococcal infection

Interstitial lung disease

Asthma

Developmental delay

Tinea capitis

Productive cough

Skin exfoliation

Aplastic anemia

Skin infection

Streptococcal infection

Urinary tract infection enterococcal

Esptein-Barr virus infection

Rhinorrhea

Congenital genital malformation

Hepatic lesion

Device occlusion

Cerebral hematoma

Adverse drug reaction

Autoimmune thrombocytopenia

Respiratory tract infection

Gastroenteritis norovirus

Gingivitis

Otitis media acute

Pharyngitis

Pneumococcal infection

Respiratory syncytial virus infection

Adenovirus test positive

Bacterial test positive

Clostridium test positive

Pulmonary function test abnormal

Serum ferritin decreased

Staphylococcus test positive

Total lung capacity decreased

Pneumonitis

Bronchial wall thickening

Bronchospasm

Epistaxis

Nasal turbinate hypertrophy

Pulmonary calcification

Pulmonary mass

Rhinitis allergic

Skin ulcer

Dermatitis diaper

Drug eruption

Dry skin

Eczema

Eczema nummular

Erythema multiforme

Lichen planus

Scab

Micropenis

Reproductive tract hypoplasia, male

Psychomotor hyperactivity

Speech disorder

Hepatomegaly

Autoimmune hepatitis

Wound

Food aversion

Deafness

Middle ear inflammation

Myopia

Sinus arrhythmia

Wandering pacemaker

Perineal erythema

Hemangioma of liver

Lipofibroma

Pyogenic granuloma

Anaphylactic reaction

Acidosis

Aspergillis infection

Campylobacter infection

Catheter site infection

Clostridium difficile infection

Escherichia sepsis

Fungal skin infection

Sinusitis

Staphylococcal sepsis

Thrombocytopenia

Epstein-Barr virus infection

Petechiae

Diarrhea

Guillian-Barre Syndrome

Autoimmune haemolytic anemia

Urticaria

Cryptorchism

Amblyopia

Refraction disorder

Pericardial effusion

Pulmonary valve stenosis

Respiratory Tract Infection

Upper Respiratory tract infection (bacterial)

Urinary Tract Infection

Viral diarrhea

Pseudomonas test positive

Spirometry abnormal

Gallbladder cholesterolosis

Hepatic fibrosis

Tibia fracture

Hypermetropia

Respiratory Tract Infection, bacterial

Influenza

Hypertonic bladder

Clostridium difficile colitis

Vomiting

Gastroesophageal reflux disease

Dental caries

Oral disorder

100%

80%

60%

40%

20%

Study treatment Arm

Gene Therapy (Pivotal)

Trial Design

1Treatment groups

Experimental Treatment

Group I: Single Intrathecal DeliveryExperimental Treatment1 Intervention

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

Gene Therapy

2002

Completed Phase 2

~20

0 / 7Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Gene therapy for Charcot-Marie-Tooth Disease (CMT) involves using adeno-associated virus (AAV) vectors to deliver functional copies of defective genes to affected cells. For example, the AAV9 vector carrying the IGHMBP2 gene aims to correct the genetic defect by providing a functional IGHMBP2 gene. This method is crucial for CMT patients as it addresses the underlying cause of the disease, offering the potential for more effective and durable treatments compared to therapies that only manage symptoms.

Adeno-associated virus gene therapy to the rescue for Charcot-Marie-Tooth disease type 4J.[Gene therapies for neuromuscular diseases].Nerve surgery and gene therapy: a neurobiological and clinical perspective.